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Background: Both pemafibrate and sodium glucose cotransporter-2 (SGLT2) inhibitor can decrease serum transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD) complicated with dyslipidemia and type 2 diabetes mellitus (T2DM), respectively. However, the effectiveness of combined therapy has been rarely reported. Methods: This is a two-center retrospective observational study. NAFLD patients complicated with T2DM treated with pemafibrate for >1 year were included, in whom prior treatment with SGLT2 inhibitor > 1 year failed to normalize serum alanine aminotransferase (ALT) levels. Hepatic inflammation, function, and fibrosis were assessed by ALT, albumin-bilirubin (ALBI) score, and Mac-2 binding protein glycosylation isomer (M2BPGi) levels, respectively. Results: Seven patients were included. The median duration of prior treatment with SGLT2 inhibitors was 2.3 years. During the one year before starting pemafibrate therapy, the therapy did not significantly change hepatic enzymes. All patients received pemafibrate 0.1 mg twice daily without dose escalations. During one year of pemafibrate therapy, triglyceride, aspartate aminotransferase, ALT, γ-glutamyl transpeptidase, ALBI score, and M2BPGi levels significantly improved (p < 0.05), although weight or hemoglobin A1c did not significantly change. Conclusions: One year of pemafibrate therapy improves markers of hepatic inflammation, function, and fibrosis in NAFLD patients in whom long-term SGLT2 inhibitor therapy failed to normalize serum ALT.

Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR–ligands modulate Protein–Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor γ (PPARγ), which describes NR–ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR–coregulator binding (KID) and NR–ligand binding (KIID), jointly recapitulated in the cooperativity factor (α) for each specific ternary ligand·NR·coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure–activity-relationships for NR–ligands and can steer NR modulator discovery and optimization via a completely novel approach.

BACKGROUND AND AIMS: Increased fatty acid (FA) flux from adipose tissue to the liver contributes to the development of NAFLD. Because free FAs are key lipotoxic triggers accelerating disease progression, inhibiting adipose triglyceride lipase (ATGL)/patatin-like phospholipase domain containing 2 (PNPLA2), the main enzyme driving lipolysis, may attenuate steatohepatitis. APPROACH AND RESULTS: Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with methionine-choline-deficient (MCD) or high-fat high-carbohydrate (HFHC) diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis, and endoplasmic reticulum (ER) stress markers were investigated. DNA binding activity for peroxisome proliferator-activated receptor (PPAR) α and PPARδ was measured. After short hairpin RNA-mediated ATGL knockdown, HepG2 cells were treated with lipopolysaccharide (LPS) or oleic acid:palmitic acid 2:1 (OP21) to explore the direct role of ATGL in inflammation in vitro. On MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared with challenged wild-type (WT) mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary-challenged ATGL LKO mice showed lower hepatic inflammation, reflected by the reduced number of Galectin3/MAC-2 and myeloperoxidase-positive cells and low mRNA expression levels of inflammatory markers (such as IL-1β and F4/80) when compared with WT mice. In line with this, protein levels of the ER stress markers protein kinase R-like endoplasmic reticulum kinase and inositol-requiring enzyme 1α were reduced in ATGL LKO mice fed with MCD diet. Accordingly, pretreatment of LPS-treated HepG2 cells with the PPARδ agonist GW0742 suppressed mRNA expression of inflammatory markers. Additionally, ATGL knockdown in HepG2 cells attenuated LPS/OP21-induced expression of proinflammatory cytokines and chemokines such as chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand (Ccl) 2, and Ccl5. CONCLUSIONS: Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis. ispartof: HEPATOLOGY vol:75 issue:1 pages:125-139 ispartof: location:United States status: published

Peroxisomes play an important role in the metabolism of a variety of biomolecules, including lipids and bile acids. Peroxisomal Membrane Protein 4 (PXMP4) is a ubiquitously expressed peroxisomal membrane protein that is transcriptionally regulated by peroxisome proliferator-activated receptor α (PPARα), but its function is still unknown. To investigate the physiological function of PXMP4, we generated a Pxmp4 knockout (Pxmp4−/−) mouse model using CRISPR/Cas9-mediated gene editing. Peroxisome function was studied under standard chow-fed conditions and after stimulation of peroxisomal activity using the PPARα ligand fenofibrate or by using phytol, a metabolite of chlorophyll that undergoes peroxisomal oxidation. Pxmp4−/− mice were viable, fertile, and displayed no changes in peroxisome numbers or morphology under standard conditions. Also, no differences were observed in the plasma levels of products from major peroxisomal pathways, including very long-chain fatty acids (VLCFAs), bile acids (BAs), and BA intermediates di- and trihydroxycholestanoic acid. Although elevated levels of the phytol metabolites phytanic and pristanic acid in Pxmp4−/− mice pointed towards an impairment in peroxisomal α-oxidation capacity, treatment of Pxmp4−/− mice with a phytol-enriched diet did not further increase phytanic/pristanic acid levels. Finally, lipidomic analysis revealed that loss of Pxmp4 decreased hepatic levels of the alkyldiacylglycerol class of neutral ether lipids, particularly those containing polyunsaturated fatty acids. Together, our data show that while PXMP4 is not critical for overall peroxisome function under the conditions tested, it may have a role in the metabolism of (ether)lipids.

Aim Alport syndrome (AS) is the second most common hereditary kidney disease caused by mutations in collagen IV genes. Patients present with microhaematuria that progressively leads to proteinuria and end stage renal disease. Currently, no specific treatment exists for AS. Using mass spectrometry based proteomics, we aimed to detect early alterations in molecular pathways implicated in AS before the stage of overt proteinuria, which could be amenable to therapeutic intervention. Methods Kidneys were harvested from male Col4a3 −/− knock out and sex and age‐matched Col4a3 +/+ wild‐type mice at 4 weeks of age. Purified peptides were separated by liquid chromatography and analysed by high resolution mass spectrometry. The Cytoscape bioinformatics tool was used for function enrichment and pathway analysis. PPARα expression levels were evaluated by immunofluorescence and immunoblotting. Results Proteomic analysis identified 415 significantly differentially expressed proteins, which were mainly involved in metabolic and cellular processes, the extracellular matrix, binding and catalytic activity. Pathway enrichment analysis revealed among others, downregulation of the proteasome and PPAR pathways. PPARα protein expression levels were observed to be downregulated in Alport mice, supporting further the results of the discovery proteomics. Conclusion This study provides additional evidence that alterations in proteins which participate in cellular metabolism and mitochondrial homeostasis in kidney cells are early events in the development of chronic kidney disease in AS. Of note is the dysregulation of the PPAR pathway, which is amenable to therapeutic intervention and provides a new potential target for therapy in AS., SUMMARY AT A GLANCE Alterations in proteins which participate in cellular metabolism and mitochondrial homeostasis in kidney cells, are early events in the development of CKD in Alport syndrome. In addition, pathway enrichment analysis revealed among others, dysregulation of the proteasome, protein digestion and absorption pathways as well as PPAR pathway in AS compared to control mice. Targeting the PPAR pathway could be a potential therapeutic approach in AS.

This in silico toxicogenomic study aims to explore the relationship between phthalates and bisphenol A (BPA) co-exposure and obesity, as well as its comorbid conditions, in order to construct a possible set of genomic biomarkers. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org ) was used as the main data mining tool, along with GeneMania (https://genemania.org), ToppGene Suite (https://toppgene.cchmc.org ) and DisGeNET (http://www. disgenet.org). Among the phthalates, bis(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) were chosen as the most frequently curated phthalates in CTD, which also share similar mechanisms of toxicity. DEHP, DBP and BPA interacted with 84, 90 and 194 obesity-related genes/proteins, involved in 67, 65 and 116 pathways, respectively. Among these, 53 genes/proteins and 42 pathways were common to all three substances. 31 genes/proteins had matching interactions for all three investigated substances, while more than half of these genes/proteins (56.49%) were in co-expression. 7 of the common genes/proteins (6 relevant to humans: CCL2, IL6, LPL, PPARG, SERPINE1, and TNF) were identified in all the investigated obesity comorbidities, while PPARG and LPL were most closely linked to obesity. These genes/proteins could serve as a target for further in vitro and in vivo studies of molecular mechanisms of DEHP, DBP and BPA mixture obesogenic properties. Analysis reported here should be applicable to any mixture of environmental chemicals and any disease present in CTD.

In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.

In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.

Background Apolipoprotein-I (ApoA-I), the major component of high-density lipoprotein (HDL) particles, mediates cholesterol efflux by which it facilitates the removal of excess cholesterol from peripheral tissues. Therefore, elevating ApoA-I production leading to the production of new pre-beta-HDL particles is thought to be beneficial in the prevention of cardiovascular diseases. Recently, we observed that amoxicillin treatment led to decreased HDL concentrations in healthy human volunteers. We questioned whether this antibiotic effect was directly or indirectly, via changed short-chain fatty acids (SCFA) concentrations through an altered gut microflora. Therefore, we here evaluated the effects of amoxicillin and various SCFA on hepatic ApoA-I expression, secretion, and the putative underlying pathways. Methods and Results Human hepatocytes (HepG2) were exposed to increasing dose of amoxicillin or SCFA for 48 hours. ApoA-I messenger RNA (mRNA) transcription and secreted protein were analyzed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. To study underlying mechanisms, changes in mRNA expression of KEAP1, CPT1, and PPAR alpha, as well as a PPAR alpha transactivation assay, were analyzed. Amoxicillin dose-dependently decreased ApoA-I mRNA transcription as well as ApoA-I protein secretion. SCFA treatment resulted in a dose-dependent stimulation of ApoA-I mRNA transcription, however, the ApoA-I protein secretion was decreased. Furthermore, SCFA treatment increased PPAR alpha transactivation, PPAR alpha and CPT1 mRNA transcription, whereas KEAP1 mRNA transcription was decreased. Conclusion Direct treatment of HepG2 cells with amoxicillin has either direct effects on lowering ApoA-I transcription and secretion or indirect effects via modified SCFA concentrations because SCFA were found to stimulate hepatic ApoA-I expression. Furthermore, BET inhibition and PPAR alpha activation were identified as possible mechanisms behind the observed effects on ApoA-I transcription.

Amaç: PPAR-Alpha gen polimorfizminin kadın futbolcular üzerindeki etkisini incelemektir. Materyal ve Metot: Çalışmaya 18-26 yaş arasında olan 24 kadın futbolcu ve 25 kadın sedanter gönüllü katılmıştır. DNA izolasyonu için çalışma ve kontrol gruplarından EDTA'lı tüplere 2 ml periferik kan uzman hemşire tarafından sağ veya sol kol ön venöz damardan alınmıştır. Bilgilendirilmiş onam formları doldurulduktan sonra Karadeniz İleri Teknoloji Araştırma ve Uygulama Merkezi (KİTAM) Laboratuvarında genotipleme yapılmıştır. PPAR-α geninin polimorfik bölgesi (rs4253778), PCR-RFLP yöntemi kullanılarak tanımlanmıştır. PPAR-α geninin intron 7 içinde yer alan ve C-T substitüsyonunu içeren 266 bç'lik segment PCR ile çoğaltılmıştır. Amplifikasyon reaksiyonu oluşturularak PCR ürünleri elde edilmiştir. Elde edilen ürünler, agaroz jelde yürütülmüş ve 266 bç'lik fragmanlar GG genotipi; 253bç, 216 bç ve 50 bç'lik fragmanlar GC genotipi ve 232bç ve 21bç'lik fragmanlar CC genotipi olarak değerlendirilip istatistiki analizler yapılmıştır. Bulgular: Sporcuların yaş ortalaması 20,04 yıl, sedanterlerin 21,24 yıl, sporcuların vücut uzunluğu 166,08 cm, sedanterlerin 164,88 cm, vücut ağırlığı sporcularda 57,08 kg, sedanterler de 58,72 kg olarak bulunmuştur. Yapılan Ki Kare analizi sonunda sporcu ve sedanter gruplar arasında farklılık yoktur (p=0,913). Sporcuların genotip dağılımları GC genotipi 6, GG genotipi 17, CC genotipi 1, sedanterlerin ise GC genotipi 5, GG genotipi 19, CC genotipi 1 olarak tespit edilmiştir. Sonuç: Çalışmamızda PPAR-alpha geni polimorfizmi verilerimizin, sporcuların belirlenmesine ve sporcuların hangi spor branşlarına yatkınlığının tespitinde önemli bir etken olacaktır. Türkiye' de PPAR -alpha genotipinin dağılımı ile ilgili buna benzer çalışmalar için bir veri tabanı oluşturulmasında kullanılabileceği düşünülmektedir. Aim: To Investigate the Effect Of PPAR-Alpha Gene Polymorphism on Female Football Players. Materials and Methods: 24 female football players and 25 female sedentary volunteers between the ages of 18-26 participated in the study. For DNA isolation, 2 ml of peripheral blood samples were taken from the right or left arm anterior venous vessel into EDTA tubes from the study and control groups by specialist nurses. Genotyping procedure was done at the Black Sea Advanced Technology Research and Application Center (KITAM) Laboratory after filling the informed consent forms. The polymorphic region (rs4253778) of the PPAR-α gene was identified by the PCR-RFLP method. The 266 bp segment located in intron 7 of the PPAR-α gene and containing the C-T substitution were amplified by PCR. PCR products were obtained by amplification reaction. The products obtained were run in agarose gel and fragments of 266 bp were evaluated as GG genotype; the 253bç, 216 bp and 50 bp fragments were evaluated as GC genotype; and 232bc and 21bp fragments were evaluated as CC genotype; and then statistical analyzes were performed. Results: The average age of the athletes is 20.04 years, the sedentary ones are 21.24 years; the height of the athletes is 166.08 cm, the sedentary ones are 164.88 cm; the weight is 57.08 kg for the athletes and 58.72 kg for the sedentary. At the end of the Chi-Square analysis, there is no significant difference between sportsmen and sedentary groups (p = 0.913). The distribution of genotypes among athletes was identified as 6 GC genotype, 17 GG genotype, 1 CC genotype; the distribution of genotypes among sedentary was identified as 5 GC genotype, 19 GG genotype, and 1 CC genotype. Conclusion: The data related to PPAR-alpha gene polymorphism will be an important factor for identifying prospective athletes and determining which sports branches the athletes are inclined to. Our study is thought to be used in the formation of data base for some similar studies about the distribution of PPAR-alpha genotype in Turkey.

Concentrations of apolipoprotein A-I (ApoA-I) decrease during inflammation, which may lead to dysfunctional ApoA-I-poor high-density lipoprotein (HDL) particles, and as such, elevate cardiovascular risk. Therefore, rescuing ApoA-I concentrations, especially during inflammation, seems beneficial. Recently, short-chain fatty acids (SCFAs) have received more attention as a strategy in reversing atherosclerosis. We here evaluated the effects of SCFAs on inflammatory pathways in relation to ApoA-I transcription. SCFAs dose&ndash, response studies were performed in the presence and absence of inflammatory cytokines. ApoA-I and interleukin 8 (IL-8) mRNA expression were analyzed using qPCR and ELISA, respectively. To study underlying mechanisms, nuclear factor kappa B (NF-&kappa, B) transactivation and changes in mRNA expressions of the genes targets of bromodomain and extra-terminal (BET) inhibition, peroxisome proliferator-activated receptor-alpha (PPAR&alpha, ) transactivation and activator protein 1 (AP-1) pathway were analyzed. SCFAs (except hexanoic acid) increased ApoA-I mRNA transcription in both normal and inflammatory conditions and lowered IL-8 mRNA expression. This anti-inflammatory effect of SCFAs was confirmed by inhibition of NF-&kappa, B transactivation. Moreover, butyric acid increased carnitine palmitoyltransferase 1 (CPT1), PPAR&alpha, target gene, mRNA transcription in both conditions, and there was a negative correlation between CPT1 and NF-&kappa, B. Therefore, PPAR&alpha, transactivation is probably involved in the anti-inflammatory effects of SCFAs, which rescues ApoA-I transcription. In conclusion, propionate, butyrate and valerate elicit anti-inflammatory effects which might rescue ApoA-I transcription in inflammatory conditions via PPAR&alpha, transactivation mediated NF-&kappa, B inhibition.

Hypercholesterolemia, also called high cholesterol, is a form of hyperlipidemia, which may be a consequence of diet, obesity or diabetes. In addition, increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL) cholesterol are associated with a higher risk of atherosclerosis and coronary heart disease. Thus, controlling cholesterol levels is commonly necessary, and fibrates have been used as lipid-lowering drugs. Gemfibrozil is a fibrate that acts via peroxisome proliferator-activated receptor alpha to promote changes in lipid metabolism and decrease serum triglyceride levels. However, anemia and leukopenia are known side effects of gemfibrozil. Considering that gemfibrozil may lead to anemia and that gemfibrozil acts via peroxisome proliferator-activated receptor alpha, we treated wild-type and peroxisome proliferator-activated receptor alpha-knockout mice with gemfibrozil for four consecutive days. Gemfibrozil treatment led to anemia seven days after the first administration of the drug, we found reduced levels of hemoglobin, as well as red blood cells, white blood cells and a reduced percentage of hematocrits. PPAR-alpha-knockout mice were capable of reversing all of those reduced parameters induced by gemfibrozil treatment. Erythropoietin levels were increased in the serum of gemfibrozil-treated animals, and we also observed an increased expression of hypoxia-inducible factor-2 alpha (HIF-2&alpha, ) and erythropoietin in renal tissue, while PPAR-alpha knockout mice treated with gemfibrozil did not present increased levels of serum erythropoietin or tissue HIF-2&alpha, and erythropoietin mRNA levels in the kidneys. We analyzed bone marrow and found that gemfibrozil reduced erythrocytes and hematopoietic stem cells in wild-type mice but not in PPAR-alpha-knockout mice, while increased colony-forming units were observed only in wild-type mice treated with gemfibrozil. Here, we show for the first time that gemfibrozil treatment leads to anemia and leukopenia via peroxisome proliferator-activated receptor alpha in mice.

Submitted by Kalina CB/A (kalikros2@gmail.com) on 2021-10-21T19:39:27Z No. of bitstreams: 1 Dissertação - Carolline Santos Miranda - 2020 - Completa.pdf: 2157672 bytes, checksum: 41ebe273ddb1dd54abb7ebd581e40775 (MD5) Made available in DSpace on 2021-10-21T19:39:27Z (GMT). No. of bitstreams: 1 Dissertação - Carolline Santos Miranda - 2020 - Completa.pdf: 2157672 bytes, checksum: 41ebe273ddb1dd54abb7ebd581e40775 (MD5) Previous issue date: 2020-02-20 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES This work aimed to analyze the effects of a selective PPAR-alpha agonist on the adverse remodeling of brown adipose tissue (TAM) (whitening) in mice fed a high fat or high fructose diet, with emphasis on thermogenesis, beta-oxidation and lipolysis. Fifty animals were randomly assigned to receive a control diet (C, 10% lipid as energy), hyperlipid diet (HF, 50% lipid as energy) or high fructose diet (HFRU, 50% fructose as energy). 12 weeks The HF and HFRU groups were redivided to initiate 5-week treatment: C, HF, HF-a, HFRU and HFRU-a. The PPAR-alpha agonist (WY14643) was mixed with the diet at a dose of 3.5 mg/kg body mass (BM). The following analyses were performed: BM, food intake, OGTT, indirect calorimetry, termography, light and confocal microscopy, plasma analyses and q-PCR. The HF group had overweight, while the HF and HFRU groups presented oral glucose intolerance and metabolic alterations, which were attenuated by PPARα activation. The HF and HFRU groups showed reduced immunostaining of UCP1 and VEGFA, but only the HF group showed a pattern of lipid droplet accumulation that resembled white adipose tissue (TAB), characterizing whitening. Whitening in the HF group was accompanied by decreased expression of genes related to thermogenesis, β-oxidation and lipolysis. All of these were increased by PPARα activation. The treated groups also showed a lower respiratory exchange rate than the untreated groups, suggesting that lipids were used as fuel for thermogenesis. In conclusion, the PPARα agonist reversed the interscapular TAM (TAMi) whitening and attenuated the histological changes in the HFRU group, inducing the thermogenic pathway, reducing the size of lipid droplets, and increasing the adrenergic stimulus and lipolysis in the treated HF group. O presente trabalho teve como objetivo analisar os efeitos de um agonista seletivo do PPAR-alfa (PPARα) sobre o remodelamento adverso do tecido adiposo marrom (TAM) (whitening) em camundongos alimentados com dieta hiperlipídica ou rica em frutose, com ênfase na termogênese, beta-oxidação (β-oxidação) e lipólise. Cinquenta animais foram designados aleatoriamente para receber dieta controle (C, 10% de lipídios como energia), dieta hiperlipídica (HF, 50% de lipídios como energia) ou dieta rica em frutose (HFRU, 50% de frutose como energia) por 12 semanas. Os grupos HF e HFRU foram redivididos para iniciar o tratamento de 5 semanas: C, HF, HF-a, HFRU e HFRU-a. O agonista PPARα (WY-14643) foi misturado à dieta na dose de 3,5 mg/kg da massa corporal (MC). Foram realizadas as seguintes análises: MC, ingestão alimentar, TOTG, calorimetria indireta, termografia, microscopia de luz e confocal, análise plasmática e q-PCR. O grupo HF apresentou aumento da MC, enquanto os grupos HF e HFRU apresentaram intolerância oral à glicose e alterações metabólicas, as quais foram atenuadas pela ativação do PPARα. Os grupos HF e HFRU apresentaram imunomarcação reduzida de UCP1 e VEGFA, mas apenas o grupo HF apresentou um padrão de acúmulo de gotículas lipídicas que se assemelhava ao tecido adiposo branco (TAB), caracterizando o whitening. O whitening no grupo HF foi acompanhado pela diminuição da expressão de genes relacionados à termogênese, β-oxidação e lipólise. Todos esses foram aumentados pela ativação do PPARα. Os grupos tratados também mostraram uma taxa de troca respiratória menor do que os não tratados, sugerindo que lipídios foram utilizados como combustível para a termogênese. Em conclusão, agonista do PPARα reverteu o whitening do TAM interescapular (TAMi) e atenuou as alterações histológicas no grupo HFRU, induzindo a via termogênica, reduzindo o tamanho das gotículas lipídicas, além do aumento do estímulo adrenérgico e lipólise no grupo HF tratado.

Aim – In hepatocytes, the peroxisome proliferator-activated receptor (PPAR)-a and insulin receptor (IR) are critical for transcriptional responses to fasting and feeding, respectively. The present report analyzes the effects of nutritional status (fasting vs feeding) on the expression of a large panel of hepatokines in hepatocyte-specific PPAR-a (Ppara hep/) and IR (IRhep/) null mice. Methods – Pparahep/ and IRhep/ mice, and their wild-type littermates, were subjected to fasting or feeding metabolic challenges, then analyzed for hepatokine gene expression. Experiments were conducted in mice of both genders. Results – Our data confirmed that PPAR-a is essential for regulating fasting-induced Fgf21 and Angptl4 expression. In mice lacking PPAR-a, fasting led to increased Igfbp1 and Gdf15 gene expression. In the absence of hepatic IR, feeding induced overexpression of Igfbp1, follistatin (Fst) and adropin (Enho), and reduced activin E (Inhbe) expression. Gender had only a modest influence on hepatokine gene expression in the liver. Conclusion – The present results highlight the potential roles of hepatokines as a class of hormones that substantially influence nutritional regulation in both female and male mice. C 2019 Elsevier Masson S Nanyang Technological University S.S. is supported by a PhD grant from INSERM. P.G and A.M. are supported by grants from the Socie´te´ francophone du diabe`te and the Socie´te´ franc¸aise de nutrition. W.W. is supported by a start-up grant from the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. This work was also funded by ANR Hepatokind (to C.P. and H.G.). W.W., A.M., P.G. and H.G. were supported by grants from Re´gion Occitanie.

Aims: The metabolic syndrome and associated comorbidities, like diabetes, hypertension and obesity, have been implicated in the development of heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms underlying the development of HFpEF remain to be elucidated. We developed a cardiome-directed network analysis and applied this to high throughput cardiac RNA-sequencing data from a well-established rat model of HFpEF, the obese and hypertensive ZSF1 rat. With this novel system biology approach, we explored the mechanisms underlying HFpEF.Methods and results: Unlike ZSF1-Lean, ZSF1-Obese and ZSF1-Obese rats fed with a high-fat diet (HFD) developed diastolic dysfunction and reduced exercise capacity. The number of differentially expressed genes amounted to 1591 and 1961 for the ZSF1-Obese vs. Lean and ZSF1-Obese+HFD vs. Lean comparison, respectively. For the cardiome-directed network analysis (CDNA) eleven biological processes related to cardiac disease were selected and used as input for the STRING protein-protein interaction database. The resulting STRING network comprised 3.460 genes and 186.653 edges. Subsequently differentially expressed genes were projected onto this network. The connectivity between the core processes within the network was assessed and important bottleneck and hub genes were identified based on their network topology.Classical gene enrichment analysis highlighted many processes related to mitochondrial oxidative metabolism. The CDNA indicated high interconnectivity between five core processes: endothelial function, inflammation, apoptosis/autophagy, sarcomere/cytoskeleton and extracellular matrix. The transcription factors Myc and Peroxisome Proliferator-Activated Receptor-alpha (Ppara) were identified as important bottlenecks in the overall network topology, with Ppara acting as important link between cardiac metabolism, inflammation and endothelial function.Conclusions: This study presents a novel systems biology approach, directly applicable to other cardiac disease related transcriptome data sets. The CDNA approach enabled the identification of critical processes and genes, including Myc and Ppara, that are putatively involved in the development of HFpEF.

Long-chain fatty acids are the main cardiac substrates from which ATP is generated continually to serve the high energy demand and sustain the normal function of the heart. Under healthy conditions, fatty acid beta-oxidation produces 50-70% of the energy demands with the remainder largely accounted for by glucose. Chronically increased dietary lipid supply often leads to excess lipid accumulation in the heart, which is linked to a variety of maladaptive phenomena, such as insulin resistance, cardiac hypertrophy and contractile dysfunction. CD36, the predominant cardiac fatty acid transporter, has a key role in setting the heart on a road to contractile dysfunction upon the onset of chronic lipid oversupply by translocating to the cell surface and opening the cellular 'doors' for fatty acids. The sequence of events after the CD36-mediated myocellular lipid accumulation is less understood, but in general it has been accepted that the excessively imported lipids cause insulin resistance, which in turn leads to contractile dysfunction. There are several gaps of knowledge in this proposed order of events which this review aims to discuss. First, the molecular mechanisms underlying lipid-induced insulin resistance are not yet completely disclosed. Specifically, several mediators have been proposed, such as diacylglycerols, ceramides, peroxisome proliferator-activated receptors (PPAR), inflammatory kinases and reactive oxygen species (ROS), but their relative contributions to the onset of insulin resistance and their putatively synergistic actions are topics of controversy. Second, there are also pieces of evidence that lipids can induce contractile dysfunction independently of insulin resistance. Perhaps, a more integrative view is needed, in which several lipid-induced pathways operate synergistically or in parallel to induce contractile dysfunction. Unraveling of these processes is expected to be important in designing effective therapeutic strategies to protect the lipid-overloaded heart. (C) 2016 Elsevier Ltd. All rights reserved.

Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondria) one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondria! unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.

Children with atopic dermatitis show an increased risk to develop asthma later in life, a phenomenon referred to as "atopic march," which emphasizes the need for secondary prevention therapies. This study aimed to investigate whether relief of skin inflammation by glucocorticoids and peroxisome proliferator-activated receptor agonists might influence the subsequent development of asthma in a murine model for the atopic march in which mice were repeatedly exposed to house dust mite via the skin, followed by exposure to house dust mite in lungs. To abrogate atopic dermatitis, mice received topical treatment with glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma agonists. Nuclear receptor ligand effects were assessed on primary keratinocytes and dendritic cells, as central players in skin inflammation. Prior house dust mite-induced skin inflammation aggravates allergic airway inflammation and induces a mixed T helper type 2/T helper type 17 response in the lungs. Cutaneous combined activation of glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma reduced skin inflammation to a higher extent compared to single activation. Additive anti-inflammatory effects were more prominent in dendritic cells, as compared to keratinocytes. Alleviation of allergic skin inflammation by activation of glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma appeared insufficient to avoid the allergic immune response in the lungs, but efficiently reduced asthma severity by counteracting the Th17 response. Glucocorticoid receptor/peroxisome proliferator-activated receptor-gamma co-activation represents a potent remedy against allergic skin inflammation and worsening of atopic march.

United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) - R01 DA12610 - R01 DA032246 - T32 DA007027-41 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) - P50AA022537 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission - T32DA007027 - R01DA032246 - R01DA012610 Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric alpha 7 nAChR reduces nicotine's rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-alpha (PPAR alpha) has been implicated as a downstream signaling target of the alpha 7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPAR alpha as a possible mediator of the effect of alpha 7 nAChR activation in nicotine dependence. Our results demonstrate the PPAR alpha antagonist GW6471 blocks actions of the alpha 7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that alpha 7 nAChR activation attenuates nicotine CPP in a PPAR alpha-dependent manner. To evaluate PPAR alpha activation in nicotine dependence we used the selective and potent PPAR alpha agonist, WY-14643 and the clinically used PPAR alpha activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPAR alpha in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPAR alpha plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of alpha 7 nAChRs in nicotine dependence.

Chronic alcohol consumption causes alcoholic liver disease, which is associated with the initiation of dysregulated lipid metabolism. Recent evidences suggest that dysregulated cholesterol metabolism plays an important role in the pathogenesis of alcoholic fatty liver disease. Ecklonia stolonifera (ES), a perennial brown marine alga that belongs to the family Laminariaceae, is rich in phlorotannins. Many studies have indicated that ES has extensive pharmacological effects, such as antioxidative, hepatoprotective, and antiinflammatory effects. However, only a few studies have investigated the protective effect of ES in alcoholic fatty liver. Male Sprague-Dawley rats were randomly divided into normal diet (ND) (fed a normal diet for 10 weeks) and ethanol diet (ED) groups. Rats in the ED group were fed a Lieber-DeCarli liquid diet (containing 5% ethanol) for 10 weeks and administered ES extract (50, 100, or 200 mg/kg/day), silymarin (100 mg/kg/day), or no treatment for 4 weeks. Each treatment group comprised of eight rats. The supplementation with ES resulted in decreased serum levels of triglycerides (TGs), total cholesterol, alanine aminotransferase, and aspartate aminotransferase. In addition, there were decreases in hepatic lipid and malondialdehyde levels. Changes in liver histology, as analyzed by Oil Red O staining, showed that the ES treatment suppressed adipogenesis. In addition, the ES treatment increased the expression of fatty acid oxidation-related genes (e.g., PPAR-α and CPT-1) but decreased the expression of SREBP 1, which is a TG synthesis-related gene. These results suggest that ES extract may be useful in preventing fatty acid oxidation and reducing lipogenesis in ethanol-induced fatty liver.

The enzyme vascular non-inflammatory molecule-1 (vanin 1) is highly expressed at gene and protein level in many organs, such as the liver, intestine, and kidney. Its major function is related to its pantetheinase activity; vanin 1 breaks down pantetheine in cysteamine and pantothenic acid, a precursor of coenzyme A. Indeed, its physiological role seems strictly related to coenzyme A metabolism, lipid metabolism, and energy production. In recent years, many studies have elucidated the role of vanin 1 under physiological conditions in relation to oxidative stress and inflammation. Vanin's enzymatic activity was found to be of key importance in certain diseases, either for its protective effect or as a sensitizer, depending on the diseased organ. In this review, we discuss the role of vanin 1 in the liver, kidney, intestine, and lung under physiological as well as pathophysiological conditions. Thus, we provide a more complete understanding and overview of its complex function and contribution to some specific pathologies.

The soluble fms-like tyrosine kinase factor 1 (sFlt-1) is a major contributor to antiangiogenesis during preeclampsia. However, little is known about the effects of sFlt-1 on fetal health. In this study we aim to evaluate the effects of the sFlt-1 concentration during pregnancy on fetal liver physiology. We used adenoviral gene delivery in Sprague-Dawley dams (seven females, 10 weeks old) during mid-gestation (gestational day 8) with adenovirus overexpressing sFlt-1, and age-matched controls (six females, 10 weeks old) with empty adenoviral virus in order to quantify the sFlt-1 concentrations in pregnant dams. Dams exposed to adenoviral sFlt-1 delivery were subdivided into a low (n=4) and high sFlt-1 (n=3) group based on host response to the virus. One-way analysis of variance showed that fetuses (five per dam) exposed to high sFlt-1 concentrations in utero show fetal growth restriction (1.84±0.043 g high sFlt-1 v. 2.32±0.036 g control; mean (M)±s.e.m.; Pv. 2.26±0.095 mean % methylation in control, M±s.e.m., P

Purpose of review Several members of the fibroblast growth factor (FGF) family have been identified as key regulators of energy metabolism in rodents and nonhuman primates. Translational studies show that their metabolic actions are largely conserved in humans, which led to the development of various FGF-based drugs, including FGF21-mimetics LY2405319, PF-05231023, and pegbelfermin, and the FGF19-mimetic NGM282. Recently, a number of clinical trials have been published that examined the safety and efficacy of these novel therapeutic proteins in the treatment of obesity, type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH), and cholestatic liver disease. In this review, we discuss the current understanding of FGFs in metabolic regulation and their clinical potential. Recent findings FGF21-based drugs induce weight loss and improve dyslipidemia in patients with obesity and T2D, and reduce steatosis in patients with NASH. FGF19-based drugs reduce steatosis in patients with NASH, and ameliorate bile acid-induced liver damage in patients with cholestasis. In contrast to their potent antidiabetic effects in rodents and nonhuman primates, FGF-based drugs do not appear to improve glycemia in humans. In addition, various safety concerns, including elevation of low-density lipoprotein cholesterol, modulation of bone homeostasis, and increased blood pressure, have been reported as well. Summary Clinical trials with FGF-based drugs report beneficial effects in lipid and bile acid metabolism, with clinical improvements in dyslipidemia, steatosis, weight loss, and liver damage. In contrast, glucose-lowering effects, as observed in preclinical models, are currently lacking.