135 results on '"Borén, Jan"'
Search Results
2. Effects of PNPLA3 I148M on hepatic lipid and very‐low‐density lipoprotein metabolism in humans.
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Borén, Jan, Adiels, Martin, Björnson, Elias, Matikainen, Niina, Söderlund, Sanni, Rämö, Joel, Henricsson, Marcus, Ripatti, Pietari, Ripatti, Samuli, Palotie, Aarno, Mancina, Rosellina M., Ainola, Mari, Hakkarainen, Antti, Romeo, Stefano, Packard, Chris J., and Taskinen, Marja‐Riitta
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LIPIDS , *LIPOPROTEINS , *METABOLISM , *LIPID metabolism , *TRIGLYCERIDES - Abstract
Background: The phospholipase domain‐containing 3 gene (PNPLA3)‐148M variant is associated with liver steatosis but its influence on the metabolism of triglyceride‐rich lipoproteins remains unclear. Here, we investigated the kinetics of large, triglyceride‐rich very‐low‐density lipoprotein (VLDL), (VLDL1), and smaller VLDL2 in homozygotes for the PNPLA3‐148M variant. Methods and results: The kinetics of apolipoprotein (apo) B100 (apoB100) and triglyceride in VLDL subfractions were analysed in nine subjects homozygous for PNPLA3‐148M and nine subjects homozygous for PNPLA3‐148I (controls). Liver fat was >3‐fold higher in the 148M subjects. Production rates for apoB100 and triglyceride in VLDL1 did not differ significantly between the two groups. Likewise, production rates for VLDL2‐apoB100 and ‐triglyceride, and fractional clearance rates for both apoB100 and triglyceride in VLDL1 and VLDL2, were not significantly different. Conclusions: Despite the higher liver fat content in PNPLA3 148M homozygotes, there was no increase in VLDL production. Equally, VLDL production was maintained at normal levels despite the putative impairment in cytosolic lipid hydrolysis in these subjects. [ABSTRACT FROM AUTHOR]
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- 2022
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3. The year 2020 in Atherosclerosis.
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Binder, Christoph J., Borén, Jan, Catapano, Alberico, Kronenberg, Florian, Mallat, Ziad, Negrini, Simona, Öörni, Katariina, Raggi, Paolo, and von Eckardstein, Arnold
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ATHEROSCLEROSIS , *LIPOPROTEINS , *BIOMARKERS , *BIOLOGY , *INFLAMMATION - Published
- 2021
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4. The year 2019 in Atherosclerosis.
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Binder, Christoph J., Borén, Jan, Catapano, Alberico L., Dallinga-Thie, Geesje, Kronenberg, Florian, Mallat, Ziad, Negrini, Simona, Raggi, Paolo, and von Eckardstein, Arnold
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ATHEROSCLEROTIC plaque , *ATHEROSCLEROSIS , *HIGH-density lipoprotein receptors - Published
- 2020
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5. Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study.
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Sattar, Naveed, McMurray, John, Borén, Jan, Rawshani, Araz, Omerovic, Elmir, Berg, Niklas, Halminen, Janita, Skoglund, Kristoffer, Eliasson, Björn, Gerstein, Hertzel C., McGuire, Darren K., Bhatt, Deepak, and Rawshani, Aidin
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HEART failure , *TYPE 2 diabetes , *CEREBROVASCULAR disease , *CARDIOVASCULAR diseases risk factors , *DISEASE risk factors , *MYOCARDIAL infarction , *GLYCOSYLATED hemoglobin - Abstract
Background: The goal of this work was to investigate trends (2001–2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects. Methods: This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model. Results: Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4–86.8) and 41.0 (95% CI, 39.5–42.6); coronary artery disease, 205.1 (95% CI, 186.8–227.5) and 80.2 (95% CI, 78.2–82.3); cerebrovascular disease, 83.9 (95% CI, 73.6–98.5) and 46.2 (95% CI, 44.9–47.6); and HF, 98.3 (95% CI, 89.4–112.0) and 75.9 (95% CI, 74.4–77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35–1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF. Conclusions: Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure. [ABSTRACT FROM AUTHOR]
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- 2023
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6. New insights into the pathophysiology of dyslipidemia in type 2 diabetes.
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Taskinen, Marja-Riitta and Borén, Jan
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CARDIOVASCULAR diseases , *TYPE 2 diabetes , *PEOPLE with diabetes , *DYSLIPIDEMIA , *LOW density lipoproteins , *DISEASE risk factors - Abstract
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality for patients with type 2 diabetes, despite recent significant advances in management strategies to lessen CVD risk factors. A major cause is the atherogenic dyslipidemia, which consists of elevated plasma concentrations of both fasting and postprandial triglyceride-rich lipoproteins (TRLs), small dense low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) cholesterol. The different components of diabetic dyslipidemia are not isolated abnormalities but closely linked to each other metabolically. The underlying disturbances are hepatic overproduction and delayed clearance of TRLs. Recent results have unequivocally shown that triglyceride-rich lipoproteins and their remnants are atherogenic. To develop novel strategies for the prevention and treatment of dyslipidaemia, it is essential to understand the pathophysiology of dyslipoproteinaemia in humans. Here, we review recent advances in our understanding of the pathophysiology of diabetic dyslipidemia. [ABSTRACT FROM AUTHOR]
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- 2015
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7. Postprandial hypertriglyceridemia as a coronary risk factor.
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Borén, Jan, Matikainen, Niina, Adiels, Martin, and Taskinen, Marja-Riitta
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HYPERTRIGLYCERIDEMIA , *CARDIOVASCULAR diseases risk factors , *METABOLIC disorders , *TRIGLYCERIDES , *LIPOPROTEINS , *INSULIN resistance - Abstract
Abstract: Postprandial hypertriglyceridemia is now established as an important risk factor for cardiovascular disease (CVD). This metabolic abnormality is principally initiated by overproduction and/or decreased catabolism of triglyceride-rich lipoproteins (TRLs) and is a consequence of predisposing genetic variations and medical conditions such as obesity and insulin resistance. Accumulation of TRLs in the postprandial state promotes the retention of remnant particles in the artery wall. Because of their size, most remnant particles cannot cross the endothelium as efficiently as smaller low-density lipoprotein (LDL) particles. However, since each remnant particle contains approximately 40 times more cholesterol compared with LDL, elevated levels of remnants may lead to accelerated atherosclerosis and CVD. The recognition of postprandial hypertriglyceridemia in the clinical setting has been severely hampered by technical difficulties and the lack of established clinical protocols for investigating postprandial lipemia. In addition, there are currently no internationally agreed management guidelines for this type of dyslipidemia. Here we review the mechanism for and consequences of excessive postprandial hypertriglyceridemia, epidemiological evidence in support of high triglycerides and remnant particles as risk factors for CVD, the definition of hypertriglyceridemia, methods to measure postprandial hypertriglyceridemia and apolipoproteins and, finally, current and future treatment opportunities. [Copyright &y& Elsevier]
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- 2014
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8. Filamins in Cardiovascular Development
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Zhou, Xianghua, Borén, Jan, and Akyürek, Levent M.
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CARDIOVASCULAR system , *CYTOPLASM , *GENETIC disorders , *ACTIN - Abstract
Filamins are classically recognized as large cytoplasmic proteins that cross-link cortical actin into dynamic 3-dimensional structures and transmit extracellular signals through integrin receptors into the cytoplasm. However, recent reports indicate that filamins interact with a large number of other proteins with diverse functions, including transcriptional factors and cellular molecules involved in signaling, adhesion, and cellular motility, and are also present in the cell nucleus. In addition, genetic mutations in filamins have been linked to a wide range of human genetic disorders, including skeletal, central nervous system, and cardiovascular malformations, highlighting distinct filamin interactions. Here, we update the cardiovascular phenotypes of patients with mutations in filamin genes and mice deficient in filamins and filamin-interacting proteins. [Copyright &y& Elsevier]
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- 2007
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9. Palmitic acid causes increased dihydroceramide levels when desaturase expression is directly silenced or indirectly lowered by silencing AdipoR2.
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Ruiz, Mario, Henricsson, Marcus, Borén, Jan, and Pilon, Marc
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PALMITIC acid , *UNSATURATED fatty acids , *CELL membranes , *MEMBRANE proteins , *BLOOD proteins , *CERAMIDES , *AMIDASES - Abstract
Background: AdipoR1 and AdipoR2 (AdipoRs) are plasma membrane proteins often considered to act as adiponectin receptors with a ceramidase activity. Additionally, the AdipoRs and their yeast and C. elegans orthologs are emerging as membrane homeostasis regulators that counter membrane rigidification by promoting fatty acid desaturation and incorporation of unsaturated fatty acids into phospholipids, thus restoring fluidity. Methods: Using cultured cells, the effects of AdipoR silencing or over-expression on the levels and composition of several sphingolipid classes were examined. Results: AdipoR2 silencing in the presence of exogenous palmitic acid potently causes increased levels of dihydroceramides, a ceramide precursor in the de novo ceramide synthesis pathway. Conversely, AdipoR2 over-expression caused a depletion of dihydroceramides. Conclusions: The results are consistent with AdipoR2 silencing leading to increased intracellular supply of palmitic acid that in turn leads to increased dihydroceramide synthesis via the rate-limiting serine palmitoyl transferase step. In agreement with this model, inhibiting the desaturase SCD or SREBF1/2 (positive regulators of SCD) also causes a strong increase in dihydroceramide levels. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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10. Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis.
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Björnson, Elias, Adiels, Martin, Taskinen, Marja-Riitta, Burgess, Stephen, Chapman, M. John, Packard, Chris J., and Borén, Jan
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LOW density lipoproteins , *GENOME-wide association studies , *SINGLE nucleotide polymorphisms , *APOLIPOPROTEIN B , *CORONARY disease , *GENE clusters - Abstract
Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate. The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle. Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed. The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis. We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2024
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11. Systems biology based drug repositioning for development of cancer therapy.
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Turanli, Beste, Altay, Ozlem, Borén, Jan, Turkez, Hasan, Nielsen, Jens, Uhlen, Mathias, Arga, Kazim Yalcin, and Mardinoglu, Adil
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SYSTEMS biology , *CANCER treatment , *DRUG development , *QUALITY of life , *COMPUTATIONAL biology - Abstract
Drug repositioning is a powerful method that can assists the conventional drug discovery process by using existing drugs for treatment of a disease rather than its original indication. The first examples of repurposed drugs were discovered serendipitously, however data accumulated by high-throughput screenings and advancements in computational biology methods have paved the way for rational drug repositioning methods. As chemotherapeutic agents have notorious side effects that significantly reduce quality of life, drug repositioning promises repurposed noncancer drugs with little or tolerable adverse effects for cancer patients. Here, we review current drug-related data types and databases including some examples of web-based drug repositioning tools. Next, we describe systems biology approaches to be used in drug repositioning for effective cancer therapy. Finally, we highlight examples of mostly repurposed drugs for cancer treatment and provide an overview of future expectations in the field for development of effective treatment strategies. [ABSTRACT FROM AUTHOR]
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- 2021
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12. Vimentin is required for normal accumulation of body fat.
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Wilhelmsson, Ulrika, Stillemark-Billton, Pia, Borén, Jan, and Pekny, Milos
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BODY composition , *BODY mass index , *DUAL-energy X-ray absorptiometry , *VIMENTIN , *CYTOPLASMIC filaments - Abstract
Intermediate filaments (nanofilaments) have many functions, especially in response to cellular stress. Mice lacking vimentin (Vim-/-) display phenotypes reflecting reduced levels of cell activation and ability to counteract stress, for example, decreased reactivity of astrocytes after neurotrauma, decreased migration of astrocytes and fibroblasts, attenuated inflammation and fibrosis in lung injury, delayed wound healing, impaired vascular adaptation to nephrectomy, impaired transendothelial migration of lymphocytes and attenuated atherosclerosis. To address the role of vimentin in fat accumulation, we assessed the body weight and fat by dual-energy X-ray absorptiometry (DEXA) in Vim-/- and matched wildtype (WT) mice. While the weight of 1.5-month-old Vim-/- and WT mice was comparable, Vim-/- mice showed decreased body weight at 3.5, 5.5 and 8.5 months (males by 19-22%, females by 18-29%). At 8.5 months, Vim-/- males and females had less body fat compared to WT mice (a decrease by 24%, p < 0.05, and 33%, p < 0.0001, respectively). The body mass index in 8.5 months old Vim-/- mice was lower in males (6.8 vs. 7.8, p < 0.005) and females (6.0 vs. 7.7, p < 0.0001) despite the slightly lower body length of Vim-/- mice. Increased mortality was observed in adult Vim-/- males. We conclude that vimentin is required for the normal accumulation of body fat. [ABSTRACT FROM AUTHOR]
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- 2019
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13. The acute effect of different NAD+ precursors included in the combined metabolic activators.
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Li, Xiangyu, Yang, Hong, Jin, Han, Turkez, Hasan, Ozturk, Gurkan, Doganay, Hamdi Levent, Zhang, Cheng, Nielsen, Jens, Uhlén, Mathias, Borén, Jan, and Mardinoglu, Adil
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NIACIN , *NICOTINAMIDE , *NAD (Coenzyme) , *NON-alcoholic fatty liver disease , *PLASMA products - Abstract
NAD+ and glutathione precursors are currently used as metabolic modulators for improving the metabolic conditions associated with various human diseases, including non-alcoholic fatty liver disease, neurodegenerative diseases, mitochondrial myopathy, and age-induced diabetes. Here, we performed a one-day double blinded, placebo-controlled human clinical study to assess the safety and acute effects of six different Combined Metabolic Activators (CMAs) with 1 g of different NAD+ precursors based on global metabolomics analysis. Our integrative analysis showed that the NAD+ salvage pathway is the main source for boosting the NAD+ levels with the administration of CMAs without NAD+ precursors. We observed that incorporation of nicotinamide (Nam) in the CMAs can boost the NAD+ products, followed by niacin (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but not flush free niacin (FFN). In addition, the NA administration led to a flushing reaction, accompanied by decreased phospholipids and increased bilirubin and bilirubin derivatives, which could be potentially risky. In conclusion, this study provided a plasma metabolomic landscape of different CMA formulations, and proposed that CMAs with Nam, NMN as well as NR can be administered for boosting NAD+ levels to improve altered metabolic conditions. [Display omitted] • The administration of serine, NAC and LCAT with NAD precursor is safe and well tolerated. • NAD salvage pathway is the main source of NAD when orally taking serine, NAC and LCAT. • Nam in the CMAs showed the best ability to boost plasma NAD+ products. • NA in the CMAs led to flushing reaction, decreased phospholipids and increased bilirubin. • Nam, NMN as well as NR are good candidates for boosting NAD level. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Longitudinal metabolomics analysis reveals the acute effect of cysteine and NAC included in the combined metabolic activators.
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Yang, Hong, Li, Xiangyu, Jin, Han, Turkez, Hasan, Ozturk, Gurkan, Doganay, Hamdi Levent, Zhang, Cheng, Nielsen, Jens, Uhlén, Mathias, Borén, Jan, and Mardinoglu, Adil
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NIACIN , *NAD (Coenzyme) , *CYSTEINE , *METABOLOMICS , *AMINO acids , *NICOTINAMIDE , *LIPID metabolism - Abstract
Growing evidence suggests that the depletion of plasma NAD+ and glutathione (GSH) may play an important role in the development of metabolic disorders. The administration of Combined Metabolic Activators (CMA), consisting of GSH and NAD+ precursors, has been explored as a promising therapeutic strategy to target multiple altered pathways associated with the pathogenesis of the diseases. Although studies have examined the therapeutic effect of CMA that contains N-acetyl- l -cysteine (NAC) as a metabolic activator, a system-wide comparison of the metabolic response to the administration of CMA with NAC and cysteine remains lacking. In this placebo-controlled study, we studied the acute effect of the CMA administration with different metabolic activators, including NAC or cysteine with/without nicotinamide or flush free niacin, and performed longitudinal untargeted-metabolomics profiling of plasma obtained from 70 well-characterized healthy volunteers. The time-series metabolomics data revealed the metabolic pathways affected after the administration of CMAs showed high similarity between CMA containing nicotinamide and NAC or cysteine as metabolic activators. Our analysis also showed that CMA with cysteine is well-tolerated and safe in healthy individuals throughout the study. Last, our study systematically provided insights into a complex and dynamics landscape involved in amino acid, lipid and nicotinamide metabolism, reflecting the metabolic responses to CMA administration containing different metabolic activators. [Display omitted] • The administration of different CMA formulas was safe and no toxic effect was seen in the healthy subjects participated in the study. • Similar plasma cysteine kinetics were observed between CMA formulas with NAC and cysteine. • Longitudinal untargeted-metabolomics profiling reveals the acute metabolic response is similar between CMA formulas with NAC and cysteine. [ABSTRACT FROM AUTHOR]
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- 2023
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15. The Extracellular Matrix Protein MAGP1 Is a Key Regulator of Adipose Tissue Remodeling During Obesity.
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Levin, Malin C. and Borén, Jan
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- 2014
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16. Treatment of Hyaluronan Accumulation Ameliorates High-Fat Diet-Induced Insulin Resistance in Mice.
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Fogelstrand, Per and Borén, Jan
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HIGH-fat diet , *LABORATORY rodents , *EXTRACELLULAR matrix , *HYALURONIC acid , *SKELETAL muscle , *INSULIN resistance - Abstract
The authors comment on a study by L. Kang and colleagues which investigated the effects of a high-fat diet on rodents published within the issue. The researchers found that such a diet led to accumulation of the extracellular matrix (ECM) molecular hyaluronan (HA) in skeletal muscle. It is noted that the authors of the study provided evidence for a causal relationship between HA expression and insulin resistance.
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- 2013
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17. In Memoriam: Sven-Olof Olofsson (1947–2011)
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Borén, Jan, Bondjers, Göran, and Wiklund, Olov
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- 2012
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18. Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome.
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Lim, Soo, Taskinen, Marja‐Riitta, and Borén, Jan
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FATTY liver , *SYNDROMES - Abstract
Summary: Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low‐grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue and de novo lipogenesis can lead to NAFLD and insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidaemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is a phenotype of cardiometabolic syndrome. Notably, researchers have discovered a close association between NAFLD and impaired glucose metabolism and focused on the role of NAFLD in the development of type 2 diabetes. Moreover, recent studies provide substantial evidence for an association between NAFLD and atherosclerosis and cardiometabolic disorders. Even if NAFLD can progress into severe liver disorders including nonalcoholic steatohepatitis (NASH) and cirrhosis, the majority of subjects with NAFLD die from cardiovascular disease eventually. In this review, we propose a potential pathological link between NAFLD/NASH and cardiometabolic syndrome. The potential factors that can play a pivotal role in this link, such as inflammation, insulin resistance, alteration in lipid metabolism, oxidative stress, genetic predisposition, and gut microbiota are discussed. [ABSTRACT FROM AUTHOR]
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- 2019
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19. AdipoR2 recruits protein interactors to promote fatty acid elongation and membrane fluidity.
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Ruiz, Mario, Devkota, Ranjan, Kaper, Delaney, Ruhanen, Hanna, Busayavalasa, Kiran, Radović, Uroš, Henricsson, Marcus, Käkelä, Reijo, Borén, Jan, and Pilon, Marc
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FATTY acids , *PROTEINS , *BLOOD proteins , *MEMBRANE proteins , *CAENORHABDITIS elegans , *MEMBRANE lipids , *PHOSPHOLIPIDS - Abstract
The human AdipoR2 and its Caenorhabditis elegans homolog PAQR-2 are multipass plasma membrane proteins that protect cells against membrane rigidification. However, how AdipoR2 promotes membrane fluidity mechanistically is not clear. Using 13C-labeled fatty acids, we show that AdipoR2 can promote the elongation and incorporation of membranefluidizing polyunsaturated fatty acids into phospholipids. To elucidate the molecular basis of these activities, we performed immunoprecipitations of tagged AdipoR2 and PAQR-2 expressed in HEK293 cells or whole C. elegans, respectively, and identified coimmunoprecipitated proteins using mass spectrometry. We found that several of the evolutionarily conserved AdipoR2/PAQR-2 interactors are important for fatty acid elongation and incorporation into phospholipids. We experimentally verified some of these interactions, namely, with the dehydratase HACD3 that is essential for the third of four steps in long-chain fatty acid elongation and ACSL4 that is important for activation of unsaturated fatty acids and their channeling into phospholipids. We conclude that AdipoR2 and PAQR-2 can recruit protein interactors to promote the production and incorporation of unsaturated fatty acids into phospholipids. [ABSTRACT FROM AUTHOR]
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- 2023
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20. Exploration of Novel Urolithin C Derivatives as Non-Competitive Inhibitors of Liver Pyruvate Kinase.
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Battisti, Umberto Maria, Monjas, Leticia, Akladios, Fady, Matic, Josipa, Andresen, Eric, Nagel, Carolin H., Hagkvist, Malin, Håversen, Liliana, Kim, Woonghee, Uhlen, Mathias, Borén, Jan, Mardinoğlu, Adil, and Grøtli, Morten
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NON-alcoholic fatty liver disease , *PYRUVATE kinase , *LIVER - Abstract
The inhibition of liver pyruvate kinase could be beneficial to halt or reverse non-alcoholic fatty liver disease (NAFLD), a progressive accumulation of fat in the liver that can lead eventually to cirrhosis. Recently, urolithin C has been reported as a new scaffold for the development of allosteric inhibitors of liver pyruvate kinase (PKL). In this work, a comprehensive structure–activity analysis of urolithin C was carried out. More than 50 analogues were synthesized and tested regarding the chemical features responsible for the desired activity. These data could pave the way to the development of more potent and selective PKL allosteric inhibitors. [ABSTRACT FROM AUTHOR]
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- 2023
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21. Cardiac arrhythmias and conduction abnormalities in patients with type 2 diabetes.
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Rawshani, Araz, McGuire, Darren K., Omerovic, Elmir, Sattar, Naveed, McMurray, John J. V., Smith, Ulf, Redfors, Bjorn, Bergfeldt, Lennart, Eliasson, Bjorn, Borén, Jan, Bhatt, Deepak L., Bergstrom, Goran, and Rawshani, Aidin
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ARRHYTHMIA , *SYSTOLIC blood pressure , *TYPE 2 diabetes , *ATRIAL flutter , *VENTRICULAR fibrillation , *VENTRICULAR tachycardia , *SINOATRIAL node , *ATRIAL fibrillation - Abstract
The association between type 2 diabetes (T2D) and the development of cardiac arrhythmias and conduction disturbances has not been extensively studied. Arrhythmia was defined as atrial fibrillation and flutter (AF/AFl), ventricular tachycardia (VT) and ventricular fibrillation (VF), and conduction abnormality as sinus node disease (SND), atrioventricular (AV) block or pacemaker implantation, and intraventricular conduction blocks (IVCB). Incidence rates and Cox regression were used to compare outcomes, and to assess optimal levels for cardiometabolic risk factors and risk associated with multifactorial risk factor control (i.e., HbA1c, LDL-C, systolic blood pressure (SBP), BMI and eGFR), between patients with versus without T2D. The analyses included data from 617,000 patients with T2D and 2,303,391 matched controls. Patients with diabetes and the general population demonstrated a gradual increase in rates for cardiac conduction abnormalities and virtually all age-groups for AF/AFI showed increased incidence during follow-up. For patients with versus without T2D, risks for cardiac arrhythmias were higher, including for AF/AFl (HR 1.17, 95% CI 1.16–1.18), the composite of SND, AV-block or pacemaker implantation (HR 1.40, 95% CI 1.37–1.43), IVCB (HR 1.23, 95% CI 1.18–1.28) and VT/VF (HR 1.08, 95% CI 1.04–1.13). For patients with T2D who had selected cardiometabolic risk factors within target ranges, compared with controls, risk of arrythmia and conduction abnormalities for T2D vs not were: AF/AFl (HR 1.09, 95% CI 1.05–1.14), the composite of SND, AV-block or pacemaker implantation (HR 1.06, 95% CI 0.94–1.18), IVCB (HR 0.80, 95% CI 0.60–0.98), and for VT/VF (HR 0.97, 95% CI 0.80–1.17). Cox models showed a linear risk increase for SBP and BMI, while eGFR showed a U-shaped association. Individuals with T2D had a higher risk of arrhythmias and conduction abnormalities than controls, but excess risk associated with T2D was virtually not evident among patients with T2D with all risk factors within target range. BMI, SBP and eGFR displayed significant associations with outcomes among patients with T2D. [ABSTRACT FROM AUTHOR]
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- 2023
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22. Left-Sided Degenerative Valvular Heart Disease in Type 1 and Type 2 Diabetes.
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Rawshani, Araz, Sattar, Naveed, McGuire, Darren K., Wallström, Oskar, Smith, Ulf, Borén, Jan, Bergström, Göran, Omerovic, Elmir, Rosengren, Annika, Eliasson, Björn, Bhatt, Deepak L., and Rawshani, Aidin
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HEART valve diseases , *TYPE 1 diabetes , *TYPE 2 diabetes , *MITRAL stenosis , *AORTIC valve insufficiency , *MITRAL valve insufficiency - Abstract
Background: The role of diabetes in the development of valvular heart disease, and, in particular, the relation with risk factor control, has not been extensively studied.Methods: We included 715 143 patients with diabetes registered in the Swedish National Diabetes Register and compared them with 2 732 333 matched controls randomly selected from the general population. First, trends were analyzed with incidence rates and Cox regression, which was also used to assess diabetes as a risk factor compared with controls, and, second, separately in patients with diabetes according to the presence of 5 risk factors.Results: The incidence of valvular outcomes is increasing among patients with diabetes and the general population. In type 2 diabetes, systolic blood pressure, body mass index, and renal function were associated with valvular lesions. Hazard ratios for patients with type 2 diabetes who had nearly all risk factors within target ranges, compared with controls, were as follows: aortic stenosis 1.34 (95% CI, 1.31-1.38), aortic regurgitation 0.67 (95% CI, 0.64-0.70), mitral stenosis 1.95 (95% CI, 1.76-2.20), and mitral regurgitation 0.82 (95% CI, 0.79-0.85). Hazard ratios for patients with type 1 diabetes and nearly optimal risk factor control were as follows: aortic stenosis 2.01 (95% CI, 1.58-2.56), aortic regurgitation 0.63 (95% CI, 0.43-0.94), and mitral stenosis 3.47 (95% CI, 1.37-8.84). Excess risk in patients with type 2 diabetes for stenotic lesions showed hazard ratios for aortic stenosis 1.62 (95% CI, 1.59-1.65), mitral stenosis 2.28 (95% CI, 2.08-2.50), and excess risk in patients with type 1 diabetes showed hazard ratios of 2.59 (95% CI, 2.21-3.05) and 11.43 (95% CI, 6.18-21.15), respectively. Risk for aortic and mitral regurgitation was lower in type 2 diabetes: 0.81 (95% CI, 0.78-0.84) and 0.95 (95% CI, 0.92-0.98), respectively.Conclusions: Individuals with type 1 and 2 diabetes have greater risk for stenotic lesions, whereas risk for valvular regurgitation was lower in patients with type 2 diabetes. Patients with well-controlled cardiovascular risk factors continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control. [ABSTRACT FROM AUTHOR]- Published
- 2022
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23. The spoils of war and the long-term spoiling of health conditions of entire nations.
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Navarese, Eliano P., Grzelakowska, Klaudyna, Mangini, Francesco, Kubica, Jacek, Banach, Maciej, Benn, Marianne, Binder, Christoph J., Borén, Jan, Catapano, Alberico, Kronenberg, Florian, Mallat, Ziad, Moulin, Philippe, Öörni, Katariina, Ray, Kausik K., Roeters van Lennep, Jeanine E., Romeo, Stefano, Tokgozoglu, Lale, von Eckardstein, Arnold, Zambon, Alberto, and Raggi, Paolo
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AGGRESSION (International law) , *HEALTH services accessibility , *NON-communicable diseases , *COVID-19 pandemic , *CARDIOVASCULAR diseases - Abstract
The healthcare system of Ukraine was already suffering from several shortfalls before February 2022, but the war of aggression started by the Russian leadership is poised to inflict a further severe blow that will have long-lasting consequences for the health of all Ukrainians. In pre-war Ukraine, noncommunicable diseases (NCDs) contributed to 91% of deaths, especially cardiovascular diseases (67%). Ukrainians have a high prevalence of risk factors for NCDs ranking among the highest levels reported by the World Health Organization (WHO) in the European (EU) Region. Cardiovascular disease is one of the key health risks for the conflict-affected Ukrainian population due to significant limitations in access to health care and interruptions in the supply of medicines and resources. The excess mortality observed during the COVID-19 pandemic, due to a combination of viral illness and chronic disease states, is bound to increase exponentially from poorly treated NCDs. In this report, we discuss the impact of the war on the public health of Ukraine and potential interventions to provide remote health assistance to the Ukrainian population. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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24. Role of endogenous incretins in the regulation of postprandial lipoprotein metabolism.
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Taskinen, Marja-Riitta, Matikainen, Niina, Björnson, Elias, Söderlund, Sanni, Ainola, Mari, Hakkarainen, Antti, Lundbom, Nina, Sihlbom, Carina, Thorsell, Annika, Andersson, Linda, Adiels, Martin, Hartmann, Bolette, Deacon, Carolyn F., Holst, Jens J., Packard, Chris J., and Borén, Jan
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INCRETINS , *GLUCAGON-like peptides , *LIPID metabolism , *CHYLOMICRONS , *METABOLISM - Abstract
Objective: Incretins are known to influence lipid metabolism in the intesti ne when administered as pharmacologic agents. The aggregate influence of endogenous incretins on chylo micron production and clearance is less clear, particularly in light of opposing effects of co-secreted hormone s. Here, we tested the hypothesis that physiological levels of incretins may impact on production or clearances rate s of chylomicrons and VLDL. Design and methods: A group of 22 overweight/obese men was studied to determine ass ociations between plasma levels of glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) after a fat-rich meal and the production and clearance rates of apoB48- and apoB100-containing triglyceride-rich lipoproteins. Subjects were stratified by above- and below-media n incretin response (area under the curve). Results: Stratification yielded subgroups that differed about two-fold in incretin response. There were neither differences in apoB48 production rates in chylomicrons or VLDL f ractions nor in apoB100 or triglyceride kinetics in VLDL between men with above-vs below-median incretin responses. The men with above-median GLP-1 and GLP-2 responses exhibited higher postprandial plasma and chylomicron triglyceride levels, but this could not be related to altered kinetic parameters. No differences were found between in cretin response subgroups and particle clearance rates. Conclusion: We found no evidence for a regulatory effect of endogenous incre tins on contemporaneous chylomicron or VLDL metabolism following a standardised fat-rich meal. The act ions of incretins at pharmacological doses may not be reflected at physiological levels of these hormones. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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25. Modified lipid metabolism and cytosolic phospholipase A2 activation in mesangial cells under pro-inflammatory conditions.
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Boi, Roberto, Ebefors, Kerstin, Henricsson, Marcus, Borén, Jan, and Nyström, Jenny
- Abstract
Diabetic kidney disease is a consequence of hyperglycemia and other complex events driven by early glomerular hemodynamic changes and a progressive expansion of the mesangium. The molecular mechanisms behind the pathophysiological alterations of the mesangium are yet to be elucidated. This study aimed at investigating whether lipid signaling might be the missing link. Stimulation of human mesangial cells with high glucose primed the inflammasome-driven interleukin 1 beta (IL-1β) secretion, which in turn stimulated platelet-derived growth factor (PDGF-BB) release. Finally, PDGF-BB increased IL-1β secretion synergistically. Both IL-1β and PDGF-BB stimulation triggered the formation of phosphorylated sphingoid bases, as shown by lipidomics, and activated cytosolic phospholipase cPLA2, sphingosine kinase 1, cyclooxygenase 2, and autotaxin. This led to the release of arachidonic acid and lysophosphatidylcholine, activating the secretion of vasodilatory prostaglandins and proliferative lysophosphatidic acids. Blocking cPLA2 release of arachidonic acid reduced mesangial cells proliferation and prostaglandin secretion. Validation was performed in silico using the Nephroseq database and a glomerular transcriptomic database. In conclusion, hyperglycemia primes glomerular inflammatory and proliferative stimuli triggering lipid metabolism modifications in human mesangial cells. The upregulation of cPLA2 was critical in this setting. Its inhibition reduced mesangial secretion of prostaglandins and proliferation, making it a potential therapeutical target. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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26. Multiomics Analysis Reveals the Impact of Microbiota on Host Metabolism in Hepatic Steatosis.
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Zeybel, Mujdat, Arif, Muhammad, Li, Xiangyu, Altay, Ozlem, Yang, Hong, Shi, Mengnan, Akyildiz, Murat, Saglam, Burcin, Gonenli, Mehmet Gokhan, Yigit, Buket, Ulukan, Burge, Ural, Dilek, Shoaie, Saeed, Turkez, Hasan, Nielsen, Jens, Zhang, Cheng, Uhlén, Mathias, Borén, Jan, and Mardinoglu, Adil
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FATTY liver , *BIOLOGICAL networks , *GUT microbiome , *INFLAMMATION , *METABOLISM - Abstract
Metabolic dysfunction‐associated fatty liver disease (MAFLD) is a complex disease involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background, and environmental factors including the microbiome. To decipher hepatic steatosis (HS) pathogenesis by excluding critical confounding factors including genetic variants and diabetes, 56 heterogenous MAFLD patients are characterized by generating multiomics data including oral and gut metagenomics as well as plasma metabolomics and inflammatory proteomics data. The dysbiosis in the oral and gut microbiome is explored and the host–microbiome interactions based on global metabolic and inflammatory processes are revealed. These multiomics data are integrated using the biological network and HS's key features are identified using multiomics data. HS is finally predicted using these key features and findings are validated in a follow‐up cohort, where 22 subjects with varying degree of HS are characterized. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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27. Sulfone-based human liver pyruvate kinase inhibitors – Design, synthesis and in vitro bioactivity.
- Author
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Matić, Josipa, Akladios, Fady, Battisti, Umberto Maria, Håversen, Liliana, Nain-Perez, Amalyn, Füchtbauer, Anders Foller, Kim, Woonghee, Monjas, Leticia, Rivero, Alexandra Rodriguez, Borén, Jan, Mardinoglu, Adil, Uhlen, Mathias, and Grøtli, Morten
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NON-alcoholic fatty liver disease , *KINASE inhibitors , *PYRUVATE kinase , *SULFONES , *LIVER , *LEAD compounds , *STRUCTURE-activity relationships - Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD. To address this critical gap, researchers have been investigating potential targets for NAFLD drug development. One promising candidate is the liver isoform of pyruvate kinase (PKL). In recent studies, Urolithin C, an allosteric inhibitor of PKL, has emerged as a potential lead compound for therapeutic intervention. Building upon this knowledge, our team has conducted a comprehensive structure-activity relationship of Urolithin C. In this work, we have employed a scaffold-hopping approach, modifying the urolithin structure by replacing the urolithin carbonyl with a sulfone moiety. Our structure-activity relationship analysis has identified the sulfone group as particularly favourable for potent PKL inhibition. Additionally, we have found that the presence of catechol moieties on the two aromatic rings further improves the inhibitory activity. The most promising inhibitor from this new series displayed nanomolar inhibition, boasting an IC 50 value of 0.07 μM. This level of potency rivals that of urolithin D and significantly surpasses the effectiveness of urolithin C by an order of magnitude. To better understand the molecular interactions underlying this inhibition, we obtained the crystal structure of one of the inhibitors complexed with PKL. This structural insight served as a valuable reference point, aiding us in the design of inhibitors. [Display omitted] • Polyphenolic tricyclic sulfones act as allosteric inhibitors of PKL. • SAR study identified sulfone moiety and -OH groups to be crucial for PKL inhibition. • The best PKL inhibitor from the series showed an IC 50 value of 0.07 μM. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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28. Cadmium exposure is accompanied by increased prevalence and future growth of atherosclerotic plaques in 64-year-old women.
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Fagerberg, Björn, Bergström, Göran, Borén, Jan, and Barregard, Lars
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CADMIUM , *ATHEROSCLEROTIC plaque , *CREATININE , *CAROTID artery , *CARBOHYDRATE intolerance - Abstract
Objectives There is currently widespread exposure to the toxic metal cadmium through the diet as well as through smoking, and it has been suggested that cadmium exposure may increase the risk of cardiovascular disease. Here we examined whether cadmium exposure is associated with prevalence and growth of atherosclerotic plaques in the carotid arteries. Design and subjects The analyses were performed in a screening-based cohort of 64-year-old Caucasian women with stratified, random selection to groups with normal glucose tolerance, impaired glucose tolerance and diabetes ( n = 599). We measured cadmium concentrations in blood and urine at baseline. In addition, we performed ultrasound examination to determine the prevalence and area of atherosclerotic plaques in the carotid arteries and assessed smoking history and other cardiovascular risk factors at baseline and at a follow-up examination after a mean of 5.4 years. Results At baseline, blood cadmium levels were associated with increased risk of plaque and a large plaque area after adjustment for confounders. In women who had never smoked, blood cadmium levels correlated positively with plaque area at baseline. The occurrence of large plaques and the change in plaque area at follow-up were associated with blood and creatinine-corrected urinary cadmium concentrations at baseline after adjustment for confounders. Blood and urine cadmium levels added information to established cardiovascular risk factors in predicting progress of atherosclerosis. Conclusions We have shown that cadmium levels in blood and urine are independent factors associated with the development of atherosclerotic plaques at baseline as well as prospectively. This novel observation emphasizes the need to consider cadmium as a pro-atherogenic pollutant. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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29. Testosterone reduces metabolic brown fat activity in male mice.
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Rodriguez, Marta Lantero, Schilperoort, Maaike, Johansson, Inger, Eriksson, Elin Svedlund, Palsdottir, Vilborg, Kroon, Jan, Henricsson, Marcus, Kooijman, Sander, Ericson, Mia, Borén, Jan, Ohlsson, Claes, Jansson, John-Olov, Levin, Malin C., Rensen, Patrick C. N., and Tivesten, Åsa
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BROWN adipose tissue , *ANDROGEN receptors , *HYPOTHERMIA , *BODY temperature , *TESTOSTERONE - Abstract
Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expre ssion of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceridederived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice (4.5-fold increase vs sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic a ctions of testosterone. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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30. Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients.
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Zeybel, Mujdat, Altay, Ozlem, Arif, Muhammad, Li, Xiangyu, Yang, Hong, Fredolini, Claudia, Akyildiz, Murat, Saglam, Burcin, Gonenli, Mehmet Gokhan, Ural, Dilek, Kim, Woonghee, Schwenk, Jochen M, Zhang, Cheng, Shoaie, Saeed, Nielsen, Jens, Uhlén, Mathias, Borén, Jan, and Mardinoglu, Adil
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NON-alcoholic fatty liver disease , *FATTY liver , *ASPARTATE aminotransferase , *ALANINE aminotransferase - Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo‐controlled 10‐week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients. SYNOPSIS: A placebo‐controlled human study shows that oral administration of Combined Metabolic Activators (CMA) reduces liver fat in nonalcoholic fatty liver disease (NAFLD) patients. CMA, consisting of L‐serine, nicotinamide riboside, N‐acetyl‐L‐cysteine, and L‐carnitine tartrate, has a profound effect on hepatic steatosis after only 70 days of treatment in NAFLD patients.CMA supplementation improved clinical parameters in NAFLD patients, such as reductions in aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine.The underlying mechanisms associated with the beneficial effect of CMA were revealed by a comprehensive analysis of plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomics. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
31. Combined Metabolic Activators Accelerates Recovery in Mild‐to‐Moderate COVID‐19.
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Altay, Ozlem, Arif, Muhammad, Li, Xiangyu, Yang, Hong, Aydın, Mehtap, Alkurt, Gizem, Kim, Woonghee, Akyol, Dogukan, Zhang, Cheng, Dinler‐Doganay, Gizem, Turkez, Hasan, Shoaie, Saeed, Nielsen, Jens, Borén, Jan, Olmuscelik, Oktay, Doganay, Levent, Uhlén, Mathias, and Mardinoglu, Adil
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COVID-19 , *NAD (Coenzyme) , *GLUTATHIONE , *BLOOD proteins , *NICOTINAMIDE , *RESPIRATORY infections , *CARNITINE - Abstract
COVID‐19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID‐19 patients. CMAs include l‐serine, N‐acetyl‐l‐cysteine, nicotinamide riboside, and l‐carnitine tartrate, salt form of l‐carnitine. Placebo‐controlled, open‐label phase 2 study and double‐blinded phase 3 clinical trials are conducted to investigate the time of symptom‐free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID‐19 with CMAs lead to a more rapid symptom‐free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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32. A genetic titration of membrane composition in Caenorhabditis elegans reveals its importance for multiple cellular and physiological traits.
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Devkota, Ranjan, Kaper, Delaney, Bodhicharla, Rakesh, Henricsson, Marcus, Borén, Jan, and Pilon, Marc
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UNSATURATED fatty acids , *HOMEOSTASIS , *GENETICS , *CAENORHABDITIS elegans , *CELL membranes , *ANIMAL experimentation , *AUTOPHAGY , *PERMEABILITY , *GENES , *PHOSPHOLIPIDS , *CELL lines , *FATTY acids - Abstract
The composition and biophysical properties of cellular membranes must be tightly regulated to maintain the proper functions of myriad processes within cells. To better understand the importance of membrane homeostasis, we assembled a panel of five Caenorhabditis elegans strains that show a wide span of membrane composition and properties, ranging from excessively rich in saturated fatty acids (SFAs) and rigid to excessively rich in polyunsaturated fatty acids (PUFAs) and fluid. The genotypes of the five strain are, from most rigid to most fluid: paqr-1(tm3262); paqr-2(tm3410), paqr-2(tm3410), N2 (wild-type), mdt-15(et14); nhr-49(et8), and mdt-15(et14); nhr-49(et8); acs-13(et54). We confirmed the excess SFA/rigidity-to-excess PUFA/fluidity gradient using the methods of fluorescence recovery after photobleaching (FRAP) and lipidomics analysis. The five strains were then studied for a variety of cellular and physiological traits and found to exhibit defects in: permeability, lipid peroxidation, growth at different temperatures, tolerance to SFA-rich diets, lifespan, brood size, vitellogenin trafficking, oogenesis, and autophagy during starvation. The excessively rigid strains often exhibited defects in opposite directions compared to the excessively fluid strains. We conclude that deviation from wild-type membrane homeostasis is pleiotropically deleterious for numerous cellular/physiological traits. The strains introduced here should prove useful to further study the cellular and physiological consequences of impaired membrane homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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33. Expression of scavenger receptor class B type I in gallbladder columnar epithelium.
- Author
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JOHNSON, MAGNUS SC, SVENSSON, PER-ARNE, BORÉN, JAN, BILLIG, HÅKAN, CARLSSON, LENA MS, and CARLSSON, BJÖRN
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BILE , *EPITHELIUM , *LIPOPROTEINS - Abstract
Abstract Background The lipid content of bile may be modified by the gallbladder epithelium. Recent studies indicate that cholesterol can be absorbed from bile and that this can be enhanced by apolipoprotein (apo) A-I. SR-BI is a multifunctional receptor capable of binding a wide array of native or modified lipoproteins, phospholipid or bile acid micelles. As apo A-I is a ligand for scavenger receptor class B type I (SR-BI) we have characterized the expression of this receptor in murine gallbladder. Methods Reverse transcription–polymerase chain reaction (RT-PCR), immunoblotting and immunohistochemistry were used to study SR-BI expression in murine gallbladders. SR-BI expression was also used to examine gallbladders from high-fat-fed wild-type and apo B-100 transgenic mice. Results SR-BI and SR-BII mRNA are expressed in gallbladder. SR-BI immunoreactivity was localized to the columnar epithelium of the gallbladder. Immunoreactive SR-BI in gallbladder had an estimated molecular weight of 57 kDa, in contrast to the expected 82 kDa. Deglycosylation experiments indicated that the size difference between the two forms of the receptor is due to post-translational modification. Fat feeding of apo B transgenic mice resulted in gallstone formation but had no effect on the abundance of SR-BI. Conclusions Gallbladder epithelial cells express SR-BI. This opens the possibility that SR-BI may influence the modification of bile in the gallbladder. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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34. Relationship between de novo lipogenesis and serum sex hormone binding globulin in humans.
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Simons, Pomme I. H. G., Valkenburg, Olivier, Telgenkamp, Ine, van der Waaij, Koen M., de Groot, David M., Veeraiah, Pandichelvam, Bons, Judith A. P., Taskinen, Marja‐Riitta, Borén, Jan, Schrauwen, Patrick, Rutten, Joost H. W., Cassiman, David, Schalkwijk, Casper G., Stehouwer, Coen D. A., Schrauwen‐Hinderling, Vera B., Hodson, Leanne, and Brouwers, Martijn C. G. J.
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SEX hormones , *LIPID synthesis , *GLOBULINS , *NON-alcoholic fatty liver disease , *FATTY liver - Abstract
Objective: Obesity and liver fat are associated with decreased levels of serum sex hormone binding globulin (SHBG). Laboratory studies suggest that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans. Design: A cross‐sectional study examining the association between DNL, measured by stable isotopes, and serum SHBG, stratified by sex. Participants: Healthy men (n = 34) and women (n = 21) were combined from two cross‐sectional studies. Forty‐two per cent of participants had hepatic steatosis, and the majority were overweight (62%) or obese (27%). Results: DNL was inversely associated with SHBG in women (β: −0.015, 95% CI: −0.030; 0.000), but not in men (β: 0.007, 95% CI: −0.005; 0.019) (p for interaction =.068). Adjustment for study population, age and body mass index did not materially change these results, although statistical significance was lost after adjustment for serum insulin. Conclusions: An inverse association between DNL and SHBG may explain the decreased SHBG levels that are observed in obesity, at least in women. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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35. Silencing of STE20‐type kinase MST3 in mice with antisense oligonucleotide treatment ameliorates diet‐induced nonalcoholic fatty liver disease.
- Author
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Caputo, Mara, Kurhe, Yeshwant, Kumari, Sima, Cansby, Emmelie, Amrutkar, Manoj, Scandalis, Eli, Booten, Sheri L., Ståhlman, Marcus, Borén, Jan, Marschall, Hanns‐Ulrich, Aghajan, Mariam, and Mahlapuu, Margit
- Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as a leading cause of chronic liver disease worldwide. Despite intensive nonclinical and clinical research in this field, no specific pharmacological therapy is currently approved to treat NAFLD, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies have identified STE20‐type kinase MST3, which localizes to intracellular lipid droplets, as a critical regulator of ectopic fat accumulation in human hepatocytes. Here, we explored whether treatment with Mst3‐targeting antisense oligonucleotides (ASOs) can promote hepatic lipid clearance and mitigate NAFLD progression in mice in the context of obesity. We found that administration of Mst3‐targeting ASOs in mice effectively ameliorated the full spectrum of high‐fat diet‐induced NAFLD including liver steatosis, inflammation, fibrosis, and hepatocellular damage. Mechanistically, Mst3 ASOs suppressed lipogenic gene expression, as well as acetyl‐CoA carboxylase (ACC) protein abundance, and substantially reduced lipotoxicity‐mediated oxidative and endoplasmic reticulum stress in the livers of obese mice. Furthermore, we found that MST3 protein levels correlated positively with the severity of NAFLD in human liver biopsies. In summary, this study provides the first in vivo evidence that antagonizing MST3 signaling is sufficient to mitigate NAFLD progression in conditions of excess dietary fuels and warrants future investigations to assess whether MST3 inhibitors may provide a new strategy for the treatment of patients with NAFLD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
36. Effects of liraglutide on the metabolism of triglyceride‐rich lipoproteins in type 2 diabetes.
- Author
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Taskinen, Marja‐Riitta, Björnson, Elias, Matikainen, Niina, Söderlund, Sanni, Pietiläinen, Kirsi H., Ainola, Mari, Hakkarainen, Antti, Lundbom, Nina, Fuchs, Johannes, Thorsell, Annika, Andersson, Linda, Adiels, Martin, Packard, Chris J., and Borén, Jan
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TYPE 2 diabetes , *LIRAGLUTIDE , *CHYLOMICRONS , *LIPOPROTEINS , *STABLE isotope tracers , *INSULIN sensitivity - Abstract
Aim: To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48‐ and apoB100‐containing triglyceride‐rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat‐rich meal. Materials and Methods: Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low‐density lipoprotein (VLDL) production and clearance after a single fat‐rich meal. Results: Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p <.0001) and increased the triglyceride/apoB48 ratio (i.e. the size) of chylomicrons (p <.001). Direct clearance of chylomicrons, a quantitatively significant pathway pretreatment, decreased by 90% on liraglutide (p <.001). Liraglutide also reduced VLDL1‐triglyceride secretion (p =.017) in parallel with reduced liver fat. Chylomicron‐apoB48 production and particle size were related to insulin sensitivity (p =.015 and p <.001, respectively), but these associations were perturbed by liraglutide. Conclusions: In a physiologically relevant setting that mirrored regular feeding in subjects with T2D, liraglutide promoted potentially beneficial changes on postprandial apoB48 metabolism. Using our data in an integrated metabolic model, we describe how the action of liraglutide in T2D on chylomicron and VLDL kinetics could lead to decreased generation of remnant lipoproteins. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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37. The C. elegans PAQR-2 and IGLR-2 membrane homeostasis proteins are uniquely essential for tolerating dietary saturated fats.
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Devkota, Ranjan, Henricsson, Marcus, Borén, Jan, and Pilon, Marc
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CAENORHABDITIS elegans , *MEMBRANE proteins , *FLUORESCENCE resonance energy transfer , *SATURATED fatty acids , *FAT , *ADIPONECTIN , *FAT content of food - Abstract
How cells maintain vital membrane lipid homeostasis while obtaining most of their constituent fatty acids from a varied diet remains largely unknown. Here, we report the first whole-organism (Caenorhabditis elegans) forward genetic screen to identify genes essential for tolerance to dietary saturated fatty acids (SFAs). We found that only the PAQR-2/IGLR-2 pathway, homologous to the human adiponectin receptor 2 (AdipoR2) pathway, is uniquely essential to prevent SFA-mediated toxicity. When provided a SFA-rich diet, worms lacking either protein accumulate an excess of SFAs in their membrane phospholipids, which is accompanied by membrane rigidification. Additionally, we used fluorescence resonance energy transfer (FRET) to show that the interaction between PAQR-2 and IGLR-2 is regulated by membrane fluidity, suggesting a mechanism by which this protein complex senses membrane properties. We also created versions of PAQR-2 that lacked parts of the cytoplasmic N-terminal domain and showed that these were still functional, though still dependent on the interaction with IGLR-2. We conclude that membrane homeostasis via the PAQR-2/IGLR-2 fluidity sensor is the only pathway specifically essential for the non-toxic uptake of dietary SFAs in C. elegans. Unlabelled Image • We screened for genes essential to tolerate dietary saturated fats in C. elegans. • The screen identified novel alleles of only two genes: paqr-2 and iglr-2. • PAQR-2 and ILGLR-2 are membrane proteins important for membrane homeostasis. • The interaction between PAQR-2 and IGLR-2 is induced by membrane rigidification. • The cytoplasmic domain of PAQR-2 is not essential for its function. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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38. Antibodies against apoB100 peptide 210 inhibit atherosclerosis in apoE-/- mice.
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Dunér, Pontus, Mattisson, Ingrid Yao, Fogelstrand, Per, Glise, Lars, Ruiz, Stacey, Farina, Christopher, Borén, Jan, Nilsson, Jan, and Bengtsson, Eva
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ATHEROSCLEROTIC plaque , *IMMUNE response , *AUTOANTIBODIES , *CARDIOVASCULAR diseases risk factors , *IMMUNOGLOBULIN G ,ANIMAL models of atherosclerosis - Abstract
Atherosclerotic plaques are characterized by an accumulation and subsequent oxidation of LDL, resulting in adaptive immune responses against formed or exposed neoepitopes of the LDL particle. Autoantibodies against native p210, the 3136–3155 amino acid sequence of the LDL protein apolipoprotein B-100 (apoB100) are common in humans and have been associated with less severe atherosclerosis and decreased risk for cardiovascular events in clinical studies. However, whether apoB100 native p210 autoantibodies play a functional role in atherosclerosis is not known. In the present study we immunized apoE-/- mice with p210-PADRE peptide to induce an antibody response against native p210. We also injected mice with murine monoclonal IgG against native p210. Control groups were immunized with PADRE peptide alone or with control murine monoclonal IgG. Immunization with p210-PADRE induced an IgG1 antibody response against p210 that was associated with reduced atherosclerotic plaque formation in the aorta and reduced MDA-LDL content in the lesions. Treatment with monoclonal p210 IgG produced a similar reduction in atherosclerosis as immunization with p210-PADRE. Our findings support an atheroprotective role of antibodies against the apoB100 native p210 and suggest that vaccines that induce the expression of native p210 IgG represent a potential therapeutic strategy for lowering cardiovascular risk. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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39. Lipid profiling of human diabetic myocardium reveals differences in triglyceride fatty acyl chain length and degree of saturation.
- Author
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Björnson, Elias, Östlund, Ylva, Ståhlman, Marcus, Adiels, Martin, Omerovic, Elmir, Jeppsson, Anders, Borén, Jan, and Levin, Malin C.
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MYOCARDIUM , *TYPE 2 diabetes , *UNSATURATED fatty acids , *PEOPLE with diabetes , *TRIGLYCERIDES , *ORTHOPEDIC shoes - Abstract
Type 2 diabetes is a major health problem in the world, and is strongly associated with impaired cardiac function and increased mortality. The causal relationship between type 2 diabetes and impaired cardiac function is still incompletely understood but changes in the cardiac lipid metabolism are believed to be a contributing factor. The objective of this study was to determine the lipid profile in human myocardial biopsies collected in vivo from patients with type 2 diabetes and compare to non-diabetic controls. We conducted full lipidomics analyses, using mass spectrometry, of 85 right atrial biopsies obtained from diabetic and non-diabetic patients undergoing elective cardiac surgery. The patients were characterized clinically and serum was analyzed for lipids and biochemical markers. The groups did not differ in BMI and in circulating triglycerides. We demonstrate that type 2 diabetes is associated with alterations in the cardiac lipidome. Interestingly, the absolute amount of lipids is not altered in the diabetic myocardium. However, triglycerides with longer fatty acyl chains are more abundant and there is a higher degree of unsaturated fatty acid chains in triglycerides in diabetic myocardium. Our study reveals that type 2 diabetes is a relatively strong determinant of the human cardiac lipidome (compared to other clinical variables). Although the total lipid content in the diabetic myocardium is not increased, the lipid composition is markedly affected. • Type 2 diabetes status correlates with variation in the human cardiac lipidome. • The absolute amount of lipids is not altered in the diabetic myocardium. • Triglycerides with longer fatty acyl chains are more abundant in diabetic myocardium. • There is a higher degree of unsaturated fatty acid chains in triglycerides in diabetic myocardium. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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40. Lack of RAC1 in macrophages protects against atherosclerosis.
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Bandaru, Sashidar, Ala, Chandu, Ekstrand, Matias, Akula, Murali K., Pedrelli, Matteo, Liu, Xi, Bergström, Göran, Håversen, Liliana, Borén, Jan, Bergo, Martin O., and Akyürek, Levent M.
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MACROPHAGES , *ATHEROSCLEROTIC plaque , *ATHEROSCLEROSIS , *TARGETED drug delivery , *SUBTILISINS , *MICROFILAMENT proteins , *AORTA , *CYTOSKELETON - Abstract
The Rho GTPase RAC1 is an important regulator of cytoskeletal dynamics, but the role of macrophage-specific RAC1 has not been explored during atherogenesis. We analyzed RAC1 expression in human carotid atherosclerotic plaques using immunofluorescence and found higher macrophage RAC1 expression in advanced plaques compared with intermediate human atherosclerotic plaques. We then produced mice with Rac1-deficient macrophages by breeding conditional floxed Rac1 mice (Rac1fl/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis was studied in vivo by infecting Rac1fl/fl and Rac1fl/fl/LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Rac1fl/fl/LC macrophages secreted lower levels of IL-6 and TNF-α and exhibited reduced foam cell formation and lipid uptake. The deficiency of Rac1 in macrophages reduced the size of aortic atherosclerotic plaques in AdPCSK9-infected Rac1fl/fl/LC mice. Compare with controls, intima/media ratios, the size of necrotic cores, and numbers of CD68-positive macrophages in atherosclerotic plaques were reduced in Rac1-deficient mice. Moreover, we found that RAC1 interacts with actin-binding filamin A. Macrophages expressed increased RAC1 levels in advanced human atherosclerosis. Genetic inactivation of RAC1 impaired macrophage function and reduced atherosclerosis in mice, suggesting that drugs targeting RAC1 may be useful in the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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41. Leveraging a gain-of-function allele of Caenorhabditis elegans paqr-1 to elucidate membrane homeostasis by PAQR proteins.
- Author
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Busayavalasa, Kiran, Ruiz, Mario, Devkota, Ranjan, Ståhlman, Marcus, Bodhicharla, Rakesh, Svensk, Emma, Hermansson, Nils-Olov, Borén, Jan, and Pilon, Marc
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GAIN-of-function mutations , *CAENORHABDITIS elegans , *FATTY acid desaturase , *UNSATURATED fatty acids , *PROTEINS , *VEGETABLE oils , *PHOSPHOLIPIDS - Abstract
The C. elegans proteins PAQR-2 (a homolog of the human seven-transmembrane domain AdipoR1 and AdipoR2 proteins) and IGLR-2 (a homolog of the mammalian LRIG proteins characterized by a single transmembrane domain and the presence of immunoglobulin domains and leucine-rich repeats in their extracellular portion) form a complex that protects against plasma membrane rigidification by promoting the expression of fatty acid desaturases and the incorporation of polyunsaturated fatty acids into phospholipids, hence increasing membrane fluidity. In the present study, we leveraged a novel gain-of-function allele of PAQR-1, a PAQR-2 paralog, to carry out structure-function studies. We found that the transmembrane domains of PAQR-2 are responsible for its functional requirement for IGLR-2, that PAQR-1 does not require IGLR-2 but acts via the same pathway as PAQR-2, and that the divergent N-terminal cytoplasmic domains of the PAQR-1 and PAQR-2 proteins serve a regulatory function and may regulate access to the catalytic site of these proteins. We also show that overexpression of human AdipoR1 or AdipoR2 alone is sufficient to confer increased palmitic acid resistance in HEK293 cells, and thus act in a manner analogous to the PAQR-1 gain-of-function allele. Author summary: Cells are enclosed within membranes primarily composed of fat. When membranes contain much saturated fats, they tend to become more rigid, as with butter. Conversely, when membranes are rich in unsaturated fats, they become more fluid, as with vegetable oils. Our goal is to better understand how cells monitor and adjust the composition and properties of their membranes. We focus on a small group of proteins found in all animals, and called AdipoR1 and AdipoR2 in humans, and PAQR-1 and PAQR-2 in the worm Caenorhabditis elegans. We now found a version of PAQR-1 that is more "active", and promotes increased levels of unsaturated fats in membranes. By swapping different parts of the PAQR-1 protein with those of PAQR-2, we were able to determine which protein parts played which roles. We found that it is the transmembrane domains of PAQR-2 that dictate its requirements for another protein called IGLR-2 and that the intracellular domains of PAQR-1 and PAQR-2 play a regulatory role. These studies help understand how AdipoR1 and AdipoR2 regulate membrane composition in human cells, which is a vital function for us to thrive on diets that vary greatly in the types of fats that they contain. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
42. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM.
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Langlois, Michel R., Nordestgaard, Børge G., Langsted, Anne, Chapman, M. John, Aakre, Kristin M., Baum, Hannsjörg, Borén, Jan, Bruckert, Eric, Catapano, Alberico, Cobbaert, Christa, Collinson, Paul, Descamps, Olivier S., Duff, Christopher J., von Eckardstein, Arnold, Hammerer-Lercher, Angelika, Kamstrup, Pia R., Kolovou, Genovefa, Kronenberg, Florian, Mora, Samia, and Pulkki, Kari
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LIPOPROTEINS , *HIGH density lipoproteins , *APOLIPOPROTEIN B , *ATHEROSCLEROSIS , *EUROPEAN integration , *LOW density lipoproteins - Abstract
The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total – HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2–10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20–100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
43. Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM.
- Author
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Nordestgaard, Børge G., Langlois, Michel R., Langsted, Anne, Chapman, M. John, Aakre, Kristin M., Baum, Hannsjörg, Borén, Jan, Bruckert, Eric, Catapano, Alberico, Cobbaert, Christa, Collinson, Paul, Descamps, Olivier S., Duff, Christopher J., von Eckardstein, Arnold, Hammerer-Lercher, Angelika, Kamstrup, Pia R., Kolovou, Genovefa, Kronenberg, Florian, Mora, Samia, and Pulkki, Kari
- Subjects
- *
LIPOPROTEINS , *APOLIPOPROTEIN B , *ATHEROSCLEROSIS , *EUROPEAN integration , *APOLIPOPROTEINS - Abstract
The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (=total – HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDL cholesterol is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDL cholesterol shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDL cholesterol decline poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2–10 mmol/L). Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apolipoprotein B measurement can detect elevated LDL particle numbers often unidentified on the basis of LDL cholesterol alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20–100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. Image 1 • Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (=total – HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. • LDL cholesterol is the primary target of lipid-lowering therapies. • Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and lipoprotein(a) should be measured at least once in all patients. • Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). • Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. • Laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
44. Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia.
- Author
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Klevstig, Martina, Arif, Muhammad, Mannila, Maria, Svedlund, Sara, Mardani, Ismena, Ståhlman, Marcus, Andersson, Linda, Lindbom, Malin, Miljanovic, Azra, Franco-Cereceda, Anders, Eriksson, Per, Jeppsson, Anders, Gan, Li-Ming, Levin, Malin, Mardinoglu, Adil, Ehrenborg, Ewa, and Borén, Jan
- Subjects
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CARRIER proteins , *CORONARY disease , *APOLIPOPROTEIN B , *HEART , *CARDIAC patients - Abstract
The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events. • Allele-specific cardiac MTTP expression makes the human heart vulnerable to ischemia. • MTTP-A deficient mice show impaired cardiac function after myocardial infarction. • No effect on MTTP expression, activity or lipid content in hearts of MTTP-A null mice • MTTP expression is linked to separate biological processes in heart compared to liver. • Expression of MTTP and genes linked to mitochondrial function is associated in heart. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
45. Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans.
- Author
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Cansby, Emmelie, Kulkarni, Nagaraj M., Magnusson, Elin, Kurhe, Yeshwant, Amrutkar, Manoj, Nerstedt, Annika, Ståhlman, Marcus, Sihlbom, Carina, Marschall, Hanns-Ulrich, Borén, Jan, Blüher, Matthias, and Mahlapuu, Margit
- Abstract
Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepatitis (NASH). Understanding the molecular networks controlling hepatocellular lipid deposition is therefore essential for developing new strategies to effectively prevent and treat this complex disease. Here, we describe a new regulator of lipid partitioning in human hepatocytes: mammalian sterile 20-like (MST) 3. We found that MST3 protein coats lipid droplets in mouse and human liver cells. Knockdown of MST3 attenuated lipid accumulation in human hepatocytes by stimulating ß-oxidation and triacylglycerol secretion while inhibiting fatty acid influx and lipid synthesis. We also observed that lipogenic gene expression and acetyl-coenzyme A carboxylase protein abundance were reduced in MST3-deficient hepatocytes, providing insight into the molecular mechanisms underlying the decreased lipid storage. Furthermore, MST3 expression was positively correlated with key features of NASH (i.e., hepatic lipid content, lobular inflammation, and hepatocellular ballooning) in human liver biopsies. In summary, our results reveal a role of MST3 in controlling the dynamic metabolic balance of liver lipid catabolism vs. lipid anabolism. Our findings highlight MST3 as a potential drug target for the prevention and treatment of NASH and related complex metabolic diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
46. Role of apolipoprotein C‐III overproduction in diabetic dyslipidaemia.
- Author
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Adiels, Martin, Taskinen, Marja‐Riitta, Björnson, Elias, Andersson, Linda, Matikainen, Niina, Söderlund, Sanni, Kahri, Juhani, Hakkarainen, Antti, Lundbom, Nina, Sihlbom, Carina, Thorsell, Annika, Zhou, Haihong, Pietiläinen, Kirsi H., Packard, Chris, and Borén, Jan
- Subjects
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PROTON magnetic resonance spectroscopy , *MASS spectrometry , *TYPE 2 diabetes , *INSULIN aspart , *BODY mass index , *OVERPRODUCTION - Abstract
Aims: To investigate how apolipoprotein C‐III (apoC‐III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC‐III, and whether improvement of glycaemic control using the glucagon‐like peptide‐1 analogue liraglutide for 16 weeks modifies apoC‐III dynamics. Materials and Methods: Postprandial apoC‐III kinetics were assessed after a bolus injection of [5,5,5‐2H3]leucine using ultrasensitive mass spectrometry techniques. We compared apoC‐III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non‐diabetic subjects. Liver fat content, subcutaneous abdominal and intra‐abdominal fat were determined using proton magnetic resonance spectroscopy. Results: Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC‐III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC‐III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC‐III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC‐III secretion rate was higher in subjects with type 2 diabetes compared with BMI‐matched non‐diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). Conclusions: The results reveal that the secretion rate of apoC‐III is associated with elevation of triglyceride‐rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC‐III. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
47. Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis.
- Author
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Bandaru, Sashidar, Ala, Chandu, Salimi, Reza, Akula, Murali K., Ekstrand, Matias, Devarakonda, Sravani, Karlsson, Joakim, Van den Eynden, Jimmy, Bergström, Göran, Larsson, Erik, Levin, Max, Borén, Jan, Bergo, Martin O., and Akyürek, Levent M.
- Subjects
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ATHEROSCLEROTIC plaque , *CELL motility , *MICROFILAMENT proteins , *ATHEROSCLEROSIS , *BONE marrow , *ANIMAL experimentation , *CARRIER proteins , *CELL culture , *COMPARATIVE studies , *GENETIC techniques , *IMMUNITY , *MACROPHAGES , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *RESEARCH , *EVALUATION research , *CHEMICAL inhibitors - Abstract
Background: The actin-binding protein FLNA (filamin A) regulates signal transduction important for cell locomotion, but the role of macrophage-specific FLNA during atherogenesis has not been explored.Methods: We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with Flna-deficient macrophages by breeding conditional Flna-knockout mice ( Flna o/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter ( LC). Atherosclerosis in vivo was studied by transplanting bone marrow from male Flna o/fl/ LC mice to atherogenic low-density lipoprotein receptor-deficient ( Ldlr-/-) mice; and by infecting Flna o/fl and Flna o/fl/ LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Furthermore, C57BL/6 mice were infected with AdPCSK9 and then treated with the calpain inhibitor calpeptin to inhibit FLNA cleavage.Results: We found that macrophage FLNA expression was higher in advanced than in intermediate human atherosclerotic plaques. Flna o/fl/ LC macrophages proliferated and migrated less than controls; expressed lower levels of phosphorylated AKT and ERK1/2; exhibited reduced foam cell formation and lipid uptake; and excreted more lipids. The deficiency of Flna in macrophages markedly reduced the size of aortic atherosclerotic plaques in both Ldlr-/-BMT: Flnao/fl/LC and AdPCSK9-infected Flna o/fl/ LC mice. Intima/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in Flna-deficient mice than in control mice. Moreover, we found that STAT3 interacts with a calpain-cleaved carboxyl-terminal fragment of FLNA. Inhibiting calpain-mediated FLNA cleavage with calpeptin in macrophages reduced nuclear levels of phosphorylated STAT3, interleukin 6 secretion, foam cell formation, and lipid uptake. Finally, calpeptin treatment reduced the size of atherosclerotic plaques in C57BL/6 mice infected with AdPCSK9.Conclusions: Genetic inactivation of Flna and chemical inhibition of calpain-dependent cleavage of FLNA impaired macrophage signaling and function, and reduced atherosclerosis in mice, suggesting that drugs targeting FLNA may be useful in the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]- Published
- 2019
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- View/download PDF
48. Localised lipid accumulation detected in infarcted mouse heart tissue using ToF-SIMS.
- Author
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Sämfors, Sanna, Ståhlman, Marcus, Klevstig, Martina, Borén, Jan, and Fletcher, John S.
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LIPID analysis , *FAT analysis , *ISCHEMIA , *ABNORMALITIES in mice , *MYOCARDIAL infarction - Abstract
Graphical abstract Highlights • ToF-SIMS imaging together with multivariate analysis can successfully identify infarcted and normal mouse heart tissue. • Highly localised lipid species can be found in the border region between damaged and normal tissue. • ToF-SIMS and LC–MS are truly complementary providing a combination of quantitative and spatial correlated information. Abstract Cardiovascular disease (CVD) is largely related to complications from atherosclerotic disease such as myocardial infarction (MI) and ischemic stroke and accounts for more than 30% of overall global mortality. Understanding the biochemical changes that occur in cardiac tissue following myocardial infarction is critical for clarifying the mechanisms underlying the impaired heart function seen after a myocardial infarction. Lipids have been shown to accumulate in ischemic cardiac tissue following an infarction. Recent data indicate that this cardiac lipid accumulation induces apoptosis and loss of muscle cells during the post-infarction period, which aggravate the functional impairment in the heart and limit its adaptive capacity for compensatory remodelling. It is therefore important to identify the lipids and molecular mechanisms that induce these destructive responses. In this study, the spatial distribution of lipids in mouse cardiac tissue after surgically induced infarction were identified using ToF-SIMS imaging with a gas cluster ion beam (GCIB). The benefits of frozen hydrated analysis versus freeze dried sample preparation were assessed as was the suitability of different multivariate analysis techniques for identification of localised chemical changes in the tissue. Results show that differences in intensity of the peaks in the mass spectrum corresponding to different lipids can be detected between the infarcted region of the heart and normal tissue region as well as specific accumulation of acyl-carnitine species at the boundary of the damaged region. Different spatial distributions of lipids were detected in both positive and negative ion mode providing insights into the changes in lipid metabolism following infarction. The ToF-SIMS results were compared with conventional lipidomics where although many lipid classes show similar changes between infarcted and non-infarcted hearts the ToF-SIMS data revealed differences due to salt adduct formation and most importantly where the changes in lipid signal are highly localised at the border between the infarcted and non-infarcted regions of the heart. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
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49. In vivo genome and base editing of a human PCSK9 knock-in hypercholesterolemic mouse model.
- Author
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Carreras, Alba, Pane, Luna Simona, Nitsch, Roberto, Madeyski-Bengtson, Katja, Porritt, Michelle, Akcakaya, Pinar, Taheri-Ghahfarokhi, Amir, Ericson, Elke, Bjursell, Mikael, Perez-Alcazar, Marta, Seeliger, Frank, Althage, Magnus, Knöll, Ralph, Hicks, Ryan, Mayr, Lorenz M., Perkins, Rosie, Lindén, Daniel, Borén, Jan, Bohlooly-Y, Mohammad, and Maresca, Marcello
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LOW density lipoproteins , *CHOLESTEROL , *CARDIOVASCULAR diseases risk factors , *HYPERCHOLESTEREMIA , *MEDICATION safety , *THERAPEUTIC use of monoclonal antibodies - Abstract
Background: Plasma concentration of low-density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates cholesterol homeostasis, has recently emerged as an approach to reduce cholesterol levels. The development of humanized animal models is an important step to validate and study human drug targets, and use of genome and base editing has been proposed as a mean to target disease alleles. Results: To address the lack of validated models to test the safety and efficacy of techniques to target human PCSK9, we generated a liver-specific human PCSK9 knock-in mouse model (hPCSK9-KI). We showed that plasma concentrations of total cholesterol were higher in hPCSK9-KI than in wildtype mice and increased with age. Treatment with evolocumab, a monoclonal antibody that targets human PCSK9, reduced cholesterol levels in hPCSK9-KI but not in wildtype mice, showing that the hypercholesterolemic phenotype was driven by overexpression of human PCSK9. CRISPR-Cas9-mediated genome editing of human PCSK9 reduced plasma levels of human and not mouse PCSK9, and in parallel reduced plasma concentrations of total cholesterol; genome editing of mouse Pcsk9 did not reduce cholesterol levels. Base editing using a guide RNA that targeted human and mouse PCSK9 reduced plasma levels of human and mouse PCSK9 and total cholesterol. In our mouse model, base editing was more precise than genome editing, and no off-target editing nor chromosomal translocations were identified. Conclusions: Here, we describe a humanized mouse model with liver-specific expression of human PCSK9 and a human-like hypercholesterolemia phenotype, and demonstrate that this mouse can be used to evaluate antibody and gene editing-based (genome and base editing) therapies to modulate the expression of human PCSK9 and reduce cholesterol levels. We predict that this mouse model will be used in the future to understand the efficacy and safety of novel therapeutic approaches for hypercholesterolemia. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
50. Liraglutide treatment improves postprandial lipid metabolism and cardiometabolic risk factors in humans with adequately controlled type 2 diabetes: A single‐centre randomized controlled study.
- Author
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Matikainen, Niina, Söderlund, Sanni, Björnson, Elias, Pietiläinen, Kirsi, Hakkarainen, Antti, Lundbom, Nina, Taskinen, Marja‐Riitta, and Borén, Jan
- Subjects
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LIPID metabolism , *HEART metabolism disorders , *TYPE 2 diabetes , *FATTY liver , *CARDIOVASCULAR diseases - Abstract
Aims: Patients with type 2 diabetes and non‐alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon‐like peptide 1 (GLP‐1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes. Methods: The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single‐blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high‐fat mixed meal were measured before and at the end of the liraglutide intervention. Results: Weight loss at Week 16 was similar between the groups: −2.4 kg (−2.5%) in the liraglutide group and −2.1 kg (−2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or β‐hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses. Conclusions: Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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