TY - JOUR
T1 - 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
AU - Shizu, Ryota
AU - Otsuka, Yuta
AU - Ezaki, Kanako
AU - Ishii, Chizuru
AU - Arakawa, Shingo
AU - Amaike, Yuto
AU - Abe, Taiki
AU - Hosaka, Takuomi
AU - Sasaki, Takamitsu
AU - Kanno, Yuichiro
AU - Miyata, Masaaki
AU - Yamazoe, Yasushi
AU - Yoshinari, Kouichi
N1 - Funding Information:
This study was supported in part by a grant-in-aid from Ministry of Education, Culture, Sports, Sciences and Technology of Japan [Grants 22390027, 17K08418, and 20K07202] and a grant from the Japan Chemical Industry Association (JCIA) Long-range Research Initiative (LRI). The authors declare that they have no conflicts of interest with contents of this article. https://doi.org/10.1124/molpharm.120.000103. s This article has supplemental material available at molpharm.aspetjournals. org.
Publisher Copyright:
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
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U2 - 10.1124/MOLPHARM.120.000103
DO - 10.1124/MOLPHARM.120.000103
M3 - Article
C2 - 32892155
AN - SCOPUS:85094684555
VL - 98
SP - 634
EP - 647
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 5
ER -