Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator‐activated receptor alpha/delta (PPAR‐α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]‐fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine‐ and choline‐deficient diet‐fed db/db mice, and CCl4‐induced fibrosis in rats). GFT505 demonstrated liver‐protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin‐1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR‐α‐independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock‐in/PPAR‐α knockout mice. In these mice, GFT505 also prevented WD‐induced liver steatosis and inflammation, indicating a contribution of PPAR‐α‐independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma‐glutamyl transpeptidase, and alkaline phosphatase. Conclusion: The dual PPAR‐α/δ agonist, GFT505, is a promising liver‐targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR‐α‐dependent and ‐independent mechanisms. (Hepatology 2013; 58:1941–1952)

An ACAT-1Inhibitor, K-604, Ameliorates Hepatic Inflammation in NAFLD and NASH Models

“…After being fed the MCD diet for 16 weeks, the mice exhibited a dramatic weight loss and a decreased supply of fatty acids, resulting in reduced lipid accumulation and COL1A1 mRNA expression in the liver (Table 1 and Figure 1J). As several groups reported, marked fibrosis was not observed in the MCD diet-fed mice [5,12,21], which is different from the observation that the MCD diet-fed Wistar rats exhibited severe fibrosis [22,23]. The MCD dietinduced the progression of steatohepatitis in the KK-Ay mice, as demonstrated by lipid droplet accumulation, inflammatory foci formation, and TNF-α gene expression.…”

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin

“…Interestingly, the induction of these genes was blunted by both elafibranor (GFT505), a mixed PPARα/δ agonist active in murine models of NASH (59) and in NASH patients (60) (Figure 6A Data are expressed as the mean ± SEM (n = 9) and were compared using a 2-tailed t-test. A P < 0.001, B P < 0.05.…”

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

“…Some but not all PPARδ agonists have had beneficial effects in preclinical models of NASH 17, 18. 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.…”