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

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.

Download Full-text

Embryonic exposures to mono-2-ethylhexyl phthalate induce larval steatosis in zebrafish independent of Nrf2a signaling

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174420000057 ◽

2020 ◽

pp. 1-9

Author(s):

Karilyn E. Sant ◽

Hadley M. Moreau ◽

Larissa M. Williams ◽

Haydee M. Jacobs ◽

Anna M. Bowsher ◽

...

Keyword(s):

Oxidative Stress ◽

Hepatic Steatosis ◽

Antioxidant Response ◽

Abnormal Development ◽

Fish Length ◽

Peroxisome Proliferator ◽

Primary Metabolite ◽

Peroxisome Proliferator Activated Receptor ◽

Expression Of Genes ◽

Ethylhexyl Phthalate

Abstract Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.

Download Full-text

A meta-analysis study of gene expression datasets in mouse liver under PPARα knockout

Genetics Research ◽

10.1017/s0016672313000098 ◽

2013 ◽

Vol 95 (2-3) ◽

pp. 78-88 ◽

Cited By ~ 1

Author(s):

KAN HE ◽

ZHEN WANG ◽

QISHAN WANG ◽

YUCHUN PAN

Keyword(s):

Gene Expression ◽

Mouse Liver ◽

Meta Analysis ◽

Expression Patterns ◽

Hepatic Tissue ◽

Marker Genes ◽

Specific Marker ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Microarray Datasets

SummaryGene expression profiling of peroxisome-proliferator-activated receptor α (PPARα) has been used in several studies, but there were no consistent results on gene expression patterns involved in PPARα activation in genome-wide due to different sample sizes or platforms. Here, we employed two published microarray datasets both PPARα dependent in mouse liver and applied meta-analysis on them to increase the power of the identification of differentially expressed genes and significantly enriched pathways. As a result, we have improved the concordance in identifying many biological mechanisms involved in PPARα activation. We suggest that our analysis not only leads to more identified genes by combining datasets from different resources together, but also provides some novel hepatic tissue-specific marker genes related to PPARα according to our re-analysis.

Download Full-text

Microarray Analysis of Gene Expression Changes in Mouse Liver Induced by Peroxisome Proliferator- Activated Receptor α Agonists

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2001.6319 ◽

2002 ◽

Vol 290 (3) ◽

pp. 1114-1122 ◽

Cited By ~ 82

Author(s):

Kazuto Yamazaki ◽

Junro Kuromitsu ◽

Isao Tanaka

Keyword(s):

Gene Expression ◽

Microarray Analysis ◽

Mouse Liver ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

Download Full-text

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

PLoS ONE ◽

10.1371/journal.pone.0124224 ◽

2015 ◽

Vol 10 (4) ◽

pp. e0124224 ◽

Cited By ~ 2

Author(s):

Keyword(s):

Gene Expression ◽

Nuclear Receptor ◽

Mouse Liver ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Liver Gene

Download Full-text

Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0220001 ◽

1999 ◽

Vol 22 (1) ◽

pp. 1-8 ◽

Cited By ~ 143

Author(s):

PR Holden ◽

JD Tugwood

Keyword(s):

Gene Expression ◽

Molecular Mechanisms ◽

Species Differences ◽

Plasma Cholesterol ◽

Specific Gene ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Apparent Lack ◽

Receptor Alpha ◽

Rats And Mice

Peroxisome proliferators (PPs) are chemicals of industrial and pharmaceutical importance that elicit liver carcinogenesis by a non-genotoxic mechanism. One of the intriguing properties of PPs is that the pleiotropic effects of these compounds (including increased DNA synthesis and peroxisome proliferation) are seen in rats and mice only, but not humans. It is important to determine the risks to humans of environmental and therapeutic exposure to these compounds by understanding the mechanisms of non-genotoxic hepatocarcinogenesis in rodents. To understand this apparent lack of human susceptibility, attention has focused on the peroxisome proliferator-activated receptor alpha (PPARalpha), which appears to mediate the effects of PPs in rodents. It is also known to mediate the hypolipidaemic effects that fibrate drugs exert on humans with elevated plasma cholesterol and triglyceride levels. Human PPARalphas share many functional characteristics with the rodent receptors, in that they can be transcriptionally activated by PPs and regulate specific gene expression. However, one key difference is that PPARalpha is less abundant in human than in rodent liver, which has led to the suggestion that species differences result from quantitative differences in gene expression. In this review we describe the effects of PPs and what is known of the molecular mechanisms of action and species differences with respect to rodents and man. Attention will be given to differences in the amounts of PPARalpha between species as well as the 'qualitative' aspects of PPARalpha-mediated gene regulation which might also explain the activation of some genes and not of others in human liver by PPs.

Download Full-text

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

PPAR Research ◽

10.1155/2010/681963 ◽

2010 ◽

Vol 2010 ◽

pp. 1-14 ◽

Cited By ~ 8

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.

Download Full-text

Comprehensive Messenger Ribonucleic Acid Profiling Reveals That Peroxisome Proliferator-Activated Receptor γ Activation Has Coordinate Effects on Gene Expression in Multiple Insulin-Sensitive Tissues

Endocrinology ◽

10.1210/endo.142.3.8037 ◽

2001 ◽

Vol 142 (3) ◽

pp. 1269-1277 ◽

Cited By ~ 133

Author(s):

James M. Way ◽

W. Wallace Harrington ◽

Kathleen K. Brown ◽

William K. Gottschalk ◽

Scott S. Sundseth ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Fatty Acid ◽

Brown Adipose Tissue ◽

White Adipose Tissue ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Expression Of Genes ◽

Brown Adipose ◽

Pparγ Agonists

Abstract Peroxisome proliferator-activated receptor γ (PPARγ) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPARγ ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPARγ in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPARγ activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPARγ agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPARγ-mediated increases in glucose utilization in muscle. In liver, PPARγ activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPARγ agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.

Download Full-text