Peroxisome Proliferator Activated Receptor-α Expression in Human Liver

Palmer, Colin N.A.; Hsu, Mei-H.; Griffin, Keith J.; Raucy, Judy L.; Johnson, Eric F.

doi:10.1124/mol.53.1.14

Cited by 432 publications

(293 citation statements)

References 40 publications

Supporting

Mentioning

282

Contrasting

Unclassified

Order By: Relevance

“…Expression of PPAR␣ in human liver is much less than in mice, and treatment of hypertriglyceridemia with fibrates, which are PPAR␣ ligands, does not cause peroxisome proliferation or up-regulate ACO. 46,47 Functionality of the human PPAR␣ gene and protein has been shown in vitro 48 and in vivo. 49 Furthermore, the L162V polymorphism in the human PPAR␣ gene that increases PPAR␣ activity has been associated with increased sensitivity of type II diabetic patients to the lipid-lowering effects of fibrates.…”

Section: Discussionmentioning

confidence: 99%

Central Role of Pparα–Dependent Hepatic Lipid Turnover in Dietary Steatohepatitis in Mice

et al. 2003

View full text Add to dashboard Cite

We have proposed that steatohepatitis results from reactive oxygen species (ROS) acting on accumulated fatty acids to form proinflammatory lipoperoxides. Cytochrome P450 4a (Cyp4a) and Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing Cyp4a through activation of peroxisome proliferator-activated receptor ␣ (PPAR␣) should aggravate steatohepatitis produced by feeding a methionine and choline deficient (MCD) diet. Conversely, we assessed dietary steatohepatitis in PPAR␣ ؊/؊ mice that cannot up-regulate Cyp4a. Male wild type (wt) or PPAR␣ ؊/؊ mice (C57BL6 background) were fed the MCD diet with or without Wy-14,643 (0.1% wt/wt), a potent PPAR␣ agonist. Controls were fed the same diet supplemented with methionine and choline. After 5 weeks, wt mice fed the MCD diet developed moderate steatohepatitis and alanine aminotransferase (ALT) levels were increased. Wy-14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas steatohepatitis was absent. Wy-14,643 up-regulated mRNA for liver fatty acid binding protein and peroxisomal ␤-oxidation enzymes (acyl-CoA oxidase, bifunctional enzyme, and ketothiolase), thereby reducing hepatic triglycerides and preventing steatosis. In wt mice, dietary feeding up-regulated Cyp4a14 mRNA 2.7-fold and increased hepatic lipoperoxides compared with controls. Wy-14,643 prevented hepatic lipoperoxides from accumulating despite an 18-fold increase in both Cyp4a10 and Cyp4a14 mRNA. PPAR␣ ؊/؊ mice fed the MCD diet developed more severe steatohepatitis than wt mice, and were unaffected by Wy-14,643. In conclusion, PPAR␣ activation both increases Cyp4a expression and enhances hepatic lipid turnover; the latter effect removes fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary steatohepatitis. (HEPATOLOGY 2003;38:123-132.)

show abstract

Section: Discussionmentioning

confidence: 99%

Central Role of Pparα–Dependent Hepatic Lipid Turnover in Dietary Steatohepatitis in Mice

et al. 2003

View full text Add to dashboard Cite

show abstract

“…For supershift analysis, 0.5 l of anti-FLAG M2 monoclonal antibody (Stratagene) was included in the incubation mixture. After incubating for 30 min at room temperature, the reaction mixtures were loaded onto a 5% polyacrylamide (37.5:1) gel as described (29). The dried gels were analyzed using a GE Healthcare PhosphorImager, model SI.…”

Section: Methodsmentioning

confidence: 99%

Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin

Hsu

Savas

Griffin

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The capacity to oxidize the terminal carbon of aliphatic chains is a highly conserved enzymatic activity of cytochrome P450s in plant and animal species. In mammals, the -hydroxylation of fatty acids provides a means to remove potentially toxic excess concentrations of free fatty acids. This is the first step in the formation of dicarboxylic acids that can be more readily excreted or are further degraded by peroxisomal ␤-oxidation. The -hydroxylases also provide pathways for the degradation of signaling molecules such as prostanoids and leukotrienes. On the other hand, -hydroxylation of arachidonic acid forms 20-hydroxyeicosatetraenoic acid (20-HETE), 2 which has been implicated in the regulation of vascular tone and blood pressure (1-3).Cytochrome P450 4F2 (P450 4F2) is a fatty acid -hydroxylase that is expressed in human liver and kidney and contributes to free fatty acid catabolism and the conversion of arachidonic acid to 20-HETE. In humans, the predominant -hydroxylases in liver and kidney are microsomal P450s 4A11, 4F2, and 4F3B (4). The -hydroxylation of saturated fatty acids is generally associated with P450 4A enzymes in non-human species, and human P450 4A11 catalyzes the -hydroxylation of lauric acid Ͼ palmitic acid Ͼ arachidonic acid (5). Selective disruption of the murine Cyp4a10 (6) and Cyp4a14 (7) genes leads to hypertensive phenotypes that are thought to reflect changes in renal 20-HETE production arising through distinct mechanisms. Interestingly, an allelic variant encodes a human CYP4A11 with reduced catalytic activity that is associated with an increased risk for hypertension in studies of three independent cohorts (8, 9). P450s 4F2 and 4F3B are highly similar in amino acid sequence and display overlapping catalytic activity profiles. Both enzymes efficiently oxidize arachidonic acid (10). An alternative transcript of the CYP4F3 gene, 4F3A, arises from differential promoter use leading to the incorporation of an alternative exon that alters substrate preferences to favor the -hydroxylation of leukotrienes (11). P450 4F3A is predominantly expressed in human leukocytes (12). Antibody inhibition experiments (13, 14) suggest that P450 4F2/4F3B in human liver and kidney microsomes contribute ϳ66% to the formation of 20-HETE. Recently, P450s 4F2 and 4F3B were found to -hydroxylate very long chain saturated fatty acids (15) as well as phytanic acid (16). Our preliminary experiments using com-* This work was supported by National Institutes of Health Grant HD004445(to E. F. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

show abstract

“…This receptor is largely responsible for lipid metabolism through transcriptional regulation of fatty acid oxidation enzymes, apolipoproteins and transporters (Peters et al, 2005). Among species there are substantial structural differences in the DNA binding element, peroxisome proliferator response element (PPRE) along with differences in basal PPARα expression, with humans exhibiting a tenth of the levels observed in rodents (Palmer et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

Woods

Kosyk

Bradford

et al. 2007

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Administration of peroxisome proliferators to rodents causes proliferation of peroxisomes, induction of β-oxidation enzymes, hepatocelluar hypertrophy and hyperplasia, with chronic exposure ultimately leading to hepatocellular carcinomas. Many responses associated with peroxisome proliferators are nuclear receptor-mediated events involving peroxisome proliferators-activated receptor alpha (PPARα). A role for nuclear receptor-independent events has also been shown, with evidence of Kupffer cell-mediated free radical production, presumably through NAPDH oxidase, induction of redox-sensitive transcription factors involved in cytokine production and cytokinemediated cell replication following acute treatment with peroxisome proliferators in rodents. Recent studies have demonstrated, by using p47 phox -null mice which are deficient in NADPH oxidase, that this enzyme is not related to the phenotypic events caused by prolonged administration of peroxisome proliferators. In an effort to determine the timing of the transition from Kupffer cell-to PPARα-dependent modulation of peroxisome proliferator effects, gene expression was assessed in liver from Pparα-null, p47 phox -null and corresponding wild-type mice following treatment with 4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid (WY-14,643) for 8 h, 24 h, 72 h, 1 wk, or 4 wks. WY-14,643-induced gene expression in p47 phox -null mouse liver differed substantially from wildtype mice at acute doses and striking differences in baseline expression of immune related genes were evident. Pathway mapping of genes that respond to WY-14,643 in a time-and dose-dependent manner demonstrates suppression of immune response, cell death and signal transduction and promotion of lipid metabolism, cell cycle and DNA repair. Furthermore, these pathways were largely dependent on PPARα, not NADPH oxidase demonstrating a temporal shift in response to peroxisome proliferators. Overall, this study shows that NADPH oxidase-dependent events, while detectable following acute treatment, are transient and short-lived. To the contrary, a strong PPARα-specific gene signature was evident in mice that were continually exposed to WY-14,643.

show abstract

Peroxisome Proliferator Activated Receptor-α Expression in Human Liver

Cited by 432 publications

References 40 publications

Central Role of Pparα–Dependent Hepatic Lipid Turnover in Dietary Steatohepatitis in Mice

Central Role of Pparα–Dependent Hepatic Lipid Turnover in Dietary Steatohepatitis in Mice

Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

Contact Info

Product

Resources

About