Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1.
Bile acid homeostasis is tightly controlled by the feedback mechanism in which an atypical orphan nuclear receptor (NR) small heterodimer partner (SHP) inactivates several NRs such as liver receptor homologue-1 and hepatocyte nuclear factor 4. Although NRs have been implicated in the transcriptional regulation of gluconeogenic genes, the effect of bile acids on gluconeogenic gene expression remained unknown. Here, we report that bile acids inhibit the expression of gluconeogenic genes, including glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase, and fructose 1,6-bis phosphatase in an SHP-dependent fashion. Cholic acid diet decreased the mRNA levels of these gluconeogenic enzymes, whereas those of SHP were increased. Reporter assays demonstrated that the promoter activity of phosphoenolpyruvate carboxykinase and fructose 1,6-bis phosphatase via hepatocyte nuclear factor 4, or that of G6Pase via the forkhead transcription factor Foxo1, was down-regulated by treatment with chenodeoxicholic acid and with transfected SHP. Remarkably, Foxo1 interacted with SHP in vivo and in vitro, which led to the repression of Foxo1-mediated G6Pase transcription by competition with a coactivator cAMP response element-binding protein-binding protein. These findings reveal a novel mechanism by which bile acids regulate gluconeogenic gene expression via an SHP-dependent regulatory pathway.
Yamagata
Kazuyuki
K
Center for Tsukuba Advanced Research Alliance, Aspect of Functional Genomic Biology, Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Daitoku
Hiroaki
H
Shimamoto
Yoko
Y
Matsuzaki
Hitomi
H
Hirota
Keiko
K
Ishida
Junji
J
Fukamizu
Akiyoshi
A
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005246:Feedback; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2