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

Abstract

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.)

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

“…In the CCl 4 therapeutic model, the rank order of antifibrotic efficacy was IVA337 ≥ fenofibrate > rosiglitazone > GW501516, with PPARγ and PPARδ agonists having a partial effect on fibrosis. Our results are consistent with published studies on the effect of selective PPAR agonists on liver fibrosis 14, 21, 39. However, results with GW501516 in our study and in the literature differ from those obtained with KD3010, another PPARδ agonist that was shown to be very active on liver fibrosis induced by CCl 4 or bile duct ligation 39.…”

“…PPARα‐ as well as PPARγ‐deficient mice are more sensitive to the development of steatohepatitis under an MCD than wild‐type mice 21, 22. Using selective PPAR agonists, it was reported that Wy‐14,643 (a PPARα agonist), GW501516 (a PPARδ agonist), and PPARγ activation by pioglitazone prevent and/or reverse MCD‐induced steatohepatitis 21, 22, 23, 24, 25.…”

“…Elafibranor (GFT505), which combines PPARα and PPARδ activation, improved metabolic disorders and reduced the severity of steatohepatitis and fibrosis in several animal models and in patients with NASH 19. Selective PPARγ activation by pioglitazone or rosiglitazone improved insulin resistance and reduced steatosis, inflammation, and fibrosis in animal models and in patients with NASH 20, 21. Taken together, these results indicate that activation of each of the three PPAR isoforms individually provides therapeutic benefit to patients with NASH.…”

Polygala tenuifolia extract inhibits lipid accumulation in 3T3-L1 adipocytes and high-fat diet–induced obese mouse model and affects hepatic transcriptome and gut microbiota profiles

“…PPARα is a ligand-activated transcription factor involved in fatty acid metabolism [47]. Earlier evidence indicated that PPARα −/− mice had severe hepatic steatosis [48]. In particular, several genes upregulated by PTE, such as Lpin-1, Pctp, and Abcg5, were direct target genes of PPARα [49].…”

Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

“…14 The fact that CYP2E1-null mice also developed liver injury was attributed to compensatory mechanisms, including the induction of CYP4A isozymes. 27,28 However, the role of CYP4A10 and CYP4A14 in the generation of LPO products and ROS has been controversially discussed 29 ; Bradford et al 14 did not find increased oxidative DNA damage in CYP2E1-null mice despite elevated CYP4A enzyme levels.…”