Bile Acids Regulate Gluconeogenic Gene Expression via Small Heterodimer Partner-mediated Repression of Hepatocyte Nuclear Factor 4 and Foxo1

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 proteinbinding protein. These findings reveal a novel mechanism by which bile acids regulate gluconeogenic gene expression via an SHP-dependent regulatory pathway.

Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin

“…It was reported that NR0B2 represses G6pc transcription mediated by the transcription factor forkhead box O1 (FOXO1) by competing with a coactivator [31]. Under our assay conditions, no significant change of expression was observed, either for Foxo1, or for phosphoenolpyruvate carboxykinase, which is also regulated by NR0B2 [31]. Taken together, the down-regulation of G6pc should be mediated by a mechanism independent of NR0B2 and the FOXO1 system.…”

“…G6pc gene expression was observed in an in vivo study to be modulated by polyunsaturated fatty acids [37]. Interestingly, as shown in Table 1, a transcription regulatory protein, Nr0b2, that regulates gluconeogenic genes [31], was down-regulated by metformin treatment, as observed in the case of G6pc.…”

“…3). Interestingly, nuclear receptor subfamily 0, group B, member 2 (Nr0b2), previously known as small heterodimer partner (Shp), which was reported to be an important factor linked to expression regulation of gluconeogenesis genes [31], was also included in the list.…”

“…Changes in the fatty acid and glycerolipid metabolism pathways may contribute to an improvement of lipid metabolism by repeated treatment with metformin, while some fatty acids might be important in modulating mRNA expression of genes such as G6pc [37]. Interestingly, changes of expression in the bile acid biosynthesis, but not the sterol biosynthesis pathway, were detected; indeed, coordinated transcriptional regulation between bile acids and gluconeogenesis [39,40], as well as suppression of gluconeogenenic genes by bile acid [31], have been reported recently. With regard to amino acid metabolism pathways, such as valine, leucine and isoleucine degradation, lysine degradation, arginine and proline metabolism and tryptophan metabolism, it has previously been reported that protein metabolism is abnormal in type 2 diabetes [41], although its relevance to the action of metformin remains to be elucidated.…”

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…SHP has been shown to be involved in BA synthesis, lipid and cholesterol metabolism, glucose homeostasis, apoptosis, and cell invasion 36, 37, 38, 39, 40, 41, 42, 43. SHP has also been identified as a mediating factor in the metabolic circadian clock 44, 45, 46, 47, 48.…”