In another experiment performed in WD-fed hApoE2 KI/PPAR-α KO mic

In another experiment performed in WD-fed hApoE2 KI/PPAR-α KO mice, the pure PPAR-γ agonist, rosiglitazone,

had no effect on inflammatory and fibrosis gene expression, whereas the pure PPAR-δ agonist, GW501516, showed a similar profile to GFT505 (Supporting Table 2). These results further suggest that, in hApoE2 KI/PPAR-α KO mice, GFT505 likely acts through activation of PPAR-δ in the liver. Olaparib To evaluate the effect of GFT505 on later stages of fatty liver disease, we next studied a model of advanced steatosis with strong inflammation induced by an MCD diet. In two independent experiments, insulin-resistant db/db mice were fed the MCD diet for 7 weeks and concomitantly treated with vehicle or 1, 3, 10 (experiment 1), or 30 mg/kg/day (experiment 2) of GFT505. The MCD diet provoked a significant increase of plasma ALT levels, associated with intrahepatic accumulation of cholesterol and TGs (Fig. 3A-C). Upon histological examination, a marked macrovesicular steatosis induced by MCD diet feeding was accompanied by increased buy Quizartinib inflammation and weak fibrosis (Fig. 4A-D). In mice concomitantly treated with GFT505, intrahepatic cholesterol and TG

content were significantly reduced in a dose-dependent manner to reach levels comparable to those in mice fed the control diet (Fig. 3B,C). Microscopic Immune system examination showed that GFT505 administration at 10 mg/kg/day completely prevented MCD diet-induced macrovesicular steatosis and inflammation (Fig. 4B,C). The weak hepatic fibrosis observed in

MCD diet-fed mice was not significantly reduced by GFT505 treatment (Fig. 4D). Consistent with liver protection by GFT505, plasma ALT activity was reduced to levels comparable to the control diet group (Fig. 3A), and liver weight was also significantly reduced (Fig. 3D). In a study performed at 30 mg/kg/day of GFT505 and giving similar results, transcriptomic analyses showed that the MCD diet-induced increased expression of hepatic inflammatory and profibrosis genes (IL-1β, TNF-α, TGF-β, and collagens) was blocked by GFT505 (Supporting Table 3). Moreover, hepatic expression of macrophage markers CD11b and F4/80 was significantly decreased by GFT505 treatment (Supporting Table 3). The effect of GFT505 on liver fibrosis was studied in a rat model induced by repeated IP injections of CCl4. Rats were injected with CCl4 or vehicle twice-weekly for 7 weeks, with parallel oral treatment with 30 mg/kg/day of GFT505 or vehicle. CCl4 administration induced a strong liver fibrosis with the formation of collagen bridges between veins (Fig. 5A), associated with an increased number of macrophages (KCs; Fig. 5B) and activated hepatic stellate cells (HSCs) expressing alpha smooth muscle actin (αSMA; Fig. 5C).

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