Antiepileptic Drug-Activated Constitutive Androstane Receptor Inhibits Peroxisome Proliferator-Activated Receptor and Peroxisome Proliferator-Activated Receptor Coactivator 1-Dependent Gene Expression to Increase Blood Triglyceride Levels.

Long-term administration of some antiepileptic drugs often increases blood lipid levels. In this study, we investigated its molecular mechanism by focusing on the nuclear receptors constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR), which are key transcription factors for enzyme induction and lipid metabolism, respectively, in the liver. Treatment of mice with the CAR activator phenobarbital, an antiepileptic drug, increased plasma triglyceride levels and decreased the hepatic expression of PPAR target genes related to lipid metabolism. The increase in PPAR target gene expression induced by fenofibrate, a PPAR ligand, was inhibited by cotreatment with phenobarbital. CAR suppressed PPAR-dependent gene transcription in HepG2 cells but not in COS-1 cells. The mRNA level of peroxisome proliferator-activated receptor coactivator 1 (PGC1), a coactivator for both CAR and PPAR, in COS-1 cells was much lower than in HepG2 cells. In reporter assays with COS-1 cells overexpressing PGC1, CAR suppressed PPAR-dependent gene transcription, depending on the coactivator-binding motif. In mammalian two-hybrid assays, CAR attenuated the interaction between PGC1 and PPAR Chemical inhibition of PGC1 prevented phenobarbital-dependent increases in plasma triglyceride levels and the inhibition of PPAR target gene expression. These results suggest that CAR inhibits the interaction between PPAR and PGC1, attenuating PPAR-dependent lipid metabolism. This might explain the antiepileptic drug-induced elevation of blood triglyceride levels. SIGNIFICANCE STATEMENT: Constitutive active/androstane receptor activated by antiepileptic drugs inhibits the peroxisome proliferator-activated receptor -dependent transcription of genes related to lipid metabolism and upregulates blood triglyceride levels. The molecular mechanism of this inhibition involves competition between these nuclear receptors for coactivator peroxisome proliferator-activated receptor coactivator-1 binding.