scholarly journals Effects of the PPARαAgonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Michael L. Cunningham ◽  
Bradley J. Collins ◽  
Milton R. Hejtmancik ◽  
Ronald A. Herbert ◽  
Gregory S. Travlos ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Hepatocyte Proliferation ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisomal Enzyme ◽  
Expression Of Genes ◽  
B6c3f1 Mice ◽  
Liver Carcinogen ◽  
Rats And Mice

Gemfibrozil is a widely prescribed hypolipidemic agent in humans and a peroxisome proliferator and liver carcinogen in rats. Three-month feed studies of gemfibrozil were conducted by the National Toxicology Program (NTP) in male Harlan Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters, primarily to examine mechanisms of hepatocarcinogenicity. There was morphologic evidence of peroxisome proliferation in rats and mice. Increased hepatocyte proliferation was observed in rats, primarily at the earliest time point. Increases in peroxisomal enzyme activities were greatest in rats, intermediate in mice, and least in hamsters. These studies demonstrate that rats are most responsive while hamsters are least responsive. These events are causally related to hepatotoxicity and hepatocarcinogenicity of gemfibrozil in rodents via peroxisome proliferator activated receptor-α(PPARα) activation; however, there is widespread evidence that activation of PPARαin humans results in expression of genes involved in lipid metabolism, but not in hepatocellular proliferation.

scholarly journals Peroxisome Proliferator-Activated Receptor (PPAR) α and PPARβ/δ, but not PPARγ, Modulate the Expression of Genes Involved in Cardiac Lipid Metabolism

2003 ◽  
Vol 92 (5) ◽  
pp. 518-524 ◽  
Author(s):  
Andries J. Gilde ◽  
Karin A.J.M. van der Lee ◽  
Peter H.M. Willemsen ◽  
Giulia Chinetti ◽  
Feike R. van der Leij ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cardiac Lipid ◽  
Expression Of Genes

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

2007 ◽  
Vol 293 (1) ◽  
pp. G355-G364 ◽  
Author(s):  
January N. Baumgardner ◽  
Kartik Shankar ◽  
Sohelia Korourian ◽  
Thomas M. Badger ◽  
Martin J. J. Ronis
Keyword(s):  
Oxidative Stress ◽  
Cellular Proliferation ◽  
Liver Steatosis ◽  
Hepatocyte Proliferation ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cyp 2E1 ◽  
Increased Risk ◽  
Etoh Group

To assess the relative contributions of undernutrition and ethanol (EtOH) exposure to alcohol-induced hepatotoxicity, female Sprague-Dawley rats were intragastrically infused liquid diets containing 187 or 154 kcal·kg−3/4·day−1 with or without 11 g·kg−1·day−1 EtOH. EtOH clearance was impaired in the 154 kcal·kg−3/4·day−1 EtOH group ( P ≤ 0.05). A combination of undernutrition and EtOH also increased the induction of hepatic cytochrome P-450 (CYP)2E1 and CYP4A1 mRNA, apoprotein, and activities ( P ≤ 0.05). This was accompanied by increased oxidative stress ( P ≤ 0.05). The severity of liver steatosis, macrophage infiltration, and focal necrosis was comparable in both EtOH groups. Alanine aminotransferase levels were elevated ( P ≤ 0.05) but did not significantly differ between the two EtOH groups. TUNEL analysis also demonstrated a comparable increase in apoptosis in the two EtOH groups ( P ≤ 0.05). The development of alcohol-induced liver pathology was accompanied by little change in fatty acid (FA) synthesis or degradation at 187 kcal·kg−3/4·day−1 but at 154 kcal·kg−3/4·day−1 was accompanied by decreased expression of FA synthesis genes and increased expression of peroxisome proliferator-activated receptor-α (PPAR-α)-regulated FA degradation pathways ( P ≤ 0.05). In addition, 154 kcal·kg−3/4·day−1 EtOH group livers exhibited greater hepatocyte proliferation ( P ≤ 0.05). We conclude that undernutrition does not exacerbate alcoholic steatohepatitis despite additional oxidative stress produced by an increased induction of CYP2E1 and CYP4A1. However, enhanced ethanol-induced cellular proliferation, perhaps as a result of enhanced PPAR-α signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.

Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-α agonist ciprofibrate

2003 ◽  
Vol 15 (1) ◽  
pp. 9-19 ◽  
Author(s):  
Fekadu Yadetie ◽  
Astrid Laegreid ◽  
Ingunn Bakke ◽  
Waclaw Kusnierczyk ◽  
Jan Komorowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Candidate Genes ◽  
Stress Responses ◽  
Inflammatory Responses ◽  
Sugar Metabolism ◽  
Hepatocyte Proliferation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Liver Gene

Fibrate class hypolipidemic drugs such as ciprofibrate activate the peroxisome proliferator-activated receptor-α (PPARα), which is involved in processes including lipid metabolism and hepatocyte proliferation in rodents. We examined the effects of ciprofibrate (50 mg/kg body wt per day for 60 days) on liver gene expression in rats using cDNA microarrays. The 60-day dosing period was chosen to elucidate both the metabolic and proliferative actions of this substance, while avoiding confounding effects from the hepatic carcinogenesis seen during more long-term stimulation. Ciprofibrate changed the expression of many genes including previously known PPARα agonist-responsive genes involved in processes such as lipid metabolism and inflammatory responses. In addition, many novel candidate genes involved in sugar metabolism, transcription, signal transduction, cell proliferation, and stress responses appeared to be differentially regulated in ciprofibrate-dosed rats. Ciprofibrate also resulted in significant increases in liver weight and hepatocyte proliferation. The cDNA microarray results were confirmed by Northern blot analysis for selected genes. This study thus identifies many genes that appear to be differentially regulated in ciprofibrate-dosed rats, and some of these are potential targets of PPARα. The functional diversity of these candidate genes suggests that most of them are likely to be differentially regulated as indirect consequence of the many processes affected by ciprofibrate in rodent liver. Although caution is advisable in the interpretation of genome-wide expression data, the genes identified in the present study provide candidates for further studies that may give new insight into the mechanisms of action of peroxisome proliferators.

scholarly journals Regulation of Proteome Maintenance Gene Expression by Activators of Peroxisome Proliferator-Activated Receptor α

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Hongzu Ren ◽  
Beena Vallanat ◽  
Holly M. Brown-Borg ◽  
Richard Currie ◽  
J. Christopher Corton
Keyword(s):  
Gene Expression ◽  
Mouse Liver ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Affymetrix Microarrays ◽  
Proteasomal Genes ◽  
Transcriptional Changes ◽  
Rats And Mice ◽  
Ethylhexyl Phthalate

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is activated by a large number of xenobiotic and hypolipidemic compounds called peroxisome proliferator chemicals (PPCs). One agonist of PPARα (WY-14,643) regulates responses in the mouse liver to chemical stress in part by altering expression of genes involved in proteome maintenance (PM) including protein chaperones in the heat shock protein (Hsp) family and proteasomal genes (Psm) involved in proteolysis. We hypothesized that other PPARα activators including diverse hypolipidemic and xenobiotic compounds also regulate PM genes in the rat and mouse liver. We examined the expression of PM genes in rat and mouse liver after exposure to 7 different PPCs (WY-14,643, clofibrate, fenofibrate, valproic acid, di-(2-ethylhexyl) phthalate, perfluorooctanoic acid, and perfluorooctane sulfonate) using Affymetrix microarrays. In rats and mice, 174 or 380 PM genes, respectively, were regulated by at least one PPC. The transcriptional changes were, for the most part, dependent on PPARα, as most changes were not observed in similarly treated PPARα-null mice and the changes were not consistently observed in rats treated with activators of the nuclear receptors CAR or PXR. In rats and mice, PM gene expression exhibited differences compared to typical direct targets of PPARα (e.g.,Cyp4afamily members). PM gene expression was usually delayed and in some cases, it was transient. Dose-response characterization of protein expression showed that Hsp86 and Hsp110 proteins were induced only at higher doses. These studies demonstrate that PPARα, activated by diverse PPC, regulates the expression of a large number of genes involved in protein folding and degradation and support an expanded role for PPARα in the regulation of genes that protect the proteome.

scholarly journals γ-Linolenic acid increases expression of key regulators of lipid metabolism in human skeletal muscle cells

2019 ◽  
Author(s):  
L.A Baker ◽  
N.R.W Martin ◽  
D.J Player ◽  
M.P Lewis
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Linolenic Acid ◽  
Metabolic Diseases ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Human Myotubes ◽  
Human Skeletal Muscle Cells

AbstractControl of skeletal muscle fat metabolism is regulated acutely through Peroxisome Proliferator Activated Receptor (PPAR) δ activation and its downstream intracellular targets. The purpose of this study was to determine whether fatty acids with high binding affinity for PPARδ can elevate the expression of genes related to fatty acid oxidation and indicators of mitochondrial biogenesis in cultured human skeletal myotubes. Myotubes were treated for 72 hours with one of four conditions: (i) Control (CON); (ii) Eicosapentaenoic acid (EPA 250μM); (iii) γ-linolenic acid (γ-LA 250μM); (iv) PPARδ Agonist (GW501516 10nM). Incubation with γ-LA induced increases in the gene expression of CD36 (p= 0.005), HADHA (p= 0.022) and PDK4 (p=0.025) in comparison with CON, with no further differences observed between conditions. Furthermore, intensity of MitoTracker® Red immunostaining in myotubes increased following incubation with γ-LA (p≤ 0.001) and EPA (p= 0.005) however these trends were not mirrored in the expression of PGC-1α as might be expected. Overall, γ-LA elevates levels the transcription of key intracellular regulators of lipid metabolism and transport in human myotubes, which may be clinically beneficial in the control of metabolic diseases.

scholarly journals Circadian Gene PER2 Silencing Downregulates PPARG and SREBF1 and Suppresses Lipid Synthesis in Bovine Mammary Epithelial Cells

Biology ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1226
Author(s):  
Yujia Jing ◽  
Yifei Chen ◽  
Shan Wang ◽  
Jialiang Ouyang ◽  
Liangyu Hu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Epithelial Cells ◽  
Circadian Clock ◽  
Lipid Droplets ◽  
Mammary Epithelial Cells ◽  
Lipid Synthesis ◽  
Mammary Epithelial ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Bovine Mammary Epithelial Cells

PER2, a circadian clock gene, is associated with mammary gland development and lipid synthesis in rodents, partly via regulating peroxisome proliferator-activated receptor gamma (PPARG). Whether such a type of molecular link existed in bovines was unclear. We hypothesized that PER2 was associated with lipid metabolism and regulated cell cycles and apoptosis in bovine mammary epithelial cells (BMECs). To test this hypothesis, BMECs isolated from three mid-lactation (average 110 d postpartum) cows were used. The transient transfection of small interfering RNA (siRNA) was used to inhibit PER2 transcription in primary BMECs. The silencing of PER2 led to lower concentrations of cellular lipid droplets and triacylglycerol along with the downregulation of lipogenic-related genes such as ACACA, FASN, LPIN1, and SCD, suggesting an overall inhibition of lipogenesis and desaturation. The downregulation of PPARG and SREBF1 in response to PER2 silencing underscored the importance of circadian clock signaling and the transcriptional regulation of lipogenesis. Although the proliferation of BMECs was not influenced by PER2 silencing, the number of cells in the G2/GM phase was upregulated. PER2 silencing did not affect cell apoptosis. Overall, the data provided evidence that PER2 participated in the coordination of mammary lipid metabolism and was potentially a component of the control of lipid droplets and TAG synthesis in ruminant mammary cells. The present data suggested that such an effect could occur through direct effects on transcriptional regulators.

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