Effects of chronic activation of peroxisome proliferator-activated receptor-α or high-fat feeding in a rat infarct model of heart failure

2006 ◽  
Vol 290 (5) ◽  
pp. H1899-H1904 ◽  
Author(s):  
Eric E. Morgan ◽  
Julie H. Rennison ◽  
Martin E. Young ◽  
Tracy A. McElfresh ◽  
Theodore A. Kung ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Ejection Fraction ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Myocardial Triglyceride ◽  
Lv Dysfunction ◽  
Fat Feeding ◽  
Pparα Agonist

Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPARα agonist increases myocardial triglyceride and/or ceramide and exacerbates LV dysfunction in HF. Rats with infarct-induced HF ( n = 38) or sham-operated rats ( n = 10) were either untreated (INF, n = 10), fed a high-fat diet (45% kcal fat, INF + Fat, n = 15), or fed the PPARα agonist fenofibrate (150 mg·kg−1·day−1, INF + Feno, n = 13) for 12 wk. LV ejection fraction was significantly reduced with HF (49 ± 6%) compared with sham operated (86 ± 2%) with no significant differences in ejection fraction (or other functional or hemodynamic measures) among the three infarcted groups. Treatment with the PPARα agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPARα-regulated genes, as well as protein expression and activity of medium chain acyl-CoA dehydrogenase (compared with INF and INF + Fat groups). Myocardial ceramide content was elevated in the INF group compared with sham-operated rats, with no further change in the INF + Fat or INF + Feno groups. Myocardial triglyceride was unaffected by infarction but increased in the INF + Fat group. In conclusion, LV dysfunction and dilation are not worsened despite upregulation of the fatty acid metabolic pathway and LV hypertrophy or accumulation of myocardial triglyceride in the rat infarct model of HF.

scholarly journals PGC-1β Induces Susceptibility To Acetaminophen-Driven Acute Liver Failure

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elena Piccinin ◽  
Simon Ducheix ◽  
Claudia Peres ◽  
Maria Arconzo ◽  
Maria Carmela Vegliante ◽  
...  
Keyword(s):  
Liver Failure ◽  
Metabolic Diseases ◽  
Fatal Outcome ◽  
Acute Hepatic Failure ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
High Doses ◽  
Fat Feeding

AbstractAcetaminophen (APAP) is a worldwide commonly used painkiller drug. However, high doses of APAP can lead to acute hepatic failure and, in some cases, death. Previous studies indicated that different factors, including life-style and metabolic diseases, could predispose to the risk of APAP-induced liver failure. However, the molecular process that could favor APAP hepatotoxicity remains understood. Here, we reported that a short-term high fat-enriched diet worsens APAP-induced liver damage, by promoting liver accumulation of lipids that induces the activation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β). Therefore, we challenged mice with hepatic-specific PGC-1β overexpression on a chow diet with a subtoxic dose of APAP and we found that PGC-1β overexpression renders the liver more sensitive to APAP damage, mainly due to intense oxidative stress, finally ending up with liver necrosis and mice death. Overall, our results indicated that during high fat feeding, PGC-1β adversely influences the ability of the liver to overcome APAP toxicity by orchestrating different metabolic pathways that finally lead to fatal outcome.

scholarly journals Peroxisome Proliferator-Activated Receptor α Mediates the Effects of High-Fat Diet on Hepatic Gene Expression

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1508-1516 ◽  
Author(s):  
David Patsouris ◽  
Janardan K. Reddy ◽  
Michael Müller ◽  
Sander Kersten
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Microarray Analysis ◽  
High Fat Diet ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Wild Type ◽  
High Fat ◽  
Fat Feeding

Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of numerous metabolic processes. The PPARα isotype is abundant in liver and activated by fasting. However, it is not very clear what other nutritional conditions activate PPARα. To examine whether PPARα mediates the effects of chronic high-fat feeding, wild-type and PPARα null mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 26 wk. HFD and PPARα deletion independently increased liver triglycerides. Furthermore, in wild-type mice HFD was associated with a significant increase in hepatic PPARα mRNA and plasma free fatty acids, leading to a PPARα-dependent increase in expression of PPARα marker genes CYP4A10 and CYP4A14. Microarray analysis revealed that HFD increased hepatic expression of characteristic PPARα target genes involved in fatty acid oxidation in a PPARα-dependent manner, although to a lesser extent than fasting or Wy14643. Microarray analysis also indicated functional compensation for PPARα in PPARα null mice. Remarkably, in PPARα null mice on HFD, PPARγ mRNA was 20-fold elevated compared with wild-type mice fed a LFD, reaching expression levels of PPARα in normal mice. Adenoviral overexpression of PPARγ in liver indicated that PPARγ can up-regulate genes involved in lipo/adipogenesis but also characteristic PPARα targets involved in fatty acid oxidation. It is concluded that 1) PPARα and PPARα-signaling are activated in liver by chronic high-fat feeding; and 2) PPARγ may compensate for PPARα in PPARα null mice on HFD.

Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice

2012 ◽  
Vol 302 (9) ◽  
pp. H1795-H1805 ◽  
Author(s):  
Corinne Pellieux ◽  
Christophe Montessuit ◽  
Irène Papageorgiou ◽  
Thierry Pedrazzini ◽  
René Lerch
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
High Fat Diet ◽  
Regulatory Proteins ◽  
Acid Oxidation ◽  
Contractile Dysfunction ◽  
High Fat ◽  
Palmitate Oxidation ◽  
Fat Feeding

Normal myocardium adapts to increase of nutritional fatty acid supply by upregulation of regulatory proteins of the fatty acid oxidation pathway. Because advanced heart failure is associated with reduction of regulatory proteins of fatty acid oxidation, we hypothesized that failing myocardium may not be able to adapt to increased fatty acid intake and therefore undergo lipid accumulation, potentially aggravating myocardial dysfunction. We determined the effect of high-fat diet in transgenic mice with overexpression of angiotensinogen in the myocardium (TG1306/R1). TG1306/R1 mice develop ANG II-mediated left ventricular hypertrophy, and at one year of age approximately half of the mice present heart failure associated with reduced expression of regulatory proteins of fatty acid oxidation and reduced palmitate oxidation during ex vivo working heart perfusion. Hypertrophied hearts from TG1306/R1 mice without heart failure adapted to high-fat feeding, similarly to hearts from wild-type mice, with upregulation of regulatory proteins of fatty acid oxidation and enhancement of palmitate oxidation. There was no myocardial lipid accumulation or contractile dysfunction. In contrast, hearts from TG1306/R1 mice presenting heart failure were unable to respond to high-fat feeding by upregulation of fatty acid oxidation proteins and enhancement of palmitate oxidation. This resulted in accumulation of triglycerides and ceramide in the myocardium, and aggravation of contractile dysfunction. In conclusion, hearts with ANG II-induced contractile failure have lost the ability to enhance fatty acid oxidation in response to increased fatty acid supply. The ensuing accumulation of lipid compounds may play a role in the observed aggravation of contractile dysfunction.

scholarly journals Effect of taurine intervention on oleic acid-induced primary hepatocyte steatosis in orange-spotted grouper (Epinephelus coioides)

2021 ◽  
pp. 43-43
Author(s):  
Ruyi Xiao ◽  
Hanmo Feng ◽  
Xingjian Niu ◽  
Fakai Bai ◽  
Jidan Ye
Keyword(s):  
Oleic Acid ◽  
Fatty Acid ◽  
Peroxisome Proliferator ◽  
Epinephelus Coioides ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling ◽  
Hepatocyte Steatosis ◽  
Amp Activated Protein Kinase ◽  
First Time

Examination of the molecular mechanism of taurine regulation of lipid metabolism in fish is limited. In this study, an oleic acid (OA)-induced hepatocyte steatosis model of orange-spotted grouper (Epinephelus coioides) was established for the first time. The model was used to test the effect of taurine on steatosis hepatocytes in Control, High-fat (0.4 mM OA) and Taurine (0.4 mM OA + 2 mM taurine) experimental groups of fish. Hepatocyte samples were subjected to transcriptome analysis. A total of 99634 unigenes was assembled, 69982 unigenes were annotated and 1831 differentially expressed genes (DEGs) in Control vs High-fat group, and 526 DEGs in the High-fat vs Taurine group were identified, of which 824 DEGs (Control vs High-fat) and 237 DEGs (High-fat vs Taurine) were observed to be upregulated, and 1007 DEGs (Control vs High-fat) and 289 DEGs (High-fat vs Taurine) were downregulated after taurine intervention. These genes are involved in peroxisome proliferator-activated receptor (PPAR) and 5' AMP-activated protein kinase (AMPK) signaling pathways, fatty acid elongation, primary bile acid biosynthesis, glycerophospholipid and glycerolipid metabolism. The findings provide new clues in understanding the regulatory role of taurine in lipid and fatty acid metabolism of fish. It is hoped that the obtained results will help in the design of feed formulations to improve grouper growth from the perspective of aquaculture nutrition.

Abstract 404: Acute Knock-down of Cardiac Peroxisome Proliferator Activated Receptor α Does Not Impair Cardiac Function

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Natasha Fillmore ◽  
Junhui Sun ◽  
Danielle Springer ◽  
Elizabeth Murphy
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Function ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Body Weight Gain ◽  
Baseline Heart Rate ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

Alterations in glucose and fatty acid metabolism are believed to contribute to the development of heart failure. Peroxisome Proliferator Activated Receptor α (PPARα) is a transcription factor that regulates fatty acid metabolism and is frequently reported to be reduced in heart failure. However, it is controversial whether this decline in PPARα mediates the development of cardiac hypertrophy and heart failure. To improve our understanding of the role of cardiac PPARα we generated a tamoxifen inducible cardiac-specific PPARα knockout mouse (cPPAR -/- ). Control (Mer-Cre-Mer and Flox -/- ) mice and cPPAR -/- (Mer-Cre-Mer and Flox +/+ ) mice were treated with tamoxifen at ~2.5 months and were studied 5 weeks after treatment. We verified loss of cardiac PPARα using western blot. cPPAR -/- mice appear healthy with normal body weight gain and survival. To examine the impact of cardiac deletion of PPARα on cardiac function we performed echocardiography on control and cPPAR -/- . There was no reduction in systolic function between control and cPPAR -/- mice. Ejection fraction (Control, 56.3±0.9; cPPAR -/- , 59.7±0.1) and fractional shortening (Control, 29.1±0.5; cPPAR -/- , 31.5±0.1) were similar in cPPAR -/- compared to control hearts. Interestingly however, baseline heart rate was significantly lower in cPPAR -/- versus control mice (Control, 531.3±18.3; cPPAR -/- , 459.8±2.9 bpm). In addition to having normal cardiac function, heart weights were similar between control and cPPAR -/- mice. Overall, these data indicate that an acute reduction in myocardial PPARα per se does not cause cardiac dysfunction. However these data do not exclude the possibility that loss of PPARα could drive cardiac pathology in the context of other signals.

scholarly journals Lonicera caerulea Extract Attenuates Non-Alcoholic Fatty Liver Disease in Free Fatty Acid-Induced HepG2 Hepatocytes and in High Fat Diet-Fed Mice

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 494 ◽  
Author(s):  
Miey Park ◽  
Jeong-Hyun Yoo ◽  
You-Suk Lee ◽  
Hae-Jeung Lee
Keyword(s):  
Fatty Acid ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Lonicera Caerulea ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Honeyberry (Lonicera caerulea) has been used for medicinal purposes for thousands of years. Its predominant anthocyanin, cyanidin-3-O-glucoside (C3G), possesses antioxidant and many other potent biological activities. We aimed to investigate the effects of honeyberry extract (HBE) supplementation on HepG2 cellular steatosis induced by free fatty acids (FFA) and in diet-induced obese mice. HepG2 cells were incubated with 1 mM FFA to induce lipid accumulation with or without HBE. Obesity in mice was induced by a 45% high fat diet (HFD) for 6 weeks and subsequent supplementation of 0.5% HBE (LH) and 1% HBE (MH) for 6 weeks. HBE suppressed fatty acid synthesis and ameliorated lipid accumulation in HepG2 cells induced by FFA. Moreover, HBE also decreased lipid accumulation in the liver in the supplemented HBE group (LH, 0.5% or MH, 1%) compared with the control group. The expressions of adipogenic genes involved in hepatic lipid metabolism of sterol regulatory element-binding protein-1 (SREBP-1c), CCAAT/enhancer-binding protein alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), and fatty acid synthase (FAS) were decreased both in the HepG2 cells and in the livers of HBE-supplemented mice. In addition, HBE increased mRNA and protein levels of carnitine palmitoyltransferase (CPT-1) and peroxisome proliferator-activated receptor α (PPARα), which are involved in fatty acid oxidation. Furthermore, HBE treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and Acetyl CoA Carboxylase (ACC). Honeyberry effectively reduced triglyceride accumulation through down-regulation of hepatic lipid metabolic gene expression and up-regulation of the activation of AMPK and ACC signaling in both the HepG2 cells as well as in livers of diet-induced obese mice. These results suggest that HBE may actively ameliorate non-alcoholic fatty liver disease.

scholarly journals Shugan Xiaozhi Decoction Attenuates Nonalcoholic Steatohepatitis by Enhancing PPARαand L-FABP Expressions in High-Fat-Fed Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yu-feng Xing ◽  
Zhen Zhang ◽  
Wen-Jun Fu ◽  
Da-qiao Zhou ◽  
Ailsa Chui-ying Yuen ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Nonalcoholic Steatohepatitis ◽  
Chemical Constituents ◽  
Ionization Mass ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Dose Dependent

This study aimed to investigate the effects of Shugan Xiaozhi decoction (SX) on nonalcoholic steatohepatitis (NASH) induced by high-fat diet in rats. The rats were randomly divided into 6 groups, namely, control, model, fenofibrate, and three different dosage of SX (10, 20, and 40 g/kg/day, p.o.). After establishing the NASH model, at 8 weeks of the experiment, treatments were administrated intragastrically to the fenofibrate and SX groups. All rats were killed after 4 weeks of treatment. Compared with the model group, alanine aminotransferase (ALT), aspartate aminotransferase (AST), free fatty acid (FFA), total cholesterol (TC), triacylglycerol (TG), and low-density lipoprotein cholesterol (LDL) serum in the serum were significantly reduced in all SX treatment groups in a dose-dependent manner. Evidence showed that SX could protect the liver by upregulating the gene and protein expressions of peroxisome proliferator-activated receptor alpha (PPARα) and liver fatty acid binding protein (L-FABP) in a dose-dependent manner. Chemical constituents of SX were further analyzed by ultraperformance liquid chromatography coupled with electrospray ionization mass spectrometry (UPLC-ESI-MS) and 30 chemicals in the ethanolic extract were tentatively identified. To conclude, our results clearly indicated that SX could protect liver functions and relieve hepatic steatosis and inflammation.

A novel PPARα agonist ameliorates insulin resistance in dogs fed a high-fat diet

2008 ◽  
Vol 294 (5) ◽  
pp. E833-E840 ◽  
Author(s):  
Masaki Tsunoda ◽  
Naoki Kobayashi ◽  
Tomohiro Ide ◽  
Mari Utsumi ◽  
Michiaki Nagasawa ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Visceral Obesity ◽  
Oral Glucose ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipid Abnormalities ◽  
Subtype Selective ◽  
Pparα Agonist

Agonism of peroxisome proliferator-activated receptor (PPAR) α, a key regulator of lipid metabolism, leads to amelioration of lipid abnormalities in dyslipidemic patients. However, whether PPARα agonism is an effective form of therapy for obesity-related insulin resistance associated with lipid abnormalities is unclear. The present study investigated the effects of a potent and subtype-selective PPARα agonist, KRP-101, in a nonrodent insulin-resistant animal model under pair-fed conditions. Beagle dogs were fed a high-fat diet for 24 wk to induce insulin resistance. During the final 12 wk, 0.03 mg·kg−1·day−1 KRP-101 ( n = 5) or vehicle ( n = 5) was administered orally once a day. KRP-101 administration resulted in a significantly lower weight of overall visceral fat, which is associated with increased adiponectin and decreased leptin in serum. KRP-101 administration improved hyperglycemia and hyperinsulinemia as well as dyslipidemia in dogs fed a high-fat diet. Oral glucose tolerance test showed that KRP-101 administration improved glucose intolerance. The KRP-101 group showed a markedly lower hepatic triglyceride concentration. Lipid oxidation was increased in the liver and skeletal muscles of the KRP-101 group. These findings in the dog model suggest that the use of potent and subtype-selective PPARα agonists as a potentially relevant therapeutic approach to treat human insulin resistance associated with visceral obesity.

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