Indeed, animals fed an MCD diet lose weight and are not insulin resistant. Moreover, PGC-1β seems to be able
to influence lipid metabolism and oxidative phosphorylation, thus acting as a key player in the protection of the liver against one of the main insults that characterizes the development of steatohepatitis, represented by the lipid accumulation within hepatocytes. Alvelestat in vitro To test the ability of PGC-1β to ameliorate steatosis, wildtype and LivPGC-1β mice were fed a high-fat diet (HFD) containing 35% fat. Similar to MCD feeding, after 8 weeks of an HFD diet the gross morphology of livers of transgenic mice appeared healthier compared with that of wildtype mice that showed selleck chemicals llc steatotic liver (Fig. 7A). Histological analysis revealed that wildtype mice challenged with HFD developed severe steatosis with macrovescicular lipid droplets,
whereas LivPGC-1β mice did not show the characteristic ballooning injury of fatty liver (Fig. 7B). Hepatic lipid analysis showed a 50% increase in TG levels and a dramatic rise of cholesterol in HFD fed wildtype liver compared with the same group fed with a standard diet (chow) (Fig. 7C). Conversely, LivPGC-1β mice presented only a slight accumulation of TG in the liver and a moderate increase of cholesterol when compared with wildtype mice fed the same diet (Fig. 7C). Oil Red staining revealed Farnesyltransferase the massive accumulation of neutral lipids within wildtype hepatocytes in mice fed with HFD compared with controls, while it demonstrated mild amount of lipids stored in microvesicles in LivPGC-1β mice (Fig. 7D).
To gain insight into the mechanism by which the overexpression of PGC-1β leads to hepatocyte protection against lipid overload, we examined the expression of genes implicated in mitochondrial function and lipid synthesis. Messenger RNA (mRNA) levels of ATPβsynt, cytC, Idh3α, Dgat1, Scd-1, and Fas were increased in livers from LivPGC-1β mice fed an HFD diet as compared with their wildtype controls (Fig. 7E). Remarkably, PGC-1β is able to sustain the expression of Scd-1 that is strongly decreased by HFD feeding (data not shown), similar to the dietary model of steatohepatitis. Taken together, these results demonstrate that the hepatic overexpression of PGC-1β prevents lipid accumulation within the hepatocytes during high-fat feeding, thus protecting very efficiently from simple steatosis. This work shows that hepatic PGC-1β is able to stimulate mitochondrial functions through the induction of key enzymes involved in oxidative phosphorylation, citrate cycle, pyruvate, and lipid metabolism, as well as to induce genes involved in TG metabolism and secretion by way of VLDL in the bloodstream.