Lack of hepatic PPARα impairs the liver's ability to use FFA from acute lipolysis, resulting in steatosis. MCD diet-induced weight loss49 50 also correlated with hepatic PPARα activity, suggesting that chronic lipolysis elevates hepatocytic PPARα activity in non-fasted mice. In agreement with the findings in whole-body PPARα-deficient mice,20 our data demonstrated that the absence of hepatocytic PPARα was sufficient to increase MCD diet-induced liver damage. FGF21 expression/circulating levels increased in steatohepatitis, supporting the possibility that elevated FGF21 may reflect liver stress without fasting. This MCD diet-induced FGF21 increase was not strictly PPARα-dependent, consistent with the findings that amino acid deprivation induces hepatic FGF21 expression through ATF4.44 PPARα presence led to greater FGF21 increase, and may contribute to hepatoprotection from lipotoxic lipid accumulation.30
