Antiepileptic drug-activated constitutive androstane receptor inhibits peroxisome proliferator-activated receptor a and peroxisome proliferator-activated receptor g coactivator 1a-dependent gene expression to increase blood triglyceride levels

Ryota Shizu, Yuta Otsuka, Kanako Ezaki, Chizuru Ishii, Shingo Arakawa, Yuto Amaike, Taiki Abe, Takuomi Hosaka, Takamitsu Sasaki, Yuichiro Kanno, Masaaki Miyata, Yasushi Yamazoe, Kouichi Yoshinari

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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 a (PPARa), 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 PPARa target genes related to lipid metabolism. The increase in PPARa target gene expression induced by fenofibrate, a PPARa ligand, was inhibited by cotreatment with phenobarbital. CAR suppressed PPARa-dependent gene transcription in HepG2 cells but not in COS-1 cells. The mRNA level of peroxisome proliferator-activated receptor g coactivator 1a (PGC1a), a coactivator for both CAR and PPARa, in COS-1 cells was much lower than in HepG2 cells. In reporter assays with COS-1 cells overexpressing PGC1a, CAR suppressed PPARa-dependent gene transcription, depending on the coactivator-binding motif. In mammalian two-hybrid assays, CAR attenuated the interaction between PGC1a and PPARa. Chemical inhibition of PGC1a prevented phenobarbital-dependent increases in plasma triglyceride levels and the inhibition of PPARa target gene expression. These results suggest that CAR inhibits the interaction between PPARa and PGC1a, attenuating PPARa-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 a-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 g coactivator-1a binding.

Original languageEnglish
Pages (from-to)634-647
Number of pages14
JournalMolecular pharmacology
Volume98
Issue number5
DOIs
Publication statusPublished - 2020 Nov 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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