| First Author | Bi Y | Year | 2018 |
| Journal | Mol Cell Biol | Volume | 38 |
| Issue | 7 | PubMed ID | 29378829 |
| Mgi Jnum | J:261619 | Mgi Id | MGI:6155881 |
| Doi | 10.1128/MCB.00654-17 | Citation | Bi Y, et al. (2018) Regulation of Cholesterol Sulfotransferase SULT2B1b by Hepatocyte Nuclear Factor 4alpha Constitutes a Negative Feedback Control of Hepatic Gluconeogenesis. Mol Cell Biol 38(7) |
| abstractText | The cholesterol sulfotransferase SULT2B1b converts cholesterol to cholesterol sulfate (CS). We previously reported that SULT2B1b inhibits hepatic gluconeogenesis by antagonizing the gluconeogenic activity of hepatocyte nuclear factor 4alpha (HNF4alpha). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4alpha, which led to our hypothesis that the induction of SULT2B1b by HNF4alpha represents a negative feedback to limit the gluconeogenic activity of HNF4alpha. Indeed, downregulation of Sult2B1b enhanced the gluconeogenic activity of HNF4alpha, which may have been accounted for by the increased acetylation of HNF4alpha as a result of decreased expression of the HNF4alpha deacetylase sirtuin 1 (Sirt1). The expression of Sult2B1b was also induced by HNF4alpha upon fasting, and the Sult2B1b null (Sult2B1b(-/-)) mice showed increased gluconeogenic gene expression and an elevated fasting glucose level, suggesting that SULT2B1b also plays a restrictive role in HNF4alpha-mediated fasting-responsive gluconeogenesis. We also developed thiocholesterol, a hydrolysis-resistant derivative of CS, which showed superior activity to that of the native CS in inhibiting gluconeogenesis and improving insulin sensitivity in high-fat-diet-induced diabetic mice. We conclude that the HNF4alpha-SULT2B1b-CS axis represents a key endogenous mechanism to prevent uncontrolled gluconeogenesis. Thiocholesterol may be used as a therapeutic agent to manage hyperglycemia. |
