Bile acid represses the peroxisome proliferator-activated receptor-gamma coactivator-1 promoter activity in a small heterodimer partner-dependent manner.
Bile acid homeostasis is tightly controlled by the feedback mechanism in which an atypical orphan nuclear receptor (NR), small heterodimer partner (SHP), inactivates several transcription factors. We previously demonstrated that bile acid represses the expression of gluconeogenic genes, including glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and fructose-1,6-bisphosphatase (FBP1) in an SHP-dependent manner. Recently, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) coactivator-1 (PGC-1) gene, a coactivator of NRs important for gluconeogenic gene expression, was also downregulated by bile acid in wild-type mice but not in farnesoid X receptor- or SHP-null mice. However, the molecular mechanism for the effect of bile acid on PGC-1 gene expression remains unknown. In the present study, a series of reporter assays demonstrated that the promoter activity of PGC-1 via a member of the forkhead transcription factors, Foxo1, FOXO3a, and Foxo4 was downregulated by treatment with chenodeoxicholic acid and with transfected SHP. These results revealed that bile acid inhibits the promoter activity of PGC-1 in an SHP-dependent manner.
Yamagata
Kazuyuki
K
Center for Tsukuba Advanced Research Alliance, Aspect of Functional Genomic Biology, Institute of Applied Biochemistry, University of Tsukuba, Ibaraki, Japan.
Yoshimochi
Kenji
K
Daitoku
Hiroaki
H
Hirota
Keiko
K
Fukamizu
Akiyoshi
A
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*
D001647:Bile Acids and Salts; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D051057:Proto-Oncogene Proteins c-akt