Peroxisome proliferator-activated receptor α-mediated pathways are altered in hepatocyte-specific retinoid x receptor α-deficient mice

Abstract

Retinoid x receptor α (RXRα) serves as an active partner of peroxisome proliferator-activated receptor (PPARα). In order to dissect the functional role of RXRα and PPARα in PPARα-mediated pathways, the hepatocyte RXRα-deficient mice have been challenged with physiological and pharmacological stresses, fasting and Wy14,643, respectively. The data demonstrate that RXRα and PPARα deficiency are different in several aspects. At the basal untreated level, RXRα deficiency resulted in marked induction of apolipoprotein A-I and C-III (apoA-I and apoC-III) mRNA levels and serum cholesterol and triglyceride levels, which was not found in PPARα-null mice. Fasting-induced PPARα activation was drastically prevented in the absence of hepatocyte RXRα. Wy14,643-mediated pleiotropic effects were also altered due to the absence of hepatocyte RXRα. Hepatocyte RXRα deficiency did not change the basal acyl-CoA oxidase, medium chain acyl-CoA dehydrogenase, and malic enzyme mRNA levels. However, the inducibility of those genes by Wy14,643 was markedly reduced in the mutant mouse livers. In contrast, the basal cytochrome P450 4A1, liver fatty acid-binding protein, and apoA-I and apoC-III mRNA levels were significantly altered in the mutant mouse livers, but the regulatory effect of Wy14,643 on expression of those genes remained the same. Wy14,643-induced hepatomegaly was partially inhibited in hepatocyte RXRα-deficient mice. Wy14,643-induced hepatocyte peroxisome proliferation was preserved in the absence of hepatocyte RXRα. These data suggested that in comparison to PPARα, hepatocyte RXRα has its unique role in lipid homeostasis and that the effect of RXRα, -β, and -γ is redundant in certain aspects.