We next examined whether the hepatocytic PPARα response to chronic lipolysis occurred during methionine-deficient and choline-deficient diet (MCD)-induced weight loss. In rodents, this diet rapidly promotes lipolysis in adipocytes, resulting in steatohepatitis. On the MCD diet, mice of each genotype showed weight loss (figure 7A), steatosis (figure 7B), and increased hepatic triglycerides, cholesterol esters (figure 7C) and plasma ALT (figure 7D). Compared with WT, Pparαhep−/− and Pparα−/− mice showed greater steatosis and liver damage, suggesting a more severe MCD diet-induced phenotype without hepatocyte PPARα. MCD also induced increased expressions of Cyp4a14 and Vanin1 in WT mice, but not Pparαhep−/− or Pparα−/− mice (figure 7E). Fgf21 mRNA (figure 7E) and circulating FGF21 (figure 7F) were increased through a mechanism that is partly dependent on hepatic PPARα. Overall, hepatocyte-specific Pparα deletion aggravated MCD diet-induced liver damage, correlating with defective PPARα-dependent pathway upregulation in response to chronic lipolysis.
