Antiepileptic Drug-Activated Constitutive Androstane Receptor Inhibits Peroxisome Proliferator-Activated Receptor α and Peroxisome Proliferator-Activated Receptor γ Coactivator 1α-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 α (PPARα), 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 PPARα target genes related to lipid metabolism. The increase in PPARα target gene expression induced by fenofibrate, a PPARα ligand, was inhibited by cotreatment with phenobarbital. CAR suppressed PPARα-dependent gene transcription in HepG2 cells but not in COS-1 cells. The mRNA level of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a coactivator for both CAR and PPARα, in COS-1 cells was much lower than in HepG2 cells. In reporter assays with COS-1 cells overexpressing PGC1α, CAR suppressed PPARα-dependent gene transcription, depending on the coactivator-binding motif. In mammalian two-hybrid assays, CAR attenuated the interaction between PGC1α and PPARα Chemical inhibition of PGC1α prevented phenobarbital-dependent increases in plasma triglyceride levels and the inhibition of PPARα target gene expression. These results suggest that CAR inhibits the interaction between PPARα and PGC1α, attenuating PPARα-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 α-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 γ coactivator-1α binding.

Shizu R ，Otsuka Y ，Ezaki K ，Ishii C ，Arakawa S ，Amaike Y ，Abe T ，Hosaka T ，Sasaki T ，Kanno Y ，Miyata M ，Yamazoe Y ，Yoshinari K ... -  《-》

Transcription coactivator PRIP, the peroxisome proliferator-activated receptor (PPAR)-interacting protein, is redundant for the function of nuclear receptors PParalpha and CAR, the constitutive androstane receptor, in mouse liver.

Sarkar J ，Qi C ，Guo D ，Ahmed MR ，Jia Y ，Usuda N ，Viswakarma N ，Rao MS ，Reddy JK ... -  《-》

PPARα Induces the Expression of CAR That Works as a Negative Regulator of PPARα Functions in Mouse Livers.

Shizu R ，Otsuka Y ，Ishii C ，Ezaki K ，Yoshinari K ... -  《-》

Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor alpha synthetic ligands in mouse liver.

Guo D ，Sarkar J ，Suino-Powell K ，Xu Y ，Matsumoto K ，Jia Y ，Yu S ，Khare S ，Haldar K ，Rao MS ，Foreman JE ，Monga SP ，Peters JM ，Xu HE ，Reddy JK ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》

PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α.

Shizu R ，Ezaki K ，Sato T ，Sugawara A ，Hosaka T ，Sasaki T ，Yoshinari K ... -  《-》