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80 results on '"Hukkanen J"'

1. Long-term thiazide use and risk of low-energy fractures among persons with Alzheimer’s disease—nested case-control study

Author: Taipale, H., Rysä, J., Hukkanen, J., Koponen, M., Tanskanen, A., Tiihonen, J., Kröger, H., Hartikainen, S., and Tolppanen, A.-M.
Published: 2019
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2. Low eating self-efficacy is associated with unfavorable eating behavior tendencies among individuals with overweight and obesity

Author: Oikarinen, N. (Noora), Jokelainen, T. (Terhi), Heikkilä, L. (Laura), Nurkkala, M. (Marjukka), Hukkanen, J. (Janne), Salonurmi, T. (Tuire), Savolainen, M. J. (Markku J.), Teeriniemi, A.-M. (Anna-Maria), Oikarinen, N. (Noora), Jokelainen, T. (Terhi), Heikkilä, L. (Laura), Nurkkala, M. (Marjukka), Hukkanen, J. (Janne), Salonurmi, T. (Tuire), Savolainen, M. J. (Markku J.), and Teeriniemi, A.-M. (Anna-Maria)
Abstract: Success in long-term weight management depends partly on psychological and behavioral aspects. Understanding the links between psychological factors and eating behavior tendencies is needed to develop more effective weight management methods. This population-based cross-sectional study examined whether eating self-efficacy (ESE) is associated with cognitive restraint (CR), uncontrolled eating (UE), emotional eating (EE), and binge eating (BE). The hypothesis was that individuals with low ESE have more unfavorable eating behavior tendencies than individuals with high ESE. Participants were classified as low ESE and high ESE by the Weight-Related Self-Efficacy questionnaire (WEL) median cut-off point. Eating behavior tendencies were assessed with Three Factor Eating Questionnaire R-18 and Binge Eating Scale, and additionally, by the number of difficulties in weight management. The difficulties were low CR, high UE, high EE, and moderate or severe BE. Five hundred and thirty-two volunteers with overweight and obesity were included in the study. Participants with low ESE had lower CR (p < 0.03) and higher UE, EE, and BE (p < 0.001) than participants with high ESE. Thirty-nine percent of men with low ESE had at least two difficulties in successful weight control while this percentage was only 8% in men with high ESE. In women, the corresponding figures were 56% and 10%. The risk of low ESE was increased by high UE [OR 5.37 (95% CI 1.99–14.51)], high EE [OR 6.05 (95% CI 2.07–17.66)], or moderate or severe BE [OR 12.31 (95% CI 1.52–99.84)] in men, and by low CR [OR 5.19 (95% CI 2.22–12.18)], high UE [OR 7.20 (95% CI 2.41–19.22)], or high EE [OR 23.66 (95% CI 4.79–116.77)] in women. Low ESE was associated with unfavorable eating behavior tendencies and multiple concomitant difficulties in successful weight loss promotion. These eating behavior tendencies should be considered when counseling patients with overweight and obesity.
Published: 2023

3. Assessing interventional components in a weight loss app

Author: Agyei, E. (Eunice), Oinas-Kukkonen, H. (Harri), Nyman, V. (Ville), Virkkula, T. (Teppo), Oikarinen, N. (Noora), Merikallio, H. (Heta), Savolainen, M. (Markku), Hukkanen, J. (Janne), Agyei, E. (Eunice), Oinas-Kukkonen, H. (Harri), Nyman, V. (Ville), Virkkula, T. (Teppo), Oikarinen, N. (Noora), Merikallio, H. (Heta), Savolainen, M. (Markku), and Hukkanen, J. (Janne)
Abstract: Many mHealth interventions for health behavior change are considered effective for improving health outcomes. However, there is a limited understanding of the role of the components in an intervention on its effectiveness. Insights into intervention components such as content and software features are needed to design efficient and effective interventions. In this study, we conducted an exploratory analysis of objective data from the usage of a weight management app to understand the role of intervention components in weight loss. We identified a positive correlation between weight loss and the use of the intervention. We also found differences in the app feature use among those who lost weight. To lose weight, users needed to comply with the intervention by completing a combination of tasks. They needed to complete 70% of some tasks and up to a maximum of 30% of other tasks. In the future, we hope to use other types of collected data (logged and survey data) to gain more nuanced insights into how interventions are used. With the help of data analytics, we may find optimal paths of use and determine a satisfactory level of compliance to achieve desired goals. This can deepen our understanding of what works in an intervention.
Published: 2023

4. The risk of developing type 2 diabetes after gestational diabetes:a registry study from Finland

Author: Perämäki, R. (Roosa), Gissler, M. (Mika), Ollila, M.-M. (Meri-Maija), Hukkanen, J. (Janne), Vääräsmäki, M. (Marja), Uotila, J. (Jukka), Metso, S. (Saara), Hakkarainen, H. (Heidi), Rintamäki, R. (Reeta), Kaaja, R. (Risto), Immonen, H. (Heidi), Perämäki, R. (Roosa), Gissler, M. (Mika), Ollila, M.-M. (Meri-Maija), Hukkanen, J. (Janne), Vääräsmäki, M. (Marja), Uotila, J. (Jukka), Metso, S. (Saara), Hakkarainen, H. (Heidi), Rintamäki, R. (Reeta), Kaaja, R. (Risto), and Immonen, H. (Heidi)
Abstract: Aims: Women with a history of gestational diabetes (GDM) have an increased risk of developing type 2 diabetes (T2DM). We studied the risk for T2DM in women with and without GDM in relation to body mass index (BMI) and examined whether insulin treatment for GDM associates with the risk of developing T2DM. In addition, we investigated whether the risk of developing T2DM after GDM had changed in 15 years. Methods: We used data by linking four registers; Medical Birth Register, Hospital Discharge Register and Primary Care Register run by THL Finnish Institute for Health and Welfare, and Medical Reimbursement Statistics run by the Social Insurance Institution of Finland (Kela). Registry data were collected from 2005 to 2020. The follow-up started from woman’s delivery in 2006–2020 and ended to the diagnosis of T2DM or December 2020. Cox proportional hazard modelling was used to estimate the effect of GDM exposure to T2DM. To assess whether the risk of developing T2DM after GDM had changed in 15 years, we compared the HR between years 2006–2008 and 2018–2020. Results: In total, 462 401 women were included in the study: 96 353 (21%) women had previous GDM. There were 5370 (1.2%) women who developed T2DM after childbirth during the follow-up. Among women with prior GDM, 3995 (4.1%) developed T2DM, while 1375 (0.4%) women without prior GDM developed T2DM during follow-up. The mean follow-up was 6.86 years (SD 4.21) for women with GDM and 9.07 years (SD 4.35) for women without GDM. The hazard ratio (HR) for developing T2DM after GDM was 18.49 (95% CI 17.39–19.67). The incidence of T2DM in women with a history of GDM began to rise almost steadily from the first year of follow-up. As BMI increased, T2DM incidence increased in both women with and without prior GDM but more in women with prior GDM. Insulin treatment had an independent association with increased risk of T2DM (HR 3.81, 95% CI 3.57–4.07). We did not observe any difference in HR between years 2006–2008 and 2
Published: 2022

5. Total fecal IgA levels increase and natural IgM antibodies decrease after gastric bypass surgery

Author: Istomin, N. (Natalie), Härma, M.-A. (Mari-Anne), Akhi, R. (Ramin), Nissinen, A. E. (Antti E.), Savolainen, M. J. (Markku J.), Adeshara, K. (Krishna), Lehto, M. (Markku), Groop, P.-H. (Per-Henrik), Koivukangas, V. (Vesa), Hukkanen, J. (Janne), Hörkkö, S. (Sohvi), Istomin, N. (Natalie), Härma, M.-A. (Mari-Anne), Akhi, R. (Ramin), Nissinen, A. E. (Antti E.), Savolainen, M. J. (Markku J.), Adeshara, K. (Krishna), Lehto, M. (Markku), Groop, P.-H. (Per-Henrik), Koivukangas, V. (Vesa), Hukkanen, J. (Janne), and Hörkkö, S. (Sohvi)
Abstract: Obesity is associated with low-grade inflammation and increased systemic oxidative stress. Roux-en-Y gastric bypass (RYGB) surgery is known to ameliorate the obesity-induced metabolic dysfunctions. We aimed to study the levels of natural antibodies in feces, before and 6 months after RYGB surgery in obese individuals with and without type 2 diabetes (T2D). Sixteen individuals with T2D and 14 non-diabetic (ND) individuals were operated. Total IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts (MAA adducts), Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44) and phosphocholine (PCho) were measured using chemiluminescence immunoassay. Total fecal IgA was elevated, while total IgM and IgG were not affected by the surgery. Fecal natural IgM specific to oxLDL decreased significantly in both T2D and ND individuals, while fecal IgM to Rgp44 and PCho decreased significantly in T2D individuals. A decrease in IgG to MAA-LDL, Rgp44 and PCho was detected. RYGB surgery increases the levels of total fecal IgA and decreases fecal natural IgG and IgM antibodies specific to oxLDL. Natural antibodies and IgA are important in maintaining the normal gut homeostasis and first-line defense against microbes, and their production is markedly altered with RYGB surgery.
Published: 2022

6. Long-term metabolic fate and mortality in obesity without metabolic syndrome

Author: Käräjämäki, A. J. (Aki Juhani), Korkiakoski, A. (Arto), Hukkanen, J. (Janne), Kesäniemi, Y. A. (Y. Antero), Ukkola, O. (Olavi), Käräjämäki, A. J. (Aki Juhani), Korkiakoski, A. (Arto), Hukkanen, J. (Janne), Kesäniemi, Y. A. (Y. Antero), and Ukkola, O. (Olavi)
Abstract: Background: Obesity and metabolic syndrome (MetS) are known to expose to atrial fibrillation (AF), cardiovascular diseases (CVD) and mortality. Metabolically healthy obesity refers to obesity without MetS. This study aimed to investigate how obesity and MetS modify the risk of CVD, AF and mortality in very long-time follow-up. Methods: Finnish middle-aged subjects (n = 1045) were grouped into four subgroups according to the presence of obesity and MetS. CVD events and AF were followed for 24 years and total mortality for 30 years. Moreover, 600 available patients had a follow-up visit for metabolic examinations after approximately 22 years. Results: One-hundred and sixty-two (30%) subjects without obesity or MetS died during the follow-up. Ninety-two (17%) of the patients in this group had a CVD event and 58 (11%) were diagnosed with AF. As compared to them, obese subjects without MetS had similar metabolic fate and mortality (mortality 26 (38%), p = .143; CVD event 12 (18%), p = .858 and AF 7 (10%), p = .912, respectively), whereas subjects with obesity and MetS had greater mortality (102 (49%), p < .001), more CVD (71 (34%), p < .001) and AF (49 (23%), p < .001). Non-obese individuals with MetS had greater rates of mortality (96 (44%), p < .001) and CVD (80 (37%), p < .001), but not of AF (26 (12%), p = .606). Of the 40 subjects with obesity but without MetS at baseline and available for the follow-up visit, 15 (38%) were metabolically healthy at the follow-up visit. Conclusions: In the present long-term follow-up study, the presence of MetS, but not obesity only, implies a greater risk of mortality and CVD. The risk of AF is increased only in subjects with both obesity and MetS. However, obesity without MetS tends to progress eventually to obesity with MetS.
Published: 2022

7. Nuclear receptor PXR in drug-induced hypercholesterolemia

Author: Karpale, M. (Mikko), Hukkanen, J. (Janne), Hakkola, J. (Jukka), Karpale, M. (Mikko), Hukkanen, J. (Janne), and Hakkola, J. (Jukka)
Abstract: Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual’s cholesterol status during the decades when the arteria-narrowing arteriosclerotic plaques are forming is critical. Several drugs are known to increase cholesterol levels; however, the mechanisms are poorly understood. Activation of pregnane X receptor (PXR), the major regulator of drug metabolism and molecular mediator of clinically significant drug–drug interactions, has been shown to induce hypercholesterolemia. As a major sensor of the chemical environment, PXR may in part mediate hypercholesterolemic effects of drug treatment. This review compiles the current knowledge of PXR in cholesterol homeostasis and discusses the role of PXR in drug-induced hypercholesterolemia.
Published: 2022

8. Rifampicin induces the bone form of alkaline phosphatase in humans

Author: Nabil, H. (Heba), Kummu, O. (Outi), Lehenkari, P. (Petri), Rysä, J. (Jaana), Risteli, J. (Juha), Hakkola, J. (Jukka), and Hukkanen, J. (Janne)
Subjects: musculoskeletal diseases, pregnane X receptor, stomatognathic system, pregnenolone 16α-carbonitrile, musculoskeletal, neural, and ocular physiology, musculoskeletal system, rifampicin, digestive system, alkaline phosphatase, bone
Abstract: Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that regulates drug metabolism in the liver and intestine. In our clinical trials on healthy volunteers to discover novel metabolic functions of PXR activation, we observed that rifampicin, a well-established ligand for human PXR, 600 mg daily for a week, increased the plasma alkaline phosphatase (ALP) significantly compared with the placebo. Further analysis with lectin affinity electrophoresis revealed that especially the bone form of ALP was elevated. To investigate the mechanism(s) of bone ALP induction, we employed osteoblast lineage differentiated from human primary bone marrow–derived mesenchymal stromal cells. Rifampicin treatment increased ALP activity and mRNA level of bone biomarker genes (ALP, MGP, OPN and OPG). PXR expression was detected in the cells, but the expression was very low compared with the human liver. To further investigate the potential role of PXR in the ALP induction, we treated mice and rats with a rodent PXR ligand pregnenolone 16α-carbonitrile (PCN). However, PCN treatment did not increase plasma ALP activity or bone ALP mRNA expression. In conclusion, rifampicin treatment induces the bone form of ALP in the serum of healthy human volunteers. Further studies are required to establish the mechanism of this novel finding.
Published: 2022

9. Serological biomarker panel in diagnosis of atrophic gastritis and Helicobacter pylori infection in gastroscopy referral patients:clinical validation of the new-generation GastroPanel® test

Author: Koivurova, O.-P. (Olli-Pekka), Koskela, R. (Ritva), Blomster, T. (Timo), Ala-Rämi, A. (Antti), Lumme, H. (Henri), Kettunen, O. (Olli), Hukkanen, J. (Janne), Karttunen, T. J. (Tuomo J.), Mäkinen, M. (Markus), Ronkainen, J. (Jukka), and Syrjänen, K. (Kari)
Subjects: gastroscopy, pepsinogen I, Helicobacter pylori, pepsinogen II, new-generation GastroPanel, biopsies, Atrophic gastritis (AG), updated Sydney System (USS), Hp IgG antibody ELISA, gastrin-17, non-invasive test, diagnostic accuracy, serological biomarker panel, clinical validation
Abstract: Background/Aim: Prompted by the increasing demand of non-invasive diagnostic tools for screening of gastric cancer (GC) risk conditions, i.e., atrophic gastritis (AG) and Helicobacter pylori (Hp) infection, the GastroPanel® test (GP: biomarker panel of PGI, PGII, G‐17, Hp IgG ELISA) that was developed in the early 2000’s, was recently updated to a new-generation (unified GP) test version. This clinical validation study evaluated the diagnostic accuracy of the new-generation GP test in detection of AG and Hp among gastroscopy referral patients in a University Clinic. Patients and Methods: Altogether, 522 patients were enrolled among the patients referred for gastroscopy at the Gastro Center, Oulu University Hospital (OUH). All patients underwent gastroscopy with biopsies classified using the Updated Sydney System (USS), and blood sampling for GP testing. Results: Biopsy-confirmed AG was found in 10.2% (53/511) of the patients. The overall agreement between the GP and the USS classification was 92.4% (95%CI=90.0‐94.6%), with the weighted kappa (κw) of 0.861 (95%CI=0.834‐0.883). In ROC analysis using moderate/severe AG of the corpus (AGC2+) as the endpoint, AUC=0.952 (95%CI=0.891‐1.000) and AUC=0.998 (95%CI=0.996‐1.000) for PGI and PGI/PGII, respectively. Hp IgG antibody ELISA detected biopsy-confirmed Hp-infection with AUC=0.993 (95%CI=0.987‐0.999). Conclusion: The new generation GastroPanel® is a precise test for non-invasive diagnosis of atrophic gastritis and Hp-infection in dyspeptic patients referred for diagnostic gastroscopy.
Published: 2021

10. Digihoidon mahdollisuudet lihavuuden hoidossa

Author: Oikarinen, N. (Noora), Hukkanen, J. (Janne), Oinas-Kukkonen, H. (Harri), and Savolainen, M. J. (Markku J.)
Abstract: Tiivistelmä Uudessa Käypä hoito -suosituksessa huomioidaan digitaalisten välineiden hyödyntäminen lihavuuden hoidossa. Suomessa lihavuuden digihoitoa on tutkittu sekä itsenäisenä hoitokeinona että yhdistettynä lihavuuden perinteisiin hoitokeinoihin. Yhdistelmähoidolla on saatu parhaimmat tulokset Suomessa ja monissa muissa maissa. Jotta digihoitoa voidaan tarjota laajemmin, tarvitaan tietoa, millainen palvelu sopii kullekin kohderyhmälle, miten käyttäjät saadaan sitoutumaan hoitoon ja mitkä digitaaliset komponentit toimivat lihavuuden hoidossa. Summary There are approximately 2.5 million overweight adults in Finland and about a million of them are obese. Effective treatment options are limited due to limited health care resources, costs and sometimes geographical barriers. In the recent Finnish Current Care Guideline on obesity, digital devices were considered to be a potential treatment method and an option for overcoming the barriers to therapy. The published literature on digital obesity treatment is difficult to evaluate due to differences in sample sizes, duration of interventions and care of control groups. However, digital obesity treatments seem to be more effective compared to controls in some instances. Especially the combination of face-to-face and digital treatment provides better weight loss results compared to traditional care. Self-monitoring, tailored content and feedback are digital features associated with successful weight loss results. In studies performed in Finland, the most effective methods combine digital and traditional treatments. This is in line with the results of international studies. There are also some promising results with commercial mobile apps for weight loss. However, due to small sample sizes, limited intervention durations and lack of follow-up periods, evidence is scarce. Further research is needed to find a suitable digital service for each target population and determine the digital components most effective in obesity treatment.
Published: 2021

11. Lääkkeellinen painonhallinta

Author: Hukkanen, J. (Janne) and Savolainen, M. J. (Markku J.)
Abstract: Tiivistelmä Lihavuuden lääkehoitoa harkitaan elintapahoidon tueksi, kun painoindeksi on ≥ 30 kg/m². Jos potilaalla on lihavuuden liitännäissairauksia, voidaan lääkitystä harkita, kun indeksi on yli 27 kg/m². Lääkevaihtoehtoja ovat orlistaatti, liraglutidi sekä naltreksonin ja bupropionin yhdistelmävalmiste. Myös semaglutidin vaikutuksesta on vahvaa näyttöä. Lääkityksen teho on yksilöllistä. Tehoton lääkitys (paino vähenee < 5 %) tulee lopettaa. Merkittävä painonnousu on tyypillinen ongelma lääkehoidon lopettamisen jälkeen. Lääkehoito pitäisi suunnitella riittävän pitkäaikaiseksi. Summary Pharmacological therapy for obesity and overweight as an adjunct to lifestyle intervention can be considered when the body mass index is ≥ 30 kg/m², or ≥ 27 kg/m² with obesity-related comorbidities. The history of anti-obesity medications is long and often problematic as several medications have been withdrawn due to cardiovascular hazards and mood disorders. There are currently three options for pharmacotherapy in Finland: orlistat, naltrexone–bupropion, and liraglutide. In addition, the diabetes medication semaglutide is currently under evaluation by the European Medicines Agency as a treatment for obesity. The most efficient drugs for weight loss are the GLP-1 agonists liraglutide and especially semaglutide. Orlistat has the most extensive accumulated long term clinical experience of safety, but its efficacy is only modest. Naltrexone–bupropion has moderate efficacy, but several contraindications and drug-drug interactions complicate its use. Cardiovascular safety is established for liraglutide and semaglutide but only in the treatment of diabetes at lower doses than indicated in obesity therapy. The challenges in pharmacotherapy for obesity include the high treatment discontinuation rates, interindividual differences in response to medications, the tendency to regain weight after the drug treatment, and high costs for the patient due to lack of reimbursement. However, liraglutide was recently granted reimbursement for patients with body mass index ≥ 35 kg/m² and prediabetes, with the additional prerequisite of drug treatment for hypertension or dyslipidaemia. Utilization of the current more efficient anti-obesity medications and better access to therapy should lead to improved long-term outcomes, especially when pharmacotherapy is combined with effective lifestyle interventions.
Published: 2021

12. Esidiabetes – medikalisaatiota vai kansansairauksien ehkäisyä?

Author: Savolainen, M. J. (Markku J.), Heikkilä, L. (Laura), Merikallio, H. (Heta), and Hukkanen, J. (Janne)
Published: 2021

13. Gastrointestinal manifestations after Roux-en-Y gastric bypass surgery in individuals with and without type 2 diabetes

Author: Härma, M.-A. (Mari-Anne), Adeshara, K. (Krishna), Istomin, N. (Natalie), Lehto, M. (Markku), Blaut, M. (Michael), Savolainen, M. J. (Markku J.), Hörkkö, S. (Sohvi), Groop, P.-H. (Per-Henrik), Koivukangas, V. (Vesa), Hukkanen, J. (Janne), Härma, M.-A. (Mari-Anne), Adeshara, K. (Krishna), Istomin, N. (Natalie), Lehto, M. (Markku), Blaut, M. (Michael), Savolainen, M. J. (Markku J.), Hörkkö, S. (Sohvi), Groop, P.-H. (Per-Henrik), Koivukangas, V. (Vesa), and Hukkanen, J. (Janne)
Abstract: Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for obesity, which improves cardiovascular health and reduces the risk of premature mortality. However, some reports have suggested that RYGB may predispose patients to adverse health outcomes, such as inflammatory bowel disease (IBD) and colorectal cancer. Objectives: The present prospective study aimed to evaluate the impact of RYGB surgery on cardiovascular risk factors and gastrointestinal inflammation in individuals with and without type 2 diabetes (T2D). Setting: University hospital setting in Finland. Methods: Blood and fecal samples were collected at baseline and 6 months after surgery from 30 individuals, of which 16 had T2D and 14 were nondiabetics. There were also single study visits for 6 healthy reference patients. Changes in cardiovascular risk factors, serum cholesterol, and triglycerides were investigated before and after surgery. Fecal samples were analyzed for calprotectin, anti-Saccharomyces cerevisiae immunoglobulin A antibodies (ASCA), active lipopolysaccharide (LPS) concentration, short-chain fatty acids (SCFAs), intestinal alkaline phosphatase activity, and methylglyoxal-hydro-imidazolone (MG-H1) protein adducts formation. Results: After RYGB, weight decreased on average −21.6% (−27.2 ± 7.8 kg), excess weight loss averaged 51%, and there were improvements in cardiovascular risk factors. Fecal calprotectin levels (P < 0.001), active LPS concentration (P < 0.002), ASCA (P < 0.02), and MG-H1 (P < 0.02) values increased significantly, whereas fecal SCFAs, especially acetate (P < 0.002) and butyrate (P < 0.03) levels, were significantly lowered. Conclusion: The intestinal homeostasis is altered after RYGB, with several fecal markers suggesting increased inflammation; however, clinical significance of the detected changes is currently uncertain. As chronic inflammation may predispose patients to adverse health effects, our findings may have relev
Published: 2021

14. Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism

Author: Karpale, M. (Mikko), Käräjämäki, A. J. (Aki Juhani), Kummu, O. (Outi), Gylling, H. (Helena), Hyötyläinen, T. (Tuulia), Orešič, M. (Matej), Tolonen, A. (Ari), Hautajärvi, H. (Heidi), Savolainen, M. J. (Markku J.), Ala-Korpela, M. (Mika), Hukkanen, J. (Janne), Hakkola, J. (Jukka), Karpale, M. (Mikko), Käräjämäki, A. J. (Aki Juhani), Kummu, O. (Outi), Gylling, H. (Helena), Hyötyläinen, T. (Tuulia), Orešič, M. (Matej), Tolonen, A. (Ari), Hautajärvi, H. (Heidi), Savolainen, M. J. (Markku J.), Ala-Korpela, M. (Mika), Hukkanen, J. (Janne), and Hakkola, J. (Jukka)
Abstract: Background and purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved. Experimental approach: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis. Key results: Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol–cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch–Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation. Conclusions and implications: PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR–SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia.
Published: 2021

15. Tiatsididiureettien käyttö suurentaa luuntiheyttä ja pienentää murtumariskiä:järjestelmällinen kirjallisuuskatsaus ja meta-analyysi

Author: Rysä, J. (Jaana), Tolppanen, A.-M. (Anna-Maija), Lehtonen, E. (Elise), and Hukkanen, J. (Janne)
Subjects: Thiazide diuretics, calcium excretion, hypertension, murtumat, luuntiheys, Tiatsididiureetit, fractures, verenpainetauti, bone mineral density, kalsiumineritys
Abstract: Tiivistelmä Verenpainetaudin hoidossa käytettävät tiatsididiureetit estävät natriumin ja kloridin takaisinimeytymistä munuaisissa, jolloin natriumin, kloridin ja veden eritys virtsaan lisääntyy. Lisäksi tiatsidit vähentävät kalsiumin ja lisäävät kaliumin eritystä. Koska tiatsidit vähentävät kalsiumin eritystä, on pohdittu tiatsididiureettien suotuisaa vaikutusta luuntiheyteen ja murtumariskiin. Teimme järjestelmällisen kirjallisuuskatsauksen tiatsididiureettien vaikutuksesta luuntiheyteen ja murtumariskiin pohjautuen satunnaistettuihin ja kontrolloituihin lääketutkimuksiin. Lisäksi teimme meta-analyysin tiatsididiureettien vaikutuksesta murtumariskiin. Järjestelmällisen kirjallisuuskatsauksen perusteella tiatsididiureettien käyttäjillä luuntiheys on suurentunut verrattuna lähtötilaan tai lume-/kontrollilääkettä käyttäneisiin. Meta-analyysin perusteella tiatsidiryhmän lääkkeet pienensivät suhteellista murtumariskiä 25 prosenttia valtaosin iäkkäistä potilaista koostuneissa tutkimuksissa. Puolessa meta-analyysiin valituista tutkimuksista ei kuitenkaan käytetty Suomessa yleisimmin käytettyä hydroklooritiatsidia. Kirjallisuuskatsauksessa ja meta-analyysissä saatiin tukea oletukselle, että tiatsididiureettien käyttö suurentaa luuntiheyttä ja pienentää murtumariskiä. Verenpainetaudin hoidossa tiatsidit näyttäisivät tuovan iäkkäillä potilailla lisähyötyä murtumariskin pienenemisen muodossa. Tiatsidien tunnetut haittavaikutukset tulee huomioida hoitopäätöstä tehdessä. Koska tiatsidien murtumavaikutuksia selvittävät tutkimukset on tehty pääosin verenpainetautia sairastavilla, ei tiatsideja voida suositella normotensiivisten potilaiden murtumariskin pienentämiseen. Summary Thiazide diuretics increase bone mineral density and lower fracture risk : systematic review and meta-analysis Thiazide diuretics exert their antihypertensive effect by inhibiting the reabsorption of sodium and chloride in kidneys, leading to increases in urinary sodium, chloride and water excretion. In addition, thiazides decrease urinary calcium excretion while increasing that of potassium. Since thiazides reduce the excretion of calcium, it has been hypothesized that thiazides could exert a beneficial effect on bone mineral density and reduce the risk of fractures. We conducted a systematic review of randomized controlled trials to determine if thiazide diuretics have any beneficial effect on bone mineral density and the risk of fractures. We also performed a meta-analysis on the effect of thiazides on the risk of fractures. The systematic literature review demonstrated that the use of thiazides was associated with an increased bone mineral density. A 25% lower risk of fractures was demonstrated in the meta-analysis of the studies with mostly elderly patients. However, hydrochlorothiazide, the most widely used thiazide in Finland, was used only in half of the studies included in the meta-analysis. Thiazide diuretics are useful in the treatment of hypertension, and the lower fracture risk is an additional benefit in older patients. However, one should take into consideration the widely recognized adverse effect of thiazides before starting the treatment. Finally, since the studies reporting on thiazide use and hip fractures were conducted in hypertensive patients, the thiazides cannot be recommended to prevent fractures in normotensive individuals.
Published: 2020

16. Pregnane X receptor activator rifampin increases blood pressure and stimulates plasma renin activity

Author: Hassani‐Nezhad‐Gashti, F. (Fatemeh), Salonurmi, T. (Tuire), Hautajärvi, H. (Heidi), Rysä, J. (Jaana), Hakkola, J. (Jukka), and Hukkanen, J. (Janne)
Subjects: polycyclic compounds
Abstract: We conducted a clinical trial with 22 healthy volunteers to investigate the effects of pregnane X receptor (PXR) agonist rifampin on blood pressure (BP). The study was randomized, crossover, single‐blind, and placebo‐controlled. Rifampin 600 mg or placebo once daily was administered for a week and the 24‐hour ambulatory BP was monitored at the end of each arm on the eighth day. Rifampin elevated the mean systolic and diastolic 24‐hour BP (4.7 mmHg, P < 0.0001, and 3.0 mmHg, P < 0.001, respectively) as well as the mean heart rate (3.5 bpm, P = 0.038). The serum renin concentration and the plasma renin activity were increased. Although rifampin increased circulating 4β‐hydroxycholesterol (4βHC) as expected, the plasma 4βHC concentration strongly negatively correlated with 24‐hour BP, especially systolic, in both rifampin and placebo arms (rifampin systolic BP, r = −0.69, P < 0.001; placebo systolic BP, r = −0.70, P < 0.001). The 4βHC, an agonist for liver X receptor (LXR), induced renin expression modestly in LXR‐α expressing Calu‐6 cells but only at unphysiologically high 4βHC concentrations. In conclusion, rifampin stimulates renin activity and has a hypertensive effect. This finding should be considered when designing interaction studies involving rifampin or other PXR agonists. Furthermore, PXR may represent a putative therapeutic target for the treatment of hypertension.
Published: 2020

17. CYP-associated drug–drug interactions:a mission accomplished?

Author: Pelkonen, O. (Olavi), Hakkola, J. (Jukka), Hukkanen, J. (Janne), and Turpeinen, M. (Miia)
Subjects: enzymes and coenzymes (carbohydrates), drug-drug interactions, organic chemicals, CYP, heterocyclic compounds, Cytochrome P450, approved drugs, respiratory system, urologic and male genital diseases
Abstract: On the basis of official Finnish Medicines Authority (Fimea)-approved drug monographs, less than half of the approved small-molecule drugs between 2007 and 2016 were substrates, inhibitors or inducers of CYP enzymes, predominantly of CYP3A4. No significant unexpected, life-threatening, CYP-associated drug-drug interactions (CYP-DDIs) of newly approved drug entities have been observed in the last 10–15 years. The present analysis seems to suggest that tools to study and predict potentially significant CYP-DDIs are working and efficient.
Published: 2020

18. PXR and 4β-hydroxycholesterol axis and the components of metabolic syndrome

Author: Hukkanen, J. (Janne), Hakkola, J. (Jukka), Hukkanen, J. (Janne), and Hakkola, J. (Jukka)
Abstract: Pregnane X receptor (PXR) activation has been found to regulate glucose and lipid metabolism and affect obesity in response to high-fat diets. PXR also modulates vascular tone. In fact, PXR appears to regulate multiple components of metabolic syndrome. In most cases, the effect of PXR action is harmful to metabolic health, and PXR can be hypothesized to play an important role in metabolic disruption elicited by exposure to endocrine-disrupting chemicals. The majority of the data on the effects of PXR activation on metabolic health come from animal and cell culture experiments. However, randomized, placebo-controlled, human trials indicate that the treatment with PXR ligands impairs glucose tolerance and increases 24-h blood pressure and heart rate. In addition, plasma 4β-hydroxycholesterol (4βHC), formed under the control of PXR in the liver, is associated with lower blood pressure in healthy volunteers. Furthermore, 4βHC regulates cholesterol transporters in peripheral tissues and may activate the beneficial reverse HDL cholesterol transport. In this review, we discuss the current knowledge on the role of PXR and the PXR–4βHC axis in the regulation of components of metabolic syndrome.
Published: 2020

19. 4β-hydroxycholesterol signals from the liver to regulate peripheral cholesterol transporters

Author: Salonurmi, T. (Tuire), Nabil, H. (Heba), Ronkainen, J. (Justiina), Hyötyläinen, T. (Tuulia), Hautajärvi, H. (Heidi), Savolainen, M. J. (Markku J.), Tolonen, A. (Ari), Orešič, M. (Matej), Känsäkoski, P. (Päivi), Rysä, J. (Jaana), Hakkola, J. (Jukka), Hukkanen, J. (Janne), Salonurmi, T. (Tuire), Nabil, H. (Heba), Ronkainen, J. (Justiina), Hyötyläinen, T. (Tuulia), Hautajärvi, H. (Heidi), Savolainen, M. J. (Markku J.), Tolonen, A. (Ari), Orešič, M. (Matej), Känsäkoski, P. (Päivi), Rysä, J. (Jaana), Hakkola, J. (Jukka), and Hukkanen, J. (Janne)
Abstract: Activation of pregnane X receptor (PXR) elevates circulating 4β-hydroxycholesterol (4βHC), an agonist of liver X receptor (LXR). PXR may also regulate 25-hydroxycholesterol and 27-hydroxycholesterol. Our aim was to elucidate the roles of PXR and oxysterols in the regulation of cholesterol transporters. We measured oxysterols in serum of volunteers dosed with PXR agonist rifampicin 600 mg/day versus placebo for a week and analyzed the expression of cholesterol transporters in mononuclear cells. The effect of 4βHC on the transport of cholesterol and the expression of cholesterol transporters was studied in human primary monocyte-derived macrophages and foam cells in vitro. The expression of cholesterol transporters was measured also in rat tissues after dosing with a PXR agonist. The levels of 4βHC were elevated, while 25-hydroxycholesterol and 27-hydroxycholesterol remained unchanged in volunteers dosed with rifampicin. The expression of ATP binding cassette transporter A1 (ABCA1) was induced in human mononuclear cells in vivo. The influx of cholesterol was repressed by 4βHC, as was the expression of influx transporter lectin-like oxidized LDL receptor-1 in vitro. The cholesterol efflux and the expression of efflux transporters ABCA1 and ABCG1 were induced. The expression of inducible degrader of the LDL receptor was induced. In rats, PXR agonist increased circulating 4βHC and expression of LXR targets in peripheral tissues, especially ABCA1 and ABCG1 in heart. In conclusion, PXR activation-elevated 4βHC is a signaling molecule that represses cholesterol influx and induces efflux. The PXR-4βHC-LXR pathway could link the hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues.
Published: 2020

20. Inhibition and induction of CYP enzymes in humans:an update

Author: Hakkola, J. (Jukka), Hukkanen, J. (Janne), Turpeinen, M. (Miia), Pelkonen, O. (Olavi), Hakkola, J. (Jukka), Hukkanen, J. (Janne), Turpeinen, M. (Miia), and Pelkonen, O. (Olavi)
Abstract: The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug–drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug–drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena.
Published: 2020

21. Metabolic syndrome but not genetic polymorphisms known to induce NAFLD predicts increased total mortality in subjects with NAFLD (OPERA study)

Author: Käräjämäki, A. J. (Aki Juhani), Hukkanen, J. (Janne), Kauma, H. (Heikki), Kesäniemi, Y. A. (Y. Antero), Ukkola, O. (Olavi), Käräjämäki, A. J. (Aki Juhani), Hukkanen, J. (Janne), Kauma, H. (Heikki), Kesäniemi, Y. A. (Y. Antero), and Ukkola, O. (Olavi)
Abstract: Metabolic syndrome (MetS) and genetic polymorphisms PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 are known inductors of non-alcoholic fatty liver disease (NAFLD). However, knowledge about how these affect the mortality of subjects with NAFLD is scarce. Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 on overall and cardiovascular disease (CVD) specific mortality among subjects with or without NAFLD. NAFLD diagnosis was based on liver ultrasound at the baseline. After this and other comprehensive examinations, 958 middle-aged Finns, 249 with NAFLD, were followed for 21 years. The mortality data was gathered from the National Death Registry. After multiple adjustments, the NAFLD individuals with MetS had increased risk of overall mortality as compared to the NAFLD subjects without MetS [2.054 (1.011–4.173, p = 0.046)]. However, PNPLA3 rs738409 [1.049 (0.650–1.692, p =0 .844)], TM6SF2 rs58542926 [0.721 (0.369–1.411, p = 0.340)] or MBOAT7 rs641738 [0.885 (0.543–1.439, p = 0.621)] did not affect the overall mortality. MetS was also a marker of increased risk of CVD mortality (15% vs. 2%, p =0.013) while genetic polymorphisms did not affect CVD mortality. In conclusion, MetS, but not the gene polymorphisms studied, predicts increased overall and CVD-specific mortality among NAFLD subjects.
Published: 2020

22. Myostatiini

Author: Hukkanen, J. (Jere)
Abstract: Tiivistelmä. Myostatiini on tärkeä lihaskasvun negatiivinen säätelijä ja sen toimintaa heikentävät mutaatiot ilmenevät ylilihaksikkaana fenotyyppinä useilla nisäkäslajeilla. (Rodriguez et al. 2014). Myostatiini syntetisoidaan inaktiivisena esiasteena, josta se saadaan vaiheittain proteolyyttisesti käsittelemällä aktiiviseen muotoonsa. Myostatiini voidaan erittää solusta joko täysin käsittelemättömänä, tai niin että se on läpikäynyt ensimmäisen proteolyyttisen käsittelyn. Käsittelemätön kompleksi sitoutuu lihaksen ekstrasellulaariseen matriksiin. Käsitelty kompleksi puolestaan siirtyy verenkiertoon, missä se kohtaa toisen proteolyyttisen käsittelyn. Tämän seurauksena kypsä myostatiini kykenee dissosioitumaan pro-peptidistään ja näin ollen aktivoitumaan (Cotton et al. 2018). Anti-hypertrofisen ja anabolisen vaikutuksensa myostatiini välittää tyypin II aktiviinireseptorin kautta. Sitoutumisen seurauksena syntyy tyypin II ja tyypin I reseptorien muodostama kompleksi, joka fosforyloi Smad2- ja Smad2-transkriptiotekijöitä, minkä seurauksena anaboliaa indusoiva AKT/mTOR-signalointi vaimenee (Rebbapragada et al. 2003, Amirouche et al. 2009, Chelh et al. 2009, Morissette et al. 2009). Vastaavasti AKT/FOXO-välitteiset kataboliset reitit mahdollisesti voimistuvat (McFarlene et al. 2006, Mendias et al. 2011). Toisaalta Taylor et al. (2001) ja Amirouche et al. (2009) eivät löytäneet merkkejä myostatiinin kyvystä lisätä proteiinien hajotusta. Myostatiinin aiheuttama AKT:n aktiivisuuden lasku ja siihen liittyvä lihaskasvu näyttävät joka tapauksessa varmoilta. Myöskin myostatiinin itsesäätely tapahtuu Smad-välitteisesti. Kohonnut Smad2:n ja Smad3:n ekspressio johtaa lisääntyneeseen Smad7:n ekspressioon (Forbes et al. 2006). Smad7 puolestaan estää reseptorikompleksin toiminnan, jolloin Smad2:n ja Smad3:n aktiivisuus laskee (Nakao et al. 1997, Forbes et al. 2006). Smad7 voisi olla yksi mahdollinen kohde, kun etsitään mahdollisia kohteita myostatiinisignaloinnin vaimentamiseen ja edelleen hoitomuotoja sairauksiin. Myostatiinin lihaskasvua estävä vaikutus johtuu osittain myös sen kyvystä estää satelliittisolujen aktivaatiota, sekä itseuudistumisprosessia. Tämä vaikutus johtuu kohonneen p21-pitoisuuden seurauksena vähentyneestä cdk-aktiivisuudesta, mikä saa solut pysähtymään solusyklin G1-vaiheeseen (Rios et al. 2002, McCroskery et al. 2003, McFarlene et al. 2006). Tulokset ovat linjassa Li et al. (2007) dekoriinin yliekspressiolla tapahtuvaa myostatiinin inhibointia koskevien tulosten kanssa. Niiden mukaan inhibition kautta lisääntynyt myogeenisten geenien ja follistatiinin ekspressio oli yhteydessä kasvaneeseen lihasmassaan. Lisäksi sydänlihas kykenee erittämänsä myostatiinin avulla säätelemään luurankolihasten massaa sydämen vajaatoiminnan yhteydessä (Heineke et al. 2010). Tämä herättää kysymyksen, sydänlihaksen kunnon merkityksestä lihasmassan säilymiseen ja kasvatukseen myöskin sydämen vajaatoimintaa sairastamattomilla ihmisillä. Myostatiinin toimintaa on mahdollista manipuloida erilaisten inhibiittoreiden avulla. Inhibiittoria voidaan joko injektoida suoraan lihakseen, tai geneettisesti muokkaamalla aiheuttaa inhibiittorin yliekspressio. Yksi mahdollisuus on injektoida myostatiini-inhibiittorina toimivaa follistatiinia lihakseen tai aiheuttaa sen yliekspressio geenivektorin avulla (Miura et al. 2006, Se-Jin 2007, Glasser et al. 2018, Castonguay et al. 2019). Dekoriinin yliekspressio plasmidivektorin avulla niin ikään aiheuttaa luurankolihasten kasvua myostatiini-inhibiition kautta (Li et al. 2007). Immuunipuolustus on myöskin mahdollista provosoida muodostamaan vasta-aineita kehon omaa myostatiinia vastaan joko injektoitavan, tai oraalisen rokotteen avulla (Tang et al. 2007, Zhang et al. 2011). Toimivan ihmiskäyttöön sopivan inhibointimenetelmän löytyminen voisi merkitä hoitomuotoa lihasrappeumaa aiheuttaviin ja siitä johtuviin sairauksiin. Menetelmän olisi kuitenkin hyvä olla vain lihaskudokseen vaikuttava, sekä toteutettavissa syntymän jälkeen. Tällaisten hoitomuotojen voinee olettaa kiinnostavan myös dopingkäytössä esimerkiksi kilpaurheilijoita tai jopa tavallisia kuntourheilijoita. Tästä syystä hoitomuotojen kehittyminen vaatii dopingtestaajilta mahdollisesti uusien testausmenetelmien kehittelyä, sekä mahdollisten eettisten kysymysten pohdintaa. Myostatiinin määrään voidaan vaikuttaa myöskin voimaharjoittelun avulla. Voimaharjoittelu näyttäisi nostavan myostatiinin ekspressiota pitkällä aikavälillä, kun taas yksittäinen harjoituskerta kykenee laskemaan sitä (Hulmi et al. 2007). Näin ollen voi päätellä, että myostatiinin alassäätelyllä on tärkeä merkitys voimaharjoittelusta seuraavaan lihaskasvun aiheuttajana. Erilaisten ravintoaineiden vaikutuksesta myostatiiniin on hieman näyttöä. Kreatiini yhdistettynä voimaharjoitteluun näyttäisi vähentävän myostatiinin ekspressiota enemmän kuin voimaharjoittelu yksinään (Saremi et al. 2010). D-vitamiini kykenee vähentämään myostatiinin ekspressiota ainakin soluviljelmällä (Garcia et al. 2011). Myöskin (-)-epikatekiini kykenee mahdollisesti pienentämään plasman ja lihaskudoksen myostatiinikonsentraatiota ja nostamaan myostatiinia inhiboivan follistatiinin pitoisuutta (Guiterrez-Salmean et al. 2014, Mafi et al. 2019). Näyttö näiden aineiden toimivuudesta myostatiini-inhibiittoreina on kuitenkin vähäistä, joskin osittain lupaavaa. Androgeenisten anabolisten steroidien anabolinen vaikutus ei välity vähentyneen myostatiinisignaloinnin seurauksena. Päinvastoin, androgeenit kykenevät suoraan lisäämään myostatiinin ekspressiota transkriptionaalisella tasolla. Näin ollen ne kykenevät itse vähentämään omaa anabolista vaikutustaan (Dubois et al. 2014). Tulos on yllättävä, kun ajatellaan anabolisten steroidien vaikutusta lihasmassaan. Kasvuhormoni puolestaan kykenee vähentämään myostatiinin määrää kasvuhormonin puutoksesta kärsivillä ihmisillä, mikä johtaa lisääntyneeseen lihasmassaan (Liu et al. 2003). Tulevaisuuden myostatiinitutkimuksen suuntana lienee saada markkinoille toimivia ja turvallisia myostatiiniantagonistejä, joiden TGF-β-signalointia inhiboiva vaikutus rajoittuu lihaskudokseen.
Published: 2019

23. Healthy nordic diet modulates the expression of genes related to mitochondrial function and immune response in peripheral blood mononuclear cells from subjects with metabolic syndrome:a SYSDIET sub-study

Author: Myhrstad, M. C. (Mari C. W.), de Mello, V. D. (Vanessa D.), Dahlman, I. (Ingrid), Kolehmainen, M. (Marjukka), Paananen, J. (Jussi), Rundblad, A. (Amanda), Carlberg, C. (Carsten), Olstad, O. K. (Ole Kristoffer), Pihlajamäki, J. (Jussi), Holven, K. B. (Kirsten B.), Hermansen, K. (Kjeld), Dragsted, L. O. (Lars O.), Gunnarsdottir, I. (Ingibjörg), Cloetens, L. (Lieselotte), Storm, M. U. (Matilda Ulmius), Åkesson, B. (Björn), Rosqvist, F. (Fredrik), Hukkanen, J. (Janne), Herzig, K. (Karl‐Heinz), Risérus, U. (Ulf), Thorsdottir , I. (Inga), Poutanen, K. S. (Kaisa S.), Savolainen, M. J. (Markku J), Schwab, U. (Ursula), Arner, P. (Peter), Uusitupa, M. (Matti), Ulven, S. M. (Stine M.), Myhrstad, M. C. (Mari C. W.), de Mello, V. D. (Vanessa D.), Dahlman, I. (Ingrid), Kolehmainen, M. (Marjukka), Paananen, J. (Jussi), Rundblad, A. (Amanda), Carlberg, C. (Carsten), Olstad, O. K. (Ole Kristoffer), Pihlajamäki, J. (Jussi), Holven, K. B. (Kirsten B.), Hermansen, K. (Kjeld), Dragsted, L. O. (Lars O.), Gunnarsdottir, I. (Ingibjörg), Cloetens, L. (Lieselotte), Storm, M. U. (Matilda Ulmius), Åkesson, B. (Björn), Rosqvist, F. (Fredrik), Hukkanen, J. (Janne), Herzig, K. (Karl‐Heinz), Risérus, U. (Ulf), Thorsdottir , I. (Inga), Poutanen, K. S. (Kaisa S.), Savolainen, M. J. (Markku J), Schwab, U. (Ursula), Arner, P. (Peter), Uusitupa, M. (Matti), and Ulven, S. M. (Stine M.)
Abstract: Scope: To explore the effect of a healthy Nordic diet on the global transcriptome profile in peripheral blood mononuclear cells (PBMCs) of subjects with metabolic syndrome. Methods and results: Subjects with metabolic syndrome undergo a 18/24 week randomized intervention study comparing an isocaloric healthy Nordic diet with an average habitual Nordic diet served as control (SYSDIET study). Altogether, 68 participants are included. PBMCs are obtained before and after intervention and total RNA is subjected to global transcriptome analysis. 1302 probe sets are differentially expressed between the diet groups (p‐value < 0.05). Twenty‐five of these are significantly regulated (FDR q‐value < 0.25) and are mainly involved in mitochondrial function, cell growth, and cell adhesion. The list of 1302 regulated probe sets is subjected to functional analyses. Pathways and processes involved in the mitochondrial electron transport chain, immune response, and cell cycle are downregulated in the healthy Nordic diet group. In addition, gene transcripts with common motifs for 42 transcription factors, including NFR1, NFR2, and NF‐κB, are downregulated in the healthy Nordic diet group. Conclusion: These results suggest that benefits of a healthy diet may be mediated by improved mitochondrial function and reduced inflammation.
Published: 2019

24. An isocaloric nordic diet modulates rela and tnfrsf1a gene expression in peripheral blood mononuclear cells in individuals with metabolic syndrome—a sysdiet sub-study

Author: Ulven, S. M. (Stine M.), Holven, K. B. (Kirsten B.), Rundblad, A. (Amanda), Myhrstad, M. C. (Mari C. W.), Leder, L. (Lena), Dahlman, I. (Ingrid), de Mello, V. D. (Vanessa D.), Schwab, U. (Ursula), Carlberg, C. (Carsten), Pihlajamäki, J. (Jussi), Hermansen, K. (Kjeld), Dragsted, L. O. (Lars O.), Gunnarsdottir, I. (Ingibjörg), Cloetens, L. (Lieselotte), Åkesson, B. (Björn), Rosqvist, F. (Fredrik), Hukkanen, J. (Janne), Herzig, K.-H. (Karl-Heinz), Savolainen, M. J. (Markku J.), Risérus, U. (Ulf), Thorsdottir, I. (Inga), Poutanen, K. S. (Kaisa S.), Arner, P. (Peter), Uusitupa, M. (Matti), Kolehmainen, M. (Marjukka), Ulven, S. M. (Stine M.), Holven, K. B. (Kirsten B.), Rundblad, A. (Amanda), Myhrstad, M. C. (Mari C. W.), Leder, L. (Lena), Dahlman, I. (Ingrid), de Mello, V. D. (Vanessa D.), Schwab, U. (Ursula), Carlberg, C. (Carsten), Pihlajamäki, J. (Jussi), Hermansen, K. (Kjeld), Dragsted, L. O. (Lars O.), Gunnarsdottir, I. (Ingibjörg), Cloetens, L. (Lieselotte), Åkesson, B. (Björn), Rosqvist, F. (Fredrik), Hukkanen, J. (Janne), Herzig, K.-H. (Karl-Heinz), Savolainen, M. J. (Markku J.), Risérus, U. (Ulf), Thorsdottir, I. (Inga), Poutanen, K. S. (Kaisa S.), Arner, P. (Peter), Uusitupa, M. (Matti), and Kolehmainen, M. (Marjukka)
Abstract: A healthy dietary pattern is associated with a lower risk of metabolic syndrome (MetS) and reduced inflammation. To explore this at the molecular level, we investigated the effect of a Nordic diet (ND) on changes in the gene expression profiles of inflammatory and lipid-related genes in peripheral blood mononuclear cells (PBMCs) of individuals with MetS. We hypothesized that the intake of an ND compared to a control diet (CD) would alter the expression of inflammatory genes and genes involved in lipid metabolism. The individuals with MetS underwent an 18/24-week randomized intervention to compare a ND with a CD. Eighty-eight participants (66% women) were included in this sub-study of the larger SYSDIET study. Fasting PBMCs were collected before and after the intervention and changes in gene expression levels were measured using TaqMan Array Micro Fluidic Cards. Forty-eight pre-determined inflammatory and lipid related gene transcripts were analyzed. The expression level of the gene tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) was down-regulated (p = 0.004), whereas the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) subunit, RELA proto-oncogene, was up-regulated (p = 0.016) in the ND group compared to the CD group. In conclusion, intake of an ND in individuals with the MetS may affect immune function.
Published: 2019

25. Long-term thiazide use and risk of low-energy fractures among persons with Alzheimer’s disease:nested case-control study

Author: Taipale, H. (H.), Rysä, J. (J.), Hukkanen, J. (J.), Koponen, M. (M.), Tanskanen, A. (A.), Tiihonen, J. (J.), Kröger, H. (H.), Hartikainen, S. (S.), Tolppanen, A.-M. (A.-M.), Taipale, H. (H.), Rysä, J. (J.), Hukkanen, J. (J.), Koponen, M. (M.), Tanskanen, A. (A.), Tiihonen, J. (J.), Kröger, H. (H.), Hartikainen, S. (S.), and Tolppanen, A.-M. (A.-M.)
Abstract: Summary: We investigated the association between thiazide use and the risk of low-energy fractures among community dwellers with Alzheimer’s disease. Longer use was associated with a decreased risk of low-energy fractures. This study extends the previous knowledge of reduced fracture risk of thiazides to persons with Alzheimer’s disease. Introduction: To investigate the association between thiazide use and the risk of low-energy fractures (LEF), and hip fracture among community dwellers with Alzheimer’s disease (AD). No prior study has evaluated the effect of thiazides on LEF risk of AD patients. Methods: LEF cases were identified from the MEDALZ study, including all community-dwelling persons diagnosed with AD in Finland 2005–2011. During the follow-up from AD diagnoses until the end of 2015, cases with LEF (N = 10,416) and hip fracture (N = 5578) were identified. LEF cases were matched with up to three controls without LEF, according to time since AD diagnosis, age and gender. Thiazide use identified from the Prescription register data was modeled with PRE2DUP method. Current use was defined in 0–30 days’ time window before the fracture/matching date, and duration of current use was assessed. The association between thiazide exposure and LEFs was assessed with conditional logistic regression. Results: Current thiazide use was observed in 10.5% of LEF cases and 12.5% of controls. Current thiazide use was associated with a decreased risk of LEF (adjusted OR [aOR] 0.83, 95% CI 0.77–0.88). In terms of the duration of use, no association was observed with short-term use (< 1 year or 1–3 years), while longer use (> 3 years) was associated with a reduced risk of LEF (aOR 0.77, 95% CI 0.71–0.83) and hip fracture (aOR 0.68, 95% CI 0.60–0.78). Conclusions: Our study extends the previous knowledge of reduced fracture risk of thiazides to persons with AD, a population with significantly increased background risk of fractures.
Published: 2019

26. Liraglutide and Renal Outcomes in Type 2 Diabetes

Author: Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, Tornøe K, Zinman B, Buse JB, LEADER Steering Committee and Investigators. 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Odugbesan A, Oliver M, Oliver T, Olmeda C, O'Neil C, Oremus R, Ortega T, Ortiz-Santos S, Osborn T, Padmanabhan S, Papacostea O, Park I, Parker A, Parker K, Parker R, Patel C, Patel M, Patel R, Patino M, Patterson S, Paulson K, Paz A, Pemba R, Pepe C, Perez J, Perez T, Perry D, Phillips B, Phillips J, Pickett A, Pinson M, Pitzer R, Poduri M, Poehls J, Poteat T, Powell L, Prasad S, Prevost J, Price E, Priest D, Prieto L, Purewal T, Purighalla R, Purighalla U, Quadrel M, Qureshi A, Radhamma R, Rafla E, Rajab H, Ramalingam R, Ramirez A, Ramirez J, Ramirez K, Ramirez M, Randall M, Rangaraj U, Rao V, Rasmussen P, Rasouli N, Ray A, Reed J, Rems L, Renaud K, Reno M, Resnick M, Reusch J, Reynolds L, Rhoton K, Rhudy J, Ricci C, Rice L, Richardson A, Richardson L, Rickard H, Rickels M, Riff D, Rightenour N, Risser J, Rizvi A, Robertson J, Robinson A, Robinson R, Rockwell M, Rodriguez JP, Rodriguez M, Rojas M, Rojas W, Rooker-Morris L, Root C, Rose M, Rosenberg R, Rosenstock J, Roth M, Ruby R, 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C, Wise J, Witte M, Wittenmyer J, Wood C, Wood R, Woodruff C, Worthington B, Wynn D, Wysham C, Xavier P, Yela S, Yenoby L, Young L, Younus N, Yourell V, Zaid M, Zubair I., Mann, Jfe, Ørsted, Dd, Brown-Frandsen, K, Marso, Sp, Poulter, Nr, Rasmussen, S, Tornøe, K, Zinman, B, Buse, Jb, Bergenstal R, LEADER Steering Committee and Investigators., Daniels, G, Moses, Ac, Nauck, M, Nissen, S, Pocock, S, Steinberg, W, Stockner, M, Kristensen, P, Ravn, L, Zychma, M, Flyvbjerg, A, Ford, I, Kloos, Rt, Schactman, Mj, Sleight, P, Swedberg, K, Tenner, Sm, Akalın, S, Arechavaleta, R, Bain, S, Babkowski, Mc, Benroubi, M, Berard, L, Comlekci, A, Czupryniak, L, Eliasson, B, Eriksson, M, Fonseca, V, Franek, E, Gross, J, Hafidh, K, Haluzik, M, Hayes, F, Huang, Yy, Jacob, S, Kaddaha, G, Khalil, A, Kilhovd, B, Laakso, M, Leiter, L, Lalic, N, Ji, L, Luedemann, J, Mannucci, E, Marre, M, Masmiquel, L, Mota, M, Omar, M, O’Shea, D, Pan, C, Petrie, J, Pieber, T, Pratley, R, Raz, I, Rea, R, Rutten, G, Satman, I, 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S, Pechmann, L, Costa da Penha, P, Perlamagna, L, Perotta, B, Pimentel, L, Pinto, M, Poço, C, Ponte, C, Prazeres, P, Quintao, E, Raduan, R, Rassi, Dt, Rassi, N, Reck, L, Montenegro, R Jr, Ribeiro, R, Rodovalho, S, Silveira Rodrigues, G, Rollin, G, Rossi, S, Sabino, C, Sales, Ap, Salles, J, Sampaio, Cr, Santana, L, Sato, V, da Silva Santos, M, Santos, Nl, Santos, R, Saraiva, J, Sartori, C, Sena, R, Sevilha, M, Sgarbi, J, Silva, D, D'albuquerque Silva, L, Silva, Me, Siqueira, K, Soares, S, Sobreira, W, Sousa, B, Souza, Ac, Souza, B, Tambascia, M, Tarantino, R, Tenor, F, Tomarchio, M, Triches, C, Tristão, Lj, Valenti, A, Vasques, E, Vencio, S, Vianna, A, Munhoz Vidotto, T, Vieira, S, Villar, H, Visconti, G, Volaco, A, Wajchenberg, B, Zanatta, L, Zimmerman, L, Abbott, Ec, Abu-Bakare, A, Advani, A, Allison, R, Bishara, P, Bowering, Ck, Cheng, A, Chouinard, S, Clayton, D, Conway, J, D'Amours, M, de Tugwell, B, Deyoung, P, D'Ignazio, G, Dube, F, Ekoe, Jm, Fagan, S, Garceau, C, Gottesman, I, 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Madireddy, S, Mae, L, Mahakala, A, Maheshwari, H, Malbari, H, Maldonado, N, Mallitz, M, Mandviwala, M, Mann, K, Mardahay, M, Marino, J, Marney, A, Marshall, L, Martin, A, Martin, E, Martinez, G, Martinez-Miss, S, Marx, P, Massara, L, Mastoor, M, Matfin, G, Maturu, A, Maurides, P, May, M, Mayfield, R, Maynard, B, Mazza, A, Mccann, K, Mccoy, J, Mccoy, T, Mccullen, Mk, Mcdaniel, C, Mcdaniel, Am, Mcdermott, M, Mcdonald, A, Mcmasters, B, Mcmurray, C, Medlin, T, Meinel, M, Mendez, I, Menefee, J, Meredith, M, Merriweather, M, Mersey, J, Messino, C, Meyer, S, Meyers, L, Michael, D, Midyett, C, Miklius, A, Milford, E, Miller, B, Miller, H, Milligan, M, Minor, A, Miranda-Palma, B, Mirarchi, N, Mittadodla, S, Mittle, J, Moffat, A, Mohaupt, S, Mohiuddin, K, Mokshagundam, S, Monaco, S, Monsaert, R, Montano-Pereira, C, Montgomery, A, Moody, K, Moon, M, Moore, D, Moore, L, Morawski, E, Moreau, C, Morin, D, Moscoa, C, Motzkin, C, Mueller, R, Munoz, C, Munoz, M, Myneni, A, Naderi, B, Nagireddy, P, 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Resnick, M, Reusch, J, Reynolds, L, Rhoton, K, Rhudy, J, Ricci, C, Rice, L, Richardson, A, Richardson, L, Rickard, H, Rickels, M, Riff, D, Rightenour, N, Risser, J, Rizvi, A, Robertson, J, Robinson, A, Robinson, R, Rockwell, M, Rodriguez, Jp, Rodriguez, M, Rojas, M, Rojas, W, Rooker-Morris, L, Root, C, Rose, M, Rosenberg, R, Rosenstock, J, Roth, M, Ruby, R, Sachson, R, Sack, P, Sadler, Rk, Sahai, S, J, Salazar, Salgam, M, Samal, A, Samson, A, Sanagorski, R, Sanchez, A, Sandberg, J, Sanderson, M, Sandoval, J, Santiago, E, Sapp, T, Saunders, J, Schill, J, Schott, C, Schreiman, R, Schu, D, Schuh, K, Schutta, M, Schwartz, J, Schweppe, L, Scofield, H, Scribner, A, Seal, J, Sealock, J, Seaton, B, Sedlak-Hanslik, T, Seekins, K, Segal, M, Seggelke, S, Semenza, S, Sentman, P, Serra, M, Seshadri, P, Sevilla, E, Shah, S, Shaheen, K, Shanik, M, Shaw, J, Sheets, M, Shellabarger, C, Sher, J, Shippey, J, Shivaswamy, V, Shomali, M, Shore, D, Shroff, P, Siddiqui, T, Siegwald, A, Silver, R, Simmons, D, 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E, Vazquez, M, Vickery, D, Villafuerte, B, Villegas, C, Vivar, J, Vivekananthan, K, Vo, G, Vukojicic, K, Wachter, A, Wahl, D, Waitmann, J, Walker, D, Walsh, J, Walsh, K, Walton, A, Wang, A, Wardell, K, Watkins, S, Watkinson, J, Watts, M, Watwe, V, Weaver, N, Weber, R, Wedick, C, Weeks, D, Weeks, L, Weindorff, K, Weinstein, R, Weiss, S, Wenger, K, Wentworth, M, Werner, A, West, M, Whelan, S, White, B, White, J, Whitmire, M, Whittington, R, Wical, J, Wigley, C, Wilkins, F, Will, K, Williams, A, Wilson, Le, Wince, M, Wine, S, Winkle, P, Winner, C, Wise, J, Witte, M, Wittenmyer, J, Wood, C, Wood, R, Woodruff, C, Worthington, B, Wynn, D, Wysham, C, Xavier, P, Yela, S, Yenoby, L, Young, L, Younus, N, Yourell, V, Zaid, M, Zubair, I., Mann J.F.E., Orsted D.D., Brown-Frandsen K., Marso S.P., Poulter N.R., Rasmussen S., Tornoe K., Zinman B., Buse J.B., and Buscemi S.
Subjects: Male, Settore MED/09 - Medicina Interna, Acute Kidney Injury, Aged, Albuminuria, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Double-Blind Method, Female, Follow-Up Studies, Glomerular Filtration Rate, Glucagon-Like Peptide 1, Humans, Hypoglycemic Agents, Intention to Treat Analysis, Kidney Failure, Chronic, Liraglutide, Middle Aged, Type 2 diabetes, 030204 cardiovascular system & hematology, urologic and male genital diseases, GLOMERULAR-FILTRATION-RATE, KIDNEY-FUNCTION, DISEASE, law.invention, Kidney Failure, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Settore MED/49 - Scienze Tecniche Dietetiche Applicate, Chronic, RISK, Kidney, Acute kidney injury, 11 Medical And Health Sciences, General Medicine, medicine.anatomical_structure, TRIAL, liraglutide, randomized controlled trial, type 2 diabetes, renal outcomes, Life Sciences & Biomedicine, Type 2, medicine.drug, medicine.medical_specialty, Renal function, 030209 endocrinology & metabolism, CARDIOVASCULAR OUTCOMES, Follow-Up Studie, 03 medical and health sciences, Medicine, General & Internal, General & Internal Medicine, Diabetes mellitus, Internal medicine, Diabetes Mellitus, Intensive care medicine, Science & Technology, business.industry, MORTALITY, medicine.disease, INTENSIVE GLUCOSE CONTROL, INDIVIDUALS, chemistry, Diabetic Nephropathie, LEADER Steering Committee and Investigators, business
Abstract: BACKGROUND: In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown. METHODS: We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. RESULTS: A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively). CONCLUSIONS: This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .).
Published: 2017

27. Resurssiperiferian muotoutuminen Suomessa

Author: Hukkanen, J.-P. (Juho-Pekka)
Subjects: Geography
Abstract: Tässä tutkielmassa olen pyrkinyt selvittämään sitä, ovatko Suomen kaupunkien ulkopuoliset alueet muuttumassa entistä selkeämmin resurssiperiferiaksi. Tutkielman teoriaosuudessa käyn läpi tilaa, keskus–periferia-mallia sekä arvonlisän muodostusta ja arvonlisän siirtymistä tilassa. Näistä osista rakennan tämän tutkielman teoreettisen viitekehyksen. Tarkastelen myös luonnonvaran ja resurssin käsitteitä, jotta resurssiperiferian konteksti täydentyisi. Tutkimusaineistonani olen käyttänyt aluepoliittisia luonnonvarojen hyödyntämiseen liittyviä suunnitelmia, joita valtio, maakunnan liitto ja kunta ovat tuottaneet. Tämä on samalla luonut tutkielmalle maantieteellisen rajauksen; tarkastelussa on Suomen valtio, Pohjois-Savon maakunta sekä Vieremän kunta. Tutkimusmetodeinani ovat olleet diskurssianalyysi ja CPE (cultural political economy), joiden avulla tutkimusaineistosta pystyy etsimään piilotettuja merkityksiä, kannanottoja ja tavoitteita. Tutkimustuloksieni mukaan talous on nykyään hyvin vallitseva aihe ja tärkein tavoite aluepoliittisissa suunnitelmissa. Luonnonvarojen hyödyntämistä halutaan lisätä, mutta tämä tavoite näyttäytyy melko kapeasti lähinnä yritysten toimintaedellytysten parantamisena. Tutkimusaineistossa mainitaan monia muitakin tavoitteita (esim. huoltovarmuus, työpaikat syrjäseuduilla), mutta ne ovat selvästi sivuosassa tai päätavoitteen sivutuote. Monia maailmalla vaikuttavia kehityskulkuja, kuten ilmastonmuutosta ja kilpailua käsitellään uhkina sekä käytetään perusteluina sille, miksi Suomen olisi suorastaan välttämätöntä lisätä luonnonvarojensa hyödyntämistä. Juuri vahva ja yksipuolinenkin keskittyminen luonnonvarojen hyödyntämiseen yritysten liiketoiminnassa, eli arvonmuodostukseen näyttää teoriakirjallisuuden perusteella merkiltä siitä, että luonnonvaroja tuottavien seutujen asema olisi yksipuolistumassa resurssiperiferiaksi. Laajempi keskustelu aluepolitiikan tavoitteista olisi hyväksi siinäkin tapauksessa, että asioita tarkastellaan talouden näkökulmasta. Arvonmuodostuksen mahdollisia seurauksia periferian kannalta, kuten ympäristöongelmia tai arvonlisän siirtymistä pois periferiasta pitäisi huomioida. Myös huoltovarmuus luonnonvarojen hyödyntämiseen liittyen (ruokaturva, energiaomavaraisuus) olisi hyvä aihe pohdittavaksi enemmän myös aluepolitiikan suunnitelmissa.
Published: 2018

28. Quantitative analysis of 4β- and 4α‑hydroxycholesterol in human plasma and serum by UHPLC/ESI-HR-MS

Author: Hautajärvi, H. (Heidi), Hukkanen, J. (Janne), Turpeinen, M. (Miia), Mattila, S. (Sampo), Tolonen, A. (Ari), Hautajärvi, H. (Heidi), Hukkanen, J. (Janne), Turpeinen, M. (Miia), Mattila, S. (Sampo), and Tolonen, A. (Ari)
Abstract: Cholesterol oxidation product 4β‑hydroxycholesterol (4β‑OHC) may possibly be used as an endogenous biomarker of CYP3A enzyme activity and as CYP3A4 is involved in the metabolism of approximately 50% of the drugs in clinical use, the monitoring of CYP3A activity by 4β‑OHC plasma or serum levels, may be of clinical significance. The plasma and serum concentrations of 4α‑hydroxycholesterol (4α‑OHC), an isomer of 4β‑OHC, increase during uncontrolled storage conditions and therefore serve as an indicator of proper handling of samples. A sensitive and simple high-throughput method for the simultaneous quantification of both 4α‑OHC and 4β‑OHC in human plasma and serum was developed utilizing ultrahigh performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC/ESI-HR-MS). The chromatographic analysis was carried out on a Waters HSS T3 C18 reversed phase column with a mobile phase composed of 0,1% formic acid with 200 mg/l sodium acetate, and methanol. 4β‑OHC and 4α‑OHC and also internal standard d7‑4β‑OHC were monitored using HR-MS as sodium adducts, which could not be used as a precursor ions in conventional tandem mass spectrometry methods due to their extensive stability in collision for MS/MS. The use of HR-MS detection enabled avoiding laborious sample derivatization, which is required with triple quadrupole mass spectrometer-based methods to achieve adequate analytical sensitivity for 4β‑OHC, as the underivatized molecule is otherwise poorly ionized to other molecular ions than sodium adduct. Chromatographic separation of 4α‑OHC and 4β‑OHC was obtained and confirmed with standard samples prepared in blank surrogate matrix. The lower limits of quantitation in the assay were 0.5 ng/ml for 4β‑OHC, and 2 ng/ml for 4α‑OHC. Endogenous levels of 4β‑OHC can vary between 10 and 100 ng/ml depending on the possible induction or inhibition of CYP3A4, whereas the levels of 4α‑OHC can vary between 5 and 100 ng/ml, depending on the storage condi
Published: 2018

29. Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver

Author: Hassani-Nezhad-Gashti, F. (Fatemeh), Rysä, J. (Jaana), Kummu, O. (Outi), Näpänkangas, J. (Juha), Buler, M. (Marcin), Karpale, M. (Mikko), Hukkanen, J. (Janne), Hakkola, J. (Jukka), Hassani-Nezhad-Gashti, F. (Fatemeh), Rysä, J. (Jaana), Kummu, O. (Outi), Näpänkangas, J. (Juha), Buler, M. (Marcin), Karpale, M. (Mikko), Hukkanen, J. (Janne), and Hakkola, J. (Jukka)
Abstract: Pregnane X receptor (PXR) is a nuclear receptor that senses chemical environment and is activated by numerous clinically used drugs and environmental contaminants. Previous studies have indicated that several drugs known to activate PXR appear to induce glucose intolerance. We now aimed to reveal the role of PXR in drug-induced glucose intolerance and characterize the mechanisms involved. We used PXR knockout mice model to investigate the significance of this nuclear receptor in the regulation of glucose tolerance. PXR ligand pregnenolone-16ɑ-carbonitrile (PCN) impaired glucose tolerance in the wildtype mice but not in the PXR knockout mice. Furthermore, DNA microarray and bioinformatics analysis of differentially expressed genes and glucose metabolism relevant pathways in PCN treated primary hepatocytes indicated that PXR regulates genes involved in glucose uptake. PCN decreased the expression of glucose transporter 2 (GLUT2) in mouse liver and in the wildtype mouse hepatocytes but not in the PXR knockout cells. Data mining of published chromatin immunoprecipitation-sequencing results indicate that Glut2 gene is a direct PXR target. Furthermore, PCN induced internalization of GLUT2 protein from the plasma membrane to the cytosol in the liver in vivo and repressed glucose uptake in the primary hepatocytes. Our results indicate that the activation of PXR impairs glucose tolerance and thus PXR represents a novel diabetogenic pathway. PXR activation dysregulates GLUT2 function by two different mechanisms. These findings may partly explain the diabetogenic effects of medications and environmental contaminants.
Published: 2018

30. Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism

Author: Ukkola, O. (Olavi), Hukkanen, J. (Janne), Käräjämäki, A. (Aki), Ukkola, O. (Olavi), Hukkanen, J. (Janne), and Käräjämäki, A. (Aki)
Abstract: Obesity, insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) form a dangerous quartet which threatens human health all over the world. About 25% of adults around the world have NAFLD, which poses risks for cardiovascular and metabolic well-being and may develop into liver cirrhosis and hepatocellular carcinoma. Apart from lifestyle modification, treatment options for NAFLD are scarce. This thesis presents atrial fibrillation (AF) as a new complication of NAFLD among general population of 958 individuals aged 40–60 years participating in the OPERA study. Even after multiple-adjustments for confounding factors, ultrasound-based NAFLD predicted the development of AF during about 16 years of follow-up. Moreover, the association between AF and liver fibrosis in 76 individuals aged 64–82 years in a cross-sectional setting is presented. The thesis also shows that individuals with metabolic syndrome (MetS), with or without NAFLD, are at increased risk of cardiovascular events, T2D and the increase of left ventricular mass index in a study population of 958 individuals aged 40–60 years during a 20-year follow-up. In other words, NAFLD without MetS does not seem to expose to these three cardiometabolic complications. The thesis also shows that rifampicin-activated pregnane X receptor (PXR), a member of the nuclear receptor superfamily of ligand-activated transcription factors with several endobiotic and xenobiotic activators, increases serum levels of cholesterol, phospholipids and certain fatty acids, assessed by nuclear magnetic resonance metabolomics technique, in a randomized, open, placebo-controlled trial among 34 young and healthy individuals. These serum lipids are considered toxic lipids and capable of transforming hepatosteatosis into steatohepatitis and even more severe forms of NAFLD. Moreover, rifampicin-activated PXR has no effect on serum triglycerides, that are non-toxic lipids, or triglyceride accumulation in the l, Tiivistelmä Maailmanlaajuisesti noin 25% täysi-ikäisistä henkilöistä sairastaa alkoholinkäyttöön liittymätöntä rasvamaksaa. Sen tiedetään altistavan sydän- ja verisuonisairauksille, aineenvaihduntahäiriöille, maksakirroosille ja jopa maksasyövälle, mutta elämäntapahoitoa lukuun ottamatta hoitomahdollisuudet ovat toistaiseksi vähäisiä. Tässä väitöskirjassa osoitetaan ensimmäistä kertaa alkoholinkäyttöön liittymättömän rasvamaksan ennustavan itsenäisesti eteisvärinän ilmaantuvuutta noin 16 vuoden seurannan aikana 958 tavallisen keski-ikäisen ihmisen aineistossa osana OPERA-tutkimusta. Lisäksi väitöskirjassa osoitetaan maksan sidekudosmuodostuksen ja eteisvärinän välillä olevan yhteys poikkileikkausasetelmassa 76 iäkkään ihmisen muodostamassa aineistossa. Väitöstutkimuksessa havaittiin myös, että metabolista oireyhtymää sairastavilla henkilöillä on suurentunut tyypin 2 diabeteksen, sydän- ja verisuonisairauksien sekä vasemman kammion koon suurentumisen riski noin 20 vuoden seurannan aikana 958 tutkittavan henkilön aineistossa riippumatta siitä, onko heillä alkoholinkäyttöön liittymätön rasvamaksa. Toisin sanoen alkoholin käyttöön liittymätön rasvamaksa ilman metabolista oireyhtymää ei lisää edellä mainittujen kolmen sairauden riskiä. Väitöstutkimuksessa esitetään lisäksi, että rifampisiinilla aikaansaatu maksan pregnane X -reseptorin aktivaatio johtaa seerumin fosfolipidien, tiettyjen rasvahappojen sekä usean eri kolesterolityypin lisääntymiseen 34 terveen nuoren henkilön aineistossa. Kirjallisuudessa näiden seerumin rasva-aineiden on esitetty aiheuttavan alkoholin käyttöön liittymätöntä maksatulehdusta ja jopa rasvamaksan vakavimpia muotoja. Toisaalta rifampisiini ei lisännyt seerumin triglyseridipitoisuutta eikä aiheuttanut magneettitutkimuksella mitattuna triglyseridien kertymistä maksaan 15 terveen nuoren henkilön aineistossa. Tämä väitöstutkimus antaa lisätietoa rasvamaksan kehittymisestä, rasva-aineenvaihdunnasta ja komplikaatioista sekä korostaa rasvamaksan moni
Published: 2017

31. The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

Author: Hukkanen, J., Puurunen, J., Hyötyläinen, Tuulia, Savolainen, M. J., Ruokonen, A., Morin-Papunen, L., Oresic, Matej, Piltonen, T., Tapanainen, J. S., Hukkanen, J., Puurunen, J., Hyötyläinen, Tuulia, Savolainen, M. J., Ruokonen, A., Morin-Papunen, L., Oresic, Matej, Piltonen, T., and Tapanainen, J. S.
Abstract: Aims: Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C). Methods: In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20mg day1 (n=15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α- epoxycholesterol ratios were used as negative controls. Results: Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference – 0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α- epoxycholesterol to cholesterol did not change. Conclusions: The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations., Cited By :4; Export Date: 12 March 2018; ArticleFunding Agencies:Duodecim Society of Oulu Finnish Medical Foundation Sigrid Juselius Foundation National Clinical Graduate School Research Foundation of Obstetrics and Gynecology Oulu University Scholarship Foundation North Ostrobothnia Regional Fund of the Finnish Cultural FoundationTyyni Tani Foundation of the University of Oulu Finnish-Norwegian Medical Foundation
Published: 2015
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32. Role of xenobiotic-sensing nuclear receptor PXR in lipid, cholesterol, and bone metabolism

Author: Abdelfattah, H. N. (Heba Nabil), Hakkola, J. (Jukka), and Hukkanen, J. (Janne)
Subjects: liver steatosis, AFOS, 4βHC, PXR, kolesteroli, PCN, ALP, cholesterol, atorvastatin, rifampisiini, rifampicin, atorvastatiini, maksan rasvoittuminen
Abstract: The pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, is a key regulator of drug and xenobiotic metabolism. Additionally, PXR regulates hepatic glucose, lipid, cholesterol, and bile acid metabolism, and inflammation. However, the mechanisms and consequences are still poorly understood. I investigated the role of PXR in the regulation of lipid metabolism and bone homeostasis. Specifically, I studied the effect of the two different PXR activators, atorvastatin and pregnenolone 16α-carbonitrile (PCN), on the hepatic transcriptome in mice. Furthermore, I studied the roles of PXR and oxysterols on reverse cholesterol transport. I also studied the role of PXR in human osteoblasts cells. This study demonstrated that atorvastatin (the most prescribed hypocholesterolemic drug in humans) regulates hepatic cholesterol and lipid synthesis PXR-dependently, but the response is distinct from PCN. Unlike PCN, atorvastatin does not induce liver steatosis. Neither PCN nor atorvastatin had a harmful effect on glucose tolerance in the high-fat diet-fed mice. In healthy volunteers treated with rifampicin, the plasma 4β-hydroxycholesterol (4βHC) was elevated compared to placebo. 4βHC is an agonist of the liver X receptor (LXR), a major regulator of lipid metabolism. In vitro studies revealed that incubation of macrophages with 4βHC represses cholesterol influx and induces efflux in macrophages. Furthermore, rifampicin increased alkaline phosphatase (ALP) plasma levels, particularly the bone specific-ALP. In vitro studies demonstrated that this is most likely via the direct effect of rifampicin in osteocytes. However, the role of PXR in this process remains unclear. Altogether, the results presented in this thesis reveal novel roles of PXR in the regulation of cholesterol and lipid metabolism. PXR mediates the atorvastatin effect on the hepatic transcriptome, particularly on the hepatic cholesterol metabolism. Moreover, through the 4βHC-LXR axis, PXR could be a novel link between hepatic xenobiotic exposure and the regulation of cholesterol transport in peripheral tissues. Tiivistelmä Pregnaani X-reseptori (PXR) on ksenobiooteja aistiva tumareseptori, ja se on keskeinen lääke- ja vierasainemetabolian säätelijä. Tämän lisäksi PXR säätelee maksan glukoosi-, lipidi-, kolesteroli-, ja sappihappometaboliaa ja tulehdusta. Näiden säätelytoimintojen mekanismit ja seuraukset ymmärretään kuitenkin edelleen puutteellisesti. Tutkimuksessani selvitin PXR välitteisen säätelyn merkitystä lipidiaineenvaihdunnalle ja luun homeostaasille. Tarkemmin ottaen tutkin kahden erilaisen PXR-aktivaattorin, atorvastatiinin ja pregnenoloni-16α-karbonitriilin (PCN) vaikutuksia maksan transkriptomiin, PXR:n ja oksisterolien osallisuutta käänteiseen kolesterolin kuljetukseen, sekä PXR:n toimintaa ihmisen osteoblastisoluissa. Tämä tutkimus osoitti, että atorvastatiini (eniten ihmisillä käytetty kolesterolia alentava lääke) säätelee maksan kolesteroli- ja lipidisynteesiä PXR-välitteisesti, mutta vaste poikkeaa PCN:n aiheuttamasta vasteesta. PCN:stä poiketen atorvastatiini ei aiheuta maksan rasvoittumista. PCN:llä ja atorvastatiinilla ei kummallakaan ollut haitallisia vaikutuksia glukoosin sietoon hiirillä, joita oli ruokittu paljon rasvaa sisältävällä ruokavaliolla. Rifampisiinin annostelu terveille vapaaehtoisille nosti plasman 4β-hydroksikolesterolia (4βHC) verrattuna plaseboon. 4βHC on keskeisen lipidimetabolian säätelijän, maksan X-reseptorin (LXR) agonisti. In vitro -tutkimukset osoittivat, että makrofagien inkubointi 4βHC:n kanssa vähensi kolesterolin influksia ja lisäsi sen effluksia makrofageissa. Rifampisiini myös lisäsi alkalisen fosfataasin (AFOS) plasmapitoisuutta erityisesti luuspesifisen AFOS:n osalta. In vitro -tutkimukset osoittivat tämän todennäköisesti johtuvan rifampisiinin suorista vaikutuksista osteosyytteihin. PXR:n rooli tässä prosessissa jäi kuitenkin avoimeksi. Kokonaisuutena tämän väitöskirjatutkimuksen tulokset paljastivat uusia mekanismeja, joilla PXR säätelee kolesteroli- ja lipidiaineenvaihduntaa. PXR välittää atorvastatiinin vaikutuksen maksan transkriptomiin, ja aivan erityisesti kolesterolimetabolian osalta. Lisäksi PXR voi olla uusi tekijä, joka yhdistää maksan ksenobioottialtistuksen kolesterolin perifeerisissä kudoksissa tapahtuvan kuljetuksen säätelyyn 4βHC-LXR-akselin välittämänä.
Published: 2022

33. Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism

Author: Käräjämäki, A. (Aki), Ukkola, O. (Olavi), and Hukkanen, J. (Janne)
Subjects: alkoholin käyttöön liittymätön rasvamaksa, pregnane X receptor, maksafibroosi, tyypin 2 diabetes, pregnaani X reseptori, non-alcoholic fatty liver disease, atrial fibrillation, type 2 diabetes, sydän- ja verisuonisairaudet, eteisvärinä, cardiovascular diseases, liver fibrosis
Abstract: Obesity, insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) form a dangerous quartet which threatens human health all over the world. About 25% of adults around the world have NAFLD, which poses risks for cardiovascular and metabolic well-being and may develop into liver cirrhosis and hepatocellular carcinoma. Apart from lifestyle modification, treatment options for NAFLD are scarce. This thesis presents atrial fibrillation (AF) as a new complication of NAFLD among general population of 958 individuals aged 40–60 years participating in the OPERA study. Even after multiple-adjustments for confounding factors, ultrasound-based NAFLD predicted the development of AF during about 16 years of follow-up. Moreover, the association between AF and liver fibrosis in 76 individuals aged 64–82 years in a cross-sectional setting is presented. The thesis also shows that individuals with metabolic syndrome (MetS), with or without NAFLD, are at increased risk of cardiovascular events, T2D and the increase of left ventricular mass index in a study population of 958 individuals aged 40–60 years during a 20-year follow-up. In other words, NAFLD without MetS does not seem to expose to these three cardiometabolic complications. The thesis also shows that rifampicin-activated pregnane X receptor (PXR), a member of the nuclear receptor superfamily of ligand-activated transcription factors with several endobiotic and xenobiotic activators, increases serum levels of cholesterol, phospholipids and certain fatty acids, assessed by nuclear magnetic resonance metabolomics technique, in a randomized, open, placebo-controlled trial among 34 young and healthy individuals. These serum lipids are considered toxic lipids and capable of transforming hepatosteatosis into steatohepatitis and even more severe forms of NAFLD. Moreover, rifampicin-activated PXR has no effect on serum triglycerides, that are non-toxic lipids, or triglyceride accumulation in the liver, assessed by magnetic resonance imaging, in 15 young and healthy individuals. In conclusion, this thesis advances the knowledge in the pathogenesis, lipid metabolism, complications and heterogeneous nature of NAFLD. These may have implications for patient care and follow-up. Tiivistelmä Maailmanlaajuisesti noin 25% täysi-ikäisistä henkilöistä sairastaa alkoholinkäyttöön liittymätöntä rasvamaksaa. Sen tiedetään altistavan sydän- ja verisuonisairauksille, aineenvaihduntahäiriöille, maksakirroosille ja jopa maksasyövälle, mutta elämäntapahoitoa lukuun ottamatta hoitomahdollisuudet ovat toistaiseksi vähäisiä. Tässä väitöskirjassa osoitetaan ensimmäistä kertaa alkoholinkäyttöön liittymättömän rasvamaksan ennustavan itsenäisesti eteisvärinän ilmaantuvuutta noin 16 vuoden seurannan aikana 958 tavallisen keski-ikäisen ihmisen aineistossa osana OPERA-tutkimusta. Lisäksi väitöskirjassa osoitetaan maksan sidekudosmuodostuksen ja eteisvärinän välillä olevan yhteys poikkileikkausasetelmassa 76 iäkkään ihmisen muodostamassa aineistossa. Väitöstutkimuksessa havaittiin myös, että metabolista oireyhtymää sairastavilla henkilöillä on suurentunut tyypin 2 diabeteksen, sydän- ja verisuonisairauksien sekä vasemman kammion koon suurentumisen riski noin 20 vuoden seurannan aikana 958 tutkittavan henkilön aineistossa riippumatta siitä, onko heillä alkoholinkäyttöön liittymätön rasvamaksa. Toisin sanoen alkoholin käyttöön liittymätön rasvamaksa ilman metabolista oireyhtymää ei lisää edellä mainittujen kolmen sairauden riskiä. Väitöstutkimuksessa esitetään lisäksi, että rifampisiinilla aikaansaatu maksan pregnane X -reseptorin aktivaatio johtaa seerumin fosfolipidien, tiettyjen rasvahappojen sekä usean eri kolesterolityypin lisääntymiseen 34 terveen nuoren henkilön aineistossa. Kirjallisuudessa näiden seerumin rasva-aineiden on esitetty aiheuttavan alkoholin käyttöön liittymätöntä maksatulehdusta ja jopa rasvamaksan vakavimpia muotoja. Toisaalta rifampisiini ei lisännyt seerumin triglyseridipitoisuutta eikä aiheuttanut magneettitutkimuksella mitattuna triglyseridien kertymistä maksaan 15 terveen nuoren henkilön aineistossa. Tämä väitöstutkimus antaa lisätietoa rasvamaksan kehittymisestä, rasva-aineenvaihdunnasta ja komplikaatioista sekä korostaa rasvamaksan monimuotoista luonnetta. Nämä löydökset saattavat parantaa rasvamaksaa sairastavien henkilöiden hoitoa ja seurantaa.
Published: 2017

34. Liver X Receptor Agonist 4β-Hydroxycholesterol as a Prognostic Factor in Coronary Artery Disease.

Author: Rahunen R, Tulppo M, Rinne V, Lepojärvi S, Perkiömäki JS, Huikuri HV, Ukkola O, Junttila J, and Hukkanen J
Subjects: Female, Humans, Male, Death, Death, Sudden, Cardiac epidemiology, Liver X Receptors, Prognosis, Risk Factors, Coronary Artery Disease, Hydroxycholesterols
Abstract: Background: Regardless of progress in treatment of coronary artery disease (CAD), there is still a significant residual risk of death in patients with CAD, highlighting the need for additional risk stratification markers. Our previous study provided evidence for a novel blood pressure-regulating mechanism involving 4β-hydroxycholesterol (4βHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4βHC as a prognostic factor in CAD., Methods and Results: The ARTEMIS (Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection) cohort consists of 1946 patients with CAD. Men and women were analyzed separately in quartiles according to plasma 4βHC. Basic characteristics, medications, ECG, and echocardiography parameters as well as mortality rate were analyzed. At baseline, subjects with a beneficial cardiovascular profile, as assessed with traditional markers such as body mass index, exercise capacity, prevalence of diabetes, and use of antihypertensives, had the highest plasma 4βHC concentrations. However, in men, high plasma 4βHC was associated with all-cause death, cardiac death, and especially sudden cardiac death (SCD) in a median follow-up of 8.8 years. Univariate and comprehensively adjusted hazard ratios for SCD in the highest quartile were 3.76 (95% CI, 1.6-8.7; P =0.002) and 4.18 (95% CI, 1.5-11.4; P =0.005), respectively. In contrast, the association of cardiac death and SCD in women showed the lowest risk in the highest 4βHC quartile., Conclusions: High plasma 4βHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4βHC as a novel sex-specific risk marker of cardiac death and especially SCD in chronic CAD., Registration Information: clinicaltrials.gov. Identifier NCT01426685.
Published: 2024
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35. Impact of RYGB surgery on plasma immunoglobulins: association between blood pressure and glucose levels six months after surgery.

Author: Happonen N, Härma MA, Akhi R, Nissinen AE, Savolainen MJ, Ruuth M, Öörni K, Adeshara K, Lehto M, Groop PH, Koivukangas V, Hukkanen J, and Hörkkö S
Subjects: Humans, Blood Glucose, Blood Pressure, Glucose, Immunoglobulin M, Immunoglobulin G, Gastric Bypass, Diabetes Mellitus, Type 2
Abstract: We aimed to study levels of natural antibodies in plasma, and their associations to clinical and fecal biomarkers, before and 6 months after Roux-en-Y gastric bypass (RYGB) surgery. Thirty individuals with obesity [16 type 2 diabetic, 14 non-diabetic (ND)] had RYGB surgery. Total plasma IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts, Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44), and phosphocholine were measured using chemiluminescence immunoassay. Associations between plasma and fecal antibodies as well as clinical markers were analyzed. RYGB surgery reduced blood pressure, and the glycemic state was improved. A higher level of diastolic blood pressure was associated with lower plasma antibodies to oxLDL after surgery. Also, lower level of glucose markers associated with lower level of plasma antibodies to bacterial virulence factors. Antibodies to oxLDL decreased after surgery, and positive association between active serum lipopolysaccharide and specific oxLDL antibodies was detected. Total IgG levels decreased after surgery, but only in ND individuals. Reduced level of total plasma IgG, improved state of hypertension and hyperglycemia and their associations with decreased levels of specific antibodies in plasma, suggest an improved state of systemic inflammation after RYGB surgery., (© 2023 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)
Published: 2024
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36. Mobile health behaviour change support system as independent treatment tool for obesity: a randomized controlled trial.

Author: Markkanen JO, Oikarinen N, Savolainen MJ, Merikallio H, Nyman V, Salminen V, Virkkula T, Karppinen P, Oinas-Kukkonen H, and Hukkanen J
Subjects: Humans, Female, Adolescent, Young Adult, Adult, Middle Aged, Aged, Male, Weight Loss, Digital Health, Health Behavior, Obesity therapy, Telemedicine methods
Abstract: Background/objectives: Digital health interventions are increasingly utilized as an adjunct to face-to-face counselling in the treatment of obesity. However, previous studies have shown inconsistent efficacy when digital interventions are used as stand-alone treatment. The purpose of this study was to investigate whether a mobile health behaviour change support system (mHBCSS) is effective in weight reduction and weight loss maintenance without additional counselling. Furthermore, changes in cardiometabolic risk factors were investigated., Methods: In this randomized controlled trial, a mHBCSS intervention was conducted for 200 volunteers with obesity (BMI 30-40 kg/m² and age 18-65 years). The study participants were randomly assigned into two groups: immediate access to mHBCSS intervention or wait-list control with access to mHBCSS after 6 months. Anthropometric and metabolic traits were also measured. The primary outcome was weight loss from the baseline to the 6-month visit., Results: Among 200 participants (88.5% women), mean BMI (SD) was 34.3 kg/m² (2.8) and age 46.5 years (9.5). The retention rate was 98.5% and 89.0% at the 6- and 12-month visits, respectively. At the 6-month visit, those with immediate access to mHBCSS had significantly greater weight loss (-2.5%, 95% CI -3.4 to -1.6, p < 0.001) compared with the wait-list control group (0.2%, 95% CI -0.4 to 0.9, p = 0.466; between groups p < 0.001). Weight loss was maintained until the 12-month time point in the mHBCSS group (-2.1%, 95% CI -3.3 to -0.9, p = 0.001). The usage of mHBCSS had no significant effect on metabolic traits., Conclusion: The mHBCSS as a stand-alone treatment of obesity results in weight reduction and weight loss maintenance with remarkable adherence rate. Further studies are needed to establish how to best implement the scalable and resource-efficient mHBCSS into the standard care of obesity to achieve optimal weight loss results., (© 2023. The Author(s).)
Published: 2024
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37. Short-Term Metabolic Changes and Their Physiological Mediators in the Roux-en-Y Gastric Bypass Bariatric Surgery.

Author: Zhao S, Hörkkö S, Savolainen MJ, Koivukangas V, Mäkinen VP, Ala-Korpela M, and Hukkanen J
Subjects: Humans, Leucine, Insulin, Glucose, Tyrosine, Gastric Bypass, Obesity, Morbid surgery, Diabetes Mellitus, Type 2 surgery, Bariatric Surgery
Abstract: Background: The Roux-en-Y gastric bypass (RYGB) is a common bariatric surgery to treat obesity. Its metabolic consequences are favourable and long-term clinical corollaries beneficial. However, detailed assessments of various affected metabolic pathways and their mediating physiological factors are scarce., Methods: We performed a clinical study with 30 RYGB patients in preoperative and 6-month postoperative visits. NMR metabolomics was applied to profiling of systemic metabolism via 80 molecular traits, representing core cardiometabolic pathways. Glucose, glycated haemoglobin (HbA1c), insulin, and apolipoprotein B-48 were measured with standard assays. Logistic regression models of the surgery effect were used for each metabolic measure and assessed individually for multiple mediating physiological factors., Results: Changes in insulin concentrations reflected those of BMI with robust decreases due to the surgery. Six months after the surgery, triglycerides, remnant cholesterol, and apolipoprotein B-100 were decreased -24%, -18%, and -14%, respectively. Lactate and glycoprotein acetyls, a systemic inflammation biomarker, decreased -16% and -9%, respectively. The concentrations of branched-chain (BCAA; leucine, isoleucine, and valine) and aromatic (phenylalanine and tyrosine) amino acids decreased after the surgery between -17% for tyrosine and -23% for leucine. Except for the most prominent metabolic changes observed for the BCAAs, all changes were almost completely mediated by weight change and insulin. Glucose and type 2 diabetes had clearly weaker effects on the metabolic changes., Conclusions: The comprehensive metabolic analyses indicate that weight loss and improved insulin sensitivity during the 6 months after the RYGB surgery are the key physiological outcomes mediating the short-term advantageous metabolic effects of RYGB. The clinical study was registered at ClinicalTrials.gov as NCT01330251., (© 2024. The Author(s).)
Published: 2024
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38. Low eating self-efficacy is associated with unfavorable eating behavior tendencies among individuals with overweight and obesity.

Author: Oikarinen N, Jokelainen T, Heikkilä L, Nurkkala M, Hukkanen J, Salonurmi T, Savolainen MJ, and Teeriniemi AM
Subjects: Male, Humans, Female, Cross-Sectional Studies, Feeding Behavior psychology, Obesity psychology, Surveys and Questionnaires, Overweight psychology, Self Efficacy
Abstract: Success in long-term weight management depends partly on psychological and behavioral aspects. Understanding the links between psychological factors and eating behavior tendencies is needed to develop more effective weight management methods. This population-based cross-sectional study examined whether eating self-efficacy (ESE) is associated with cognitive restraint (CR), uncontrolled eating (UE), emotional eating (EE), and binge eating (BE). The hypothesis was that individuals with low ESE have more unfavorable eating behavior tendencies than individuals with high ESE. Participants were classified as low ESE and high ESE by the Weight-Related Self-Efficacy questionnaire (WEL) median cut-off point. Eating behavior tendencies were assessed with Three Factor Eating Questionnaire R-18 and Binge Eating Scale, and additionally, by the number of difficulties in weight management. The difficulties were low CR, high UE, high EE, and moderate or severe BE. Five hundred and thirty-two volunteers with overweight and obesity were included in the study. Participants with low ESE had lower CR (p < 0.03) and higher UE, EE, and BE (p < 0.001) than participants with high ESE. Thirty-nine percent of men with low ESE had at least two difficulties in successful weight control while this percentage was only 8% in men with high ESE. In women, the corresponding figures were 56% and 10%. The risk of low ESE was increased by high UE [OR 5.37 (95% CI 1.99-14.51)], high EE [OR 6.05 (95% CI 2.07-17.66)], or moderate or severe BE [OR 12.31 (95% CI 1.52-99.84)] in men, and by low CR [OR 5.19 (95% CI 2.22-12.18)], high UE [OR 7.20 (95% CI 2.41-19.22)], or high EE [OR 23.66 (95% CI 4.79-116.77)] in women. Low ESE was associated with unfavorable eating behavior tendencies and multiple concomitant difficulties in successful weight loss promotion. These eating behavior tendencies should be considered when counseling patients with overweight and obesity., (© 2023. The Author(s).)
Published: 2023
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39. Effects of rifampicin on porphyrin metabolism in healthy volunteers.

Author: Tolonen H, Ranta S, Hämäläinen E, Kauppinen R, and Hukkanen J
Subjects: Humans, Erythrocytes, Healthy Volunteers, Heme metabolism, Pregnane X Receptor drug effects, Pregnane X Receptor metabolism, Porphyrins metabolism, Porphyrins urine, Rifampin pharmacology
Abstract: Pregnane X receptor (PXR) is known to stimulate haem synthesis, but detailed knowledge on the effects of PXR activation on porphyrin metabolism in humans is lacking. We utilized a randomized, crossover, open (blinded laboratory) and placebo-controlled trial with 600-mg rifampicin or placebo dosed for a week to investigate the effects of PXR activation on erythrocyte, plasma, faecal and urine porphyrins. Sixteen healthy volunteers participated on the trial, but the number of volunteers for blood and urine porphyrin analyses was 15 while the number of samples for faecal analyses was 14. Rifampicin increased urine pentaporphyrin concentration 3.7-fold (mean 1.80 ± 0.6 vs. 6.73 ± 4.4 nmol/L, p = 0.003) in comparison with placebo. Urine coproporphyrin I increased 23% (p = 0.036). Faecal protoporphyrin IX decreased (mean 31.6 ± 23.5 vs. 19.2 ± 27.8 nmol/g, p = 0.023). The number of blood erythrocytes was slightly elevated, and plasma bilirubin, catabolic metabolite of haem, was decreased. In conclusion, rifampicin dosing elevated the excretion of certain urinary porphyrin metabolites and decreased faecal protoporphyrin IX excretion. As urine pentaporphyrin and coproporphyrin I are not precursors in haem biosynthesis, increased excretion may serve as a hepatoprotective shunt when haem synthesis or porphyrin levels are increased., (© 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)
Published: 2023
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40. Pregnane X receptor gene variant rs7643645 and total mortality in subjects with nonalcoholic fatty liver disease.

Author: Käräjämäki AJ, Hukkanen J, and Ukkola O
Subjects: Middle Aged, Humans, Pregnane X Receptor genetics, Liver, Promoter Regions, Genetic genetics, Non-alcoholic Fatty Liver Disease genetics, Receptors, Steroid genetics
Abstract: Pregnane X receptor (PXR) gene variants rs7643645 and rs2461823 are reported to associate with clinically and histologically more severe liver injury in nonalcoholic fatty liver disease (NAFLD). It is known that the more progressive the NAFLD, the higher the hepatic and extra-hepatic mortality and morbidity. Thus, we investigated the total mortality in Finnish middle-aged ultrasonographically verified NAFLD patients with PXR rs7643645 AA/AG ( n = 217) or GG ( n = 27) variants and rs2461823 CC/CT ( n = 215) or TT ( n = 27) variants. In up to 30 years of follow-up, PXR rs7643645 GG subjects were at an increased risk of total mortality compared with AA/AG subjects, 1.676 (1.014-2.772), P = 0.044. The statistically significant difference prevailed after multiple adjustments for potentially confounding factors, RR, 2.024 (1.191-3.440), P = 0.009. In the subjects without NAFLD ( n = 731), the mortality risk was not associated with rs7643645 variants, 1.051 (0.708-1.560; P = 0.804). There was no difference in the total mortality between the PXR rs2461823 variant subgroups, 1.141 (0.663-1.962; P = 0.634). As the rs7643645 G variant disrupts a putative hepatocyte nuclear factor 4α binding site located in the PXR gene promoter and is associated with lower hepatic expression of PXR and its target genes, our result suggests that genetic disruption of xenobiotic metabolism increases mortality in subjects with NAFLD. Further studies are needed to confirm the results of the present study., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
Published: 2023
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41. Long-term metabolic fate and mortality in obesity without metabolic syndrome.

Author: Käräjämäki AJ, Korkiakoski A, Hukkanen J, Kesäniemi YA, and Ukkola O
Subjects: Finland epidemiology, Follow-Up Studies, Humans, Middle Aged, Obesity complications, Risk Factors, Atrial Fibrillation diagnosis, Atrial Fibrillation epidemiology, Cardiovascular Diseases, Metabolic Syndrome complications, Metabolic Syndrome diagnosis, Metabolic Syndrome epidemiology
Abstract: Background: Obesity and metabolic syndrome (MetS) are known to expose to atrial fibrillation (AF), cardiovascular diseases (CVD) and mortality. Metabolically healthy obesity refers to obesity without MetS. This study aimed to investigate how obesity and MetS modify the risk of CVD, AF and mortality in very long-time follow-up., Methods: Finnish middle-aged subjects ( n = 1045) were grouped into four subgroups according to the presence of obesity and MetS. CVD events and AF were followed for 24 years and total mortality for 30 years. Moreover, 600 available patients had a follow-up visit for metabolic examinations after approximately 22 years., Results: One-hundred and sixty-two (30%) subjects without obesity or MetS died during the follow-up. Ninety-two (17%) of the patients in this group had a CVD event and 58 (11%) were diagnosed with AF. As compared to them, obese subjects without MetS had similar metabolic fate and mortality (mortality 26 (38%), p = .143; CVD event 12 (18%), p = .858 and AF 7 (10%), p = .912, respectively), whereas subjects with obesity and MetS had greater mortality (102 (49%), p < .001), more CVD (71 (34%), p < .001) and AF (49 (23%), p < .001). Non-obese individuals with MetS had greater rates of mortality (96 (44%), p < .001) and CVD (80 (37%), p < .001), but not of AF (26 (12%), p = .606). Of the 40 subjects with obesity but without MetS at baseline and available for the follow-up visit, 15 (38%) were metabolically healthy at the follow-up visit., Conclusions: In the present long-term follow-up study, the presence of MetS, but not obesity only, implies a greater risk of mortality and CVD. The risk of AF is increased only in subjects with both obesity and MetS. However, obesity without MetS tends to progress eventually to obesity with MetS. Key messagesThe presence of metabolic syndrome (MetS), but not obesity only, entails a greater risk of mortality and cardiovascular diseases.The risk of atrial fibrillation is increased only in subjects with both obesity and MetS.Obesity without MetS tends to progress eventually to obesity with MetS.
Published: 2022
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42. Total fecal IgA levels increase and natural IgM antibodies decrease after gastric bypass surgery.

Author: Istomin N, Härma MA, Akhi R, Nissinen AE, Savolainen MJ, Adeshara K, Lehto M, Groop PH, Koivukangas V, Hukkanen J, and Hörkkö S
Subjects: Acetaldehyde, Feces, Gingipain Cysteine Endopeptidases, Hemagglutinins, Humans, Immunoglobulin A, Immunoglobulin G, Immunoglobulin M, Lipoproteins, LDL, Malondialdehyde, Obesity surgery, Phosphorylcholine, Diabetes Mellitus, Type 2 surgery, Gastric Bypass
Abstract: Obesity is associated with low-grade inflammation and increased systemic oxidative stress. Roux-en-Y gastric bypass (RYGB) surgery is known to ameliorate the obesity-induced metabolic dysfunctions. We aimed to study the levels of natural antibodies in feces, before and 6 months after RYGB surgery in obese individuals with and without type 2 diabetes (T2D). Sixteen individuals with T2D and 14 non-diabetic (ND) individuals were operated. Total IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts (MAA adducts), Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44) and phosphocholine (PCho) were measured using chemiluminescence immunoassay. Total fecal IgA was elevated, while total IgM and IgG were not affected by the surgery. Fecal natural IgM specific to oxLDL decreased significantly in both T2D and ND individuals, while fecal IgM to Rgp44 and PCho decreased significantly in T2D individuals. A decrease in IgG to MAA-LDL, Rgp44 and PCho was detected. RYGB surgery increases the levels of total fecal IgA and decreases fecal natural IgG and IgM antibodies specific to oxLDL. Natural antibodies and IgA are important in maintaining the normal gut homeostasis and first-line defense against microbes, and their production is markedly altered with RYGB surgery., (© 2022 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)
Published: 2022
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43. Pregnane X Receptor‒4β-Hydroxycholesterol Axis in the Regulation of Overweight- and Obesity-Induced Hypertension.

Author: Rahunen R, Kummu O, Koivukangas V, Hautajärvi H, Hakkola J, Rysä J, and Hukkanen J
Subjects: Animals, Blood Pressure, Female, Humans, Hydroxycholesterols, Male, Obesity complications, Pregnane X Receptor metabolism, Rats, Rifampin pharmacology, Hypertension drug therapy, Overweight complications
Abstract: Background Mechanisms mediating hypertensive effects of overweight and obesity have not been fully elucidated. We showed previously that activation of pregnane X receptor (PXR) by rifampicin elevates 24-hour blood pressure (BP) and plasma 4β-hydroxycholesterol (4βHC), agonist for liver X receptor (LXR). Methods and Results In combined "PXR activation data set" (n=62) of 4 clinical trials, 1 week rifampicin dosing increased office systolic BP (SBP) by 3.1 mm Hg, DBP 1.8 mm Hg, and mean arterial pressure 2.2 mm Hg in comparison with placebo ( P <0.01). Plasma 4βHC had negative correlation with SBP both in rifampicin ( r =-0.46, P =0.0002) and placebo ( r =-0.45, P =0.0003) arms, although 4βHC was elevated >3-fold by rifampicin. In "non-intervention data set" (n=102) of patients with obesity and healthy volunteers (body mass index, 19.2-55.2 kg/m 2 ), 4βHC had negative correlations ( P <0.00001) with office SBP ( r =-0.51), diastolic BP ( r =-0.50), and mean arterial pressure ( r =-0.54). Lean women had higher 4βHC than men, with increasing weight repressing 4βHC ( r =-0.62, P <0.00001) in both sexes. In multiple linear regression analysis, the only statistically significant predictor for SBP was 4βHC. Six-day PXR agonist dosing elevated SBP in rats (n=7-8/group). PXR activation elevated 4βHC and after PXR agonist was withdrawn and elevated 4βHC was left to act alone, SBP was reduced on days 7 to 14 in comparison with control rats. Conclusions PXR activation elevates SBP. Elevated circulating 4βHC lowers SBP in rats, and higher 4βHC is an independent predictor of lower SBP in humans. PXR-4βHC-LXR is novel BP-regulating pathway deregulated in overweight and obesity by repressed 4βHC, with implications for sex-specific BP regulation. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00985270, NCT01293422, NCT01690104, NCT02329405, and NCT01330251.
Published: 2022
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44. Analysis of the SYSDIET Healthy Nordic Diet randomized trial based on metabolic profiling reveal beneficial effects on glucose metabolism and blood lipids.

Author: Gürdeniz G, Uusitupa M, Hermansen K, Savolainen MJ, Schwab U, Kolehmainen M, Brader L, Cloetens L, Herzig KH, Hukkanen J, Rosqvist F, Ulven SM, Gunnarsdóttir I, Thorsdottir I, Oresic M, Poutanen KS, Risérus U, Åkesson B, and Dragsted LO
Subjects: Area Under Curve, Biomarkers blood, Biomarkers urine, Cardiometabolic Risk Factors, Eating physiology, Fasting blood, Fasting urine, Female, Humans, Inflammation Mediators blood, Lipids blood, Lipoproteins blood, Male, Metabolic Syndrome complications, Middle Aged, Overweight complications, Overweight diet therapy, Principal Component Analysis, Randomized Controlled Trials as Topic, Scandinavian and Nordic Countries, Triglycerides blood, Blood Glucose metabolism, Diet, Healthy methods, Metabolic Syndrome diet therapy, Metabolomics methods, Nutrition Assessment
Abstract: Background & Aims: Intake assessment in multicenter trials is challenging, yet important for accurate outcome evaluation. The present study aimed to characterize a multicenter randomized controlled trial with a healthy Nordic diet (HND) compared to a Control diet (CD) by plasma and urine metabolic profiles and to associate them with cardiometabolic markers., Methods: During 18-24 weeks of intervention, 200 participants with metabolic syndrome were advised at six centres to eat either HND (e.g. whole-grain products, berries, rapeseed oil, fish and low-fat dairy) or CD while being weight stable. Of these 166/159 completers delivered blood/urine samples. Metabolic profiles of fasting plasma and 24 h pooled urine were analysed to identify characteristic diet-related patterns. Principal components analysis (PCA) scores (i.e. PC1 and PC2 scores) were used to test their combined effect on blood glucose response (primary endpoint), serum lipoproteins, triglycerides, and inflammatory markers., Results: The profiles distinguished HND and CD with AUC of 0.96 ± 0.03 and 0.93 ± 0.02 for plasma and urine, respectively, with limited heterogeneity between centers, reflecting markers of key foods. Markers of fish, whole grain and polyunsaturated lipids characterized HND, while CD was reflected by lipids containing palmitoleic acid. The PC1 scores of plasma metabolites characterizing the intervention is associated with HDL (β = 0.05; 95% CI: 0.02, 0.08; P = 0.001) and triglycerides (β = -0.06; 95% CI: -0.09, -0.03; P < 0.001). PC2 scores were related with glucose metabolism (2 h Glucose, β = 0.1; 95% CI: 0.05, 0.15; P < 0.001), LDL (β = 0.06; 95% CI: 0.01, 0.1; P = 0.02) and triglycerides (β = 0.11; 95% CI: 0.06, 0.15; P < 0.001). For urine, the scores were related with LDL cholesterol., Conclusions: Plasma and urine metabolite profiles from SYSDIET reflected good compliance with dietary recommendations across the region. The scores of metabolites characterizing the diets associated with outcomes related with cardio-metabolic risk. Our analysis therefore offers a novel way to approach a per protocol analysis with a balanced compliance assessment in larger multicentre dietary trials. The study was registered at clinicaltrials.gov with NCT00992641., Competing Interests: Conflict of interest The authors declare they have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2022
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45. Nuclear Receptor PXR in Drug-Induced Hypercholesterolemia.

Author: Karpale M, Hukkanen J, and Hakkola J
Subjects: Cholesterol metabolism, Humans, Lipoproteins, LDL metabolism, Atherosclerosis metabolism, Hypercholesterolemia chemically induced, Pregnane X Receptor metabolism
Abstract: Atherosclerosis is a major global health concern. The central modifiable risk factors and causative agents of the disease are high total and low-density lipoprotein (LDL) cholesterol. To reduce morbidity and mortality, a thorough understanding of the factors that influence an individual's cholesterol status during the decades when the arteria-narrowing arteriosclerotic plaques are forming is critical. Several drugs are known to increase cholesterol levels; however, the mechanisms are poorly understood. Activation of pregnane X receptor (PXR), the major regulator of drug metabolism and molecular mediator of clinically significant drug-drug interactions, has been shown to induce hypercholesterolemia. As a major sensor of the chemical environment, PXR may in part mediate hypercholesterolemic effects of drug treatment. This review compiles the current knowledge of PXR in cholesterol homeostasis and discusses the role of PXR in drug-induced hypercholesterolemia.
Published: 2022
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46. Rifampicin induces the bone form of alkaline phosphatase in humans.

Author: Nabil H, Kummu O, Lehenkari P, Rysä J, Risteli J, Hakkola J, and Hukkanen J
Subjects: Alkaline Phosphatase genetics, Animals, Cross-Over Studies, Humans, Liver drug effects, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Osteoblasts drug effects, Osteoblasts metabolism, Pregnane X Receptor metabolism, Pregnenolone Carbonitrile pharmacology, RNA, Messenger genetics, Rats, Rats, Sprague-Dawley, Alkaline Phosphatase blood, Pregnane X Receptor drug effects, Rifampin pharmacology
Abstract: Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that regulates drug metabolism in the liver and intestine. In our clinical trials on healthy volunteers to discover novel metabolic functions of PXR activation, we observed that rifampicin, a well-established ligand for human PXR, 600 mg daily for a week, increased the plasma alkaline phosphatase (ALP) significantly compared with the placebo. Further analysis with lectin affinity electrophoresis revealed that especially the bone form of ALP was elevated. To investigate the mechanism(s) of bone ALP induction, we employed osteoblast lineage differentiated from human primary bone marrow-derived mesenchymal stromal cells. Rifampicin treatment increased ALP activity and mRNA level of bone biomarker genes (ALP, MGP, OPN and OPG). PXR expression was detected in the cells, but the expression was very low compared with the human liver. To further investigate the potential role of PXR in the ALP induction, we treated mice and rats with a rodent PXR ligand pregnenolone 16α-carbonitrile (PCN). However, PCN treatment did not increase plasma ALP activity or bone ALP mRNA expression. In conclusion, rifampicin treatment induces the bone form of ALP in the serum of healthy human volunteers. Further studies are required to establish the mechanism of this novel finding., (© 2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)
Published: 2022
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47. Serological Biomarker Panel in Diagnosis of Atrophic Gastritis and Helicobacter pylori Infection in Gastroscopy Referral Patients: Clinical Validation of the New-Generation GastroPanel ® Test.

Author: Koivurova OP, Koskela R, Blomster T, Ala-Rämi A, Lumme H, Kettunen O, Hukkanen J, Karttunen TJ, Mäkinen M, Ronkainen J, and Syrjänen K
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Bacterial blood, Biomarkers blood, Biopsy, Enzyme-Linked Immunosorbent Assay, Female, Finland, Gastritis, Atrophic blood, Gastritis, Atrophic microbiology, Helicobacter Infections blood, Helicobacter Infections microbiology, Helicobacter pylori immunology, Host-Pathogen Interactions, Humans, Male, Middle Aged, Predictive Value of Tests, Referral and Consultation, Reproducibility of Results, Young Adult, Gastrins blood, Gastritis, Atrophic diagnosis, Gastroscopy, Helicobacter Infections diagnosis, Helicobacter pylori pathogenicity, Pepsinogen A blood, Pepsinogen C blood, Serologic Tests
Abstract: Background/aim: Prompted by the increasing demand of non-invasive diagnostic tools for screening of gastric cancer (GC) risk conditions, i.e., atrophic gastritis (AG) and Helicobacter pylori (Hp) infection, the GastroPanel ® test (GP: biomarker panel of PGI, PGII, G-17, Hp IgG ELISA) that was developed in the early 2000's, was recently updated to a new-generation (unified GP) test version. This clinical validation study evaluated the diagnostic accuracy of the new-generation GP test in detection of AG and Hp among gastroscopy referral patients in a University Clinic., Patients and Methods: Altogether, 522 patients were enrolled among the patients referred for gastroscopy at the Gastro Center, Oulu University Hospital (OUH). All patients underwent gastroscopy with biopsies classified using the Updated Sydney System (USS), and blood sampling for GP testing., Results: Biopsy-confirmed AG was found in 10.2% (53/511) of the patients. The overall agreement between the GP and the USS classification was 92.4% (95%CI=90.0-94.6%), with the weighted kappa (κ w ) of 0.861 (95%CI=0.834-0.883). In ROC analysis using moderate/severe AG of the corpus (AGC2+) as the endpoint, AUC=0.952 (95%CI=0.891-1.000) and AUC=0.998 (95%CI=0.996-1.000) for PGI and PGI/PGII, respectively. Hp IgG antibody ELISA detected biopsy-confirmed Hp-infection with AUC=0.993 (95%CI=0.987-0.999)., Conclusion: The new generation GastroPanel ® is a precise test for non-invasive diagnosis of atrophic gastritis and Hp-infection in dyspeptic patients referred for diagnostic gastroscopy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
Published: 2021
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48. Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism.

Author: Karpale M, Käräjämäki AJ, Kummu O, Gylling H, Hyötyläinen T, Orešič M, Tolonen A, Hautajärvi H, Savolainen MJ, Ala-Korpela M, Hukkanen J, and Hakkola J
Subjects: Animals, Humans, Mice, Pregnane X Receptor, Receptors, LDL genetics, Sterol Regulatory Element Binding Protein 2 genetics, Pharmaceutical Preparations, Proprotein Convertase 9 genetics
Abstract: Background and Purpose: Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved., Experimental Approach: We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis., Key Results: Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation., Conclusion and Implications: PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Published: 2021
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49. Gastrointestinal manifestations after Roux-en-Y gastric bypass surgery in individuals with and without type 2 diabetes.

Author: Härma MA, Adeshara K, Istomin N, Lehto M, Blaut M, Savolainen MJ, Hörkkö S, Groop PH, Koivukangas V, and Hukkanen J
Subjects: Humans, Obesity, Prospective Studies, Weight Loss, Diabetes Mellitus, Type 2, Gastric Bypass adverse effects, Obesity, Morbid surgery
Abstract: Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective treatment for obesity, which improves cardiovascular health and reduces the risk of premature mortality. However, some reports have suggested that RYGB may predispose patients to adverse health outcomes, such as inflammatory bowel disease (IBD) and colorectal cancer., Objectives: The present prospective study aimed to evaluate the impact of RYGB surgery on cardiovascular risk factors and gastrointestinal inflammation in individuals with and without type 2 diabetes (T2D)., Setting: University hospital setting in Finland., Methods: Blood and fecal samples were collected at baseline and 6 months after surgery from 30 individuals, of which 16 had T2D and 14 were nondiabetics. There were also single study visits for 6 healthy reference patients. Changes in cardiovascular risk factors, serum cholesterol, and triglycerides were investigated before and after surgery. Fecal samples were analyzed for calprotectin, anti-Saccharomyces cerevisiae immunoglobulin A antibodies (ASCA), active lipopolysaccharide (LPS) concentration, short-chain fatty acids (SCFAs), intestinal alkaline phosphatase activity, and methylglyoxal-hydro-imidazolone (MG-H1) protein adducts formation., Results: After RYGB, weight decreased on average -21.6% (-27.2 ± 7.8 kg), excess weight loss averaged 51%, and there were improvements in cardiovascular risk factors. Fecal calprotectin levels (P < .001), active LPS concentration (P < .002), ASCA (P < .02), and MG-H1 (P < .02) values increased significantly, whereas fecal SCFAs, especially acetate (P < .002) and butyrate (P < .03) levels, were significantly lowered., Conclusion: The intestinal homeostasis is altered after RYGB, with several fecal markers suggesting increased inflammation; however, clinical significance of the detected changes is currently uncertain. As chronic inflammation may predispose patients to adverse health effects, our findings may have relevance for the suggested association between RYGB and increased risks of incident IBD and colorectal cancer., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)
Published: 2021
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50. PXR and 4β-Hydroxycholesterol Axis and the Components of Metabolic Syndrome.

Author: Hukkanen J and Hakkola J
Subjects: Animals, Blood Pressure, Glucose metabolism, Humans, Metabolic Syndrome physiopathology, Obesity metabolism, Obesity physiopathology, Hydroxycholesterols metabolism, Metabolic Syndrome metabolism, Pregnane X Receptor metabolism
Abstract: Pregnane X receptor (PXR) activation has been found to regulate glucose and lipid metabolism and affect obesity in response to high-fat diets. PXR also modulates vascular tone. In fact, PXR appears to regulate multiple components of metabolic syndrome. In most cases, the effect of PXR action is harmful to metabolic health, and PXR can be hypothesized to play an important role in metabolic disruption elicited by exposure to endocrine-disrupting chemicals. The majority of the data on the effects of PXR activation on metabolic health come from animal and cell culture experiments. However, randomized, placebo-controlled, human trials indicate that the treatment with PXR ligands impairs glucose tolerance and increases 24-h blood pressure and heart rate. In addition, plasma 4β-hydroxycholesterol (4βHC), formed under the control of PXR in the liver, is associated with lower blood pressure in healthy volunteers. Furthermore, 4βHC regulates cholesterol transporters in peripheral tissues and may activate the beneficial reverse HDL cholesterol transport. In this review, we discuss the current knowledge on the role of PXR and the PXR-4βHC axis in the regulation of components of metabolic syndrome.
Published: 2020
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