Abstract
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.
Highlights
Hepatic gluconeogenesis is strictly controlled by the activities of rate-limiting enzymes such as glucose-6-phosphatase (G6Pase),1 phosphoenolpyruvate carboxykinase (PEPCK), and
Bile Acids Repress Gluconeogenic Gene Promoter Activities—To evaluate the effects of bile acids on hepatic gluconeogenic gene expression in vivo, C57BL/6J mice were treated for 7 days with a diet containing cholic acid, which is known to be a natural ligand of the nuclear receptor farnesoid X receptor (FXR) [23]
HepG2 cells were transfected with each reporter construct and treated with increasing concentrations of chenodeoxycholic acid (CDCA), which is a primary bile acid and induces small heterodimer partner (SHP) via the FXR-dependent pathway [12, 13, 24, 25]
Summary
G6Pase, glucose-6-phosphatase; NR, nuclear receptor; FXR, farnesoid X receptor; CDCA, chenodeoxycholic acid; CYP7A1, cholesterol 7␣-hydroxylase; SHP, small heterodimer partner; PEPCK, phosphoenolpyruvate carboxykinase; FBP1, fructose1,6-bisphosphatase; CBP, cAMP response element-binding protein (CREB)-binding protein; HNF-4, hepatocyte nuclear factor 4; GST, glufructose 1,6-bis phosphatase (FBP1). Recent studies demonstrated that glucagon or glucocorticoid signals strikingly induce the levels of PGC-1 protein [5, 9], which subsequently up-regulates G6Pase and PEPCK gene expression by coactivating HNF-4 [6] and Foxo1 [2]. Bile acid metabolism plays a critical role for the elimination of excess cholesterol in the liver This pathway is achieved via transcriptional regulation of cholesterol 7␣-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid biosynthesis [10, 11]. We show that bile acids efficiently suppress the mRNA levels and promoter activities of G6Pase, PEPCK, and FBP1 in mouse liver and HepG2 cells, respectively. Our findings provide evidence that bile acids repress gluconeogenic gene transcription via the effect of the negative nuclear receptor SHP on HNF-4 or Foxo
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