[15] In these studies, groups of PPAR-α-expressing WD-fed hApoE2 KI mice were included for comparison. Treatment of PPAR-α-expressing

hApoE2 KI mice with GFT505 significantly reduced plasma total cholesterol, triglycerides (TGs), and free fatty acids (FFAs) and strongly increased high-density lipoprotein (HDL) cholesterol levels (Fig. 1A-D). In hApoE2 KI/PPAR-α KO mice, GFT505 failed to influence plasma TGs (Fig. 1A). However, in this strain of mice, GFT505 still decreased plasma FFAs and total cholesterol and increased HDL cholesterol, albeit to a lesser extent (Fig. 1B-D). These data suggest that GFT505 selleckchem may have favorable effects on plasma lipids that are independent of activation of PPAR-α. In contrast, in a similar study, the PPAR-α reference agonist, fenofibrate (100 mg/kg/day), did not show any lipid-modulating effects in hApoE2 KI/PPAR-α KO mice (Supporting Fig. 2A-D). As expected in rodents exposed to a PPAR-α agonist,[11] GFT505 significantly

increased liver weight in hApoE2 KI mice, but not in hApoE2 KI/PPAR-α KO mice (Fig. GSK2126458 1E), illustrating the hyperresponsiveness of rodents to PPAR-α-induced peroxisomal proliferation and hepatomegaly. Similar findings were observed with fenofibrate (data not shown). Microscopic examination of livers revealed both macro- and microsteatosis in WD-fed hApoE2 KI/PPAR-α KO mice, whereas PPAR-α-expressing hApoE2 KI mice were relatively resistant to WD-induced steatosis (Fig. 2A-C). In hApoE2 KI/PPAR-α KO mice, GFT505 administration reduced both diet-induced macro- and microsteatosis Osimertinib ic50 (Fig. 2A-C) and significantly reduced circulating

levels of the liver dysfunction markers, aspartate aminotransferase (AST) and ALT (data not shown). Interestingly, GFT505 reduced WD-induced increased cellularity in sinusoids (KCs) in both hApoE2 KI and hApoE2 KI/PPAR-α KO mice (Fig. 2D). In contrast, fenofibrate had no effect on cellularity of sinusoids in ApoE2 KI/PPAR-α KO mice (Supporting Fig. 2E,F). These results suggested that GFT505 has liver-protective effects through combined PPAR-α-dependent and -independent mechanisms. In hApoE2 KI mice, GFT505 provoked a significant reduction in hepatic expression of proinflammatory genes, such as interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), the macrophage marker, F4/80, and the fibrosis genes, transforming growth factor beta (TGF-β) and tissue inhibitor of metalloproteinase (TIMP)−2 (Supporting Table 2). In hApoE2 KI/PPAR-α KO mice, these genes were also reduced by GFT505, with significant down-regulation of additional profibrosis markers, such as collagens (Supporting Table 2). In contrast, fenofibrate significantly reduced the expression of proinflammatory and profibrotic genes in hApoE2 KI mice, but had little effect in hApoE2 KI/PPAR-α KO mice. In keeping with PPAR-α agonist-induced hepatomegaly in rodents (Fig.