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 Lipid Metabolism Gene Expression And Cellularity of Intramuscular Adipocytes Within The Longissimus Muscle of Angus- And Wagyu-Sired Cattle When Raised To A Similar Age or Body Weight

2021 ◽  
Author(s):  
Jerad Jaborek ◽  
Francis Fluharty ◽  
Kichoon Lee ◽  
Henry Zerby ◽  
Alejandro Relling
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Binding Protein ◽  
Peroxisome Proliferator ◽  
Longissimus Muscle ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipid Metabolism Gene ◽  
Metabolism Gene

Abstract Background: This study investigates intramuscular (IM) adipocyte development and growth in the Longissimus muscle (LM) between Wagyu- and Angus-sired steers compared at a similar age and days on feed (DOF) endpoint or similar body weight (BW) endpoint by measuring IM adipocyte cell area and lipid metabolism gene expression. Methods: Angus-sired steers (AN, n=6) were compared with steers from two different Wagyu sires, selected for either growth or marbling, to be compared at a similar DOF (WA-GD, n=5 and WA-MD, n=5) in experiment 1 or BW (WA-GB, n=4 and WA-MB, n=5) in experiment 2, respectively. Results: In experiment 1, WA-MD steers had a greater percentage of IM fat in the LM compared with AN and WA-GD steers. In experiment 2, WA-MB steers had a greater percentage of IM fat in the LM compared with AN and WA-GB steers. The distribution of IM adipocyte area was unimodal at all biopsy collections, with IM adipocyte area becoming progressively larger as cattle age and BW increased (P≤0.01). Peroxisome proliferator activated receptor delta (PPARd) was upregulated earlier for WA-MD and WA-MB cattle compared with other steers at a similar age and BW (P≤0.02; treatment×biopsy interaction). An earlier upregulation of PPARd is believed to have then upregulated peroxisome proliferator activated receptor gamma (PPARg) at a lesser BW for WA-MB steers (P=0.09; treatment×biopsy interaction), while WA-MD steers had a greater (P≤0.04) overall mean PPARg expression compared with other steers. Glycerol-3-phosphate acyltransferase, lipin 1, and hormone sensitive lipase demonstrated expression patterns similar to PPARg and PPARd or CCAAT enhancer binding protein beta, which emphasizes their importance in marbling development and growth. Additionally, WA-MD and WA-MB steers often had a greater early expression of fatty acid transporters (fatty acid transport protein 1; P<0.02; treatment×biopsy interaction) and binding proteins (fatty acid binding protein 4) compared with other steers. With many lipolytic genes upregulated at harvest, acetyl-CoA carboxylase beta may be inhibiting fatty acid oxidation in the LM to allow greater IM fat accumulation.Conclusions: Cattle with a greater marbling propensity appear to upregulate adipogenesis at a lesser maturity through PPARd, PPARg, and possibly adipogenic regulating compounds in lysophosphatidic acid and diacylglycerol.

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.

The Role of Peroxisome Proliferator-Activated Receptor γ in Mediating Cardioprotection Against Ischemia/Reperfusion Injury

2017 ◽  
Vol 23 (1) ◽  
pp. 46-56 ◽  
Author(s):  
Chong-Bin Zhong ◽  
Xi Chen ◽  
Xu-Yue Zhou ◽  
Xian-Bao Wang
Keyword(s):  
Lipid Metabolism ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism ◽  
Cardioprotective Effects

Myocardial infarction (MI) is a serious cardiovascular disease resulting in high rates of morbidity and mortality. Although advances have been made in restoring myocardial perfusion in ischemic areas, decreases in cardiomyocyte death and infarct size are still limited, attributing to myocardial ischemia/reperfusion (I/R) injury. It is necessary to develop therapies to restrict myocardial I/R injury and protect cardiomyocytes against further damage after MI. Many studies have suggested that peroxisome proliferator-activated receptor γ (PPARγ), a ligand-inducible nuclear receptor that predominantly regulates glucose and lipid metabolism, is a promising therapeutic target for ameliorating myocardial I/R injury. Thus, this review focuses on the role of PPARγ in cardioprotection during myocardial I/R. The cardioprotective effects of PPARγ, including attenuating oxidative stress, inhibiting inflammatory responses, improving glucose and lipid metabolism, and antagonizing apoptosis, are described. Additionally, the underlying mechanisms of cardioprotective effects of PPARγ, such as regulating the expression of target genes, influencing other transcription factors, and modulating kinase signaling pathways, are further discussed.

scholarly journals Identification of Modulators of the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α (PPARα) in a Mouse Liver Gene Expression Compendium

PLoS ONE ◽  
2015 ◽  
Vol 10 (2) ◽  
pp. e0112655 ◽  
Author(s):  
Keiyu Oshida ◽  
Naresh Vasani ◽  
Russell S. Thomas ◽  
Dawn Applegate ◽  
Mitch Rosen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Mouse Liver ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Liver Gene

scholarly journals Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells

2017 ◽  
Vol 312 (3) ◽  
pp. G283-G299 ◽  
Author(s):  
Chad N. Brocker ◽  
Jiang Yue ◽  
Donghwan Kim ◽  
Aijuan Qu ◽  
Jessica A. Bonzo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Lipid Metabolism ◽  
Target Genes ◽  
Elevated Serum ◽  
Hepatocyte Proliferation ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Nonparenchymal Cells ◽  
Specific Regulation

Peroxisome proliferator-activated receptor-α (PPARA) is a nuclear transcription factor and key mediator of systemic lipid metabolism. Prolonged activation in rodents causes hepatocyte proliferation and hepatocellular carcinoma. Little is known about the contribution of nonparenchymal cells (NPCs) to PPARA-mediated cell proliferation. NPC contribution to PPARA agonist-induced hepatomegaly was assessed in hepatocyte ( Ppara△Hep)- and macrophage ( Ppara△Mac)-specific Ppara null mice. Mice were treated with the agonist Wy-14643 for 14 days, and response of conditional null mice was compared with conventional knockout mice ( Ppara−/−). Wy-14643 treatment caused weight loss and severe hepatomegaly in wild-type and Ppara△Mac mice, and histological analysis revealed characteristic hepatocyte swelling; Ppara△Hep and Ppara−/− mice were protected from these effects. Ppara△Mac serum chemistries, as well as aspartate aminotransferase and alanine aminotransferase levels, matched wild-type mice. Agonist-treated Ppara△Hep mice had elevated serum cholesterol, phospholipids, and triglycerides when compared with Ppara−/− mice, indicating a possible role for extrahepatic PPARA in regulating circulating lipid levels. BrdU labeling confirmed increased cell proliferation only in wild-type and Ppara△Mac mice. Macrophage PPARA disruption did not impact agonist-induced upregulation of lipid metabolism, cell proliferation, or DNA damage and repair-related gene expression, whereas gene expression was repressed in Ppara△Hep mice. Interestingly, downregulation of inflammatory cytokines IL-15 and IL-18 was dependent on macrophage PPARA. Cell type-specific regulation of target genes was confirmed in primary hepatocytes and Kupffer cells. These studies conclusively show that cell proliferation is mediated exclusively by PPARA activation in hepatocytes and that Kupffer cell PPARA has an important role in mediating the anti-inflammatory effects of PPARA agonists.

scholarly journals Caffeic and Chlorogenic Acids Synergistically Activate Browning Program in Human Adipocytes: Implications of AMPK- and PPAR-Mediated Pathways

2020 ◽  
Vol 21 (24) ◽  
pp. 9740
Author(s):  
Liliya V. Vasileva ◽  
Martina S. Savova ◽  
Kristiana M. Amirova ◽  
Zhivka Balcheva-Sivenova ◽  
Claudio Ferrante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Metabolic Effects ◽  
Brown Adipocyte ◽  
Peroxisome Proliferator ◽  
Human Adipocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling

Caffeic acid (CA) and chlorogenic acid (CGA) are phenolic compounds claimed to be responsible for the metabolic effects of coffee and tea consumption. Along with their structural similarities, they share common mechanisms such as activation of the AMP-activated protein kinase (AMPK) signaling. The present study aimed to investigate the anti-obesity potential of CA and CGA as co-treatment in human adipocytes. The molecular interactions of CA and CGA with key adipogenic transcription factors were simulated through an in silico molecular docking approach. The expression levels of white and brown adipocyte markers, as well as genes related to lipid metabolism, were analyzed by real-time quantitative PCR and Western blot analyses. Mechanistically, the CA/CGA combination induced lipolysis, upregulated AMPK and browning gene expression and downregulated peroxisome proliferator-activated receptor γ (PPARγ) at both transcriptional and protein levels. The gene expression profiles of the CA/CGA-co-treated adipocytes strongly resembled brown-like signatures. Major pathways identified included the AMPK- and PPAR-related signaling pathways. Collectively, these findings indicated that CA/CGA co-stimulation exerted a browning-inducing potential superior to that of either compound used alone which merits implementation in obesity management. Further, the obtained data provide additional insights on how CA and CGA modify adipocyte function, differentiation and lipid metabolism.

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