| Title | Regulation of Cholesterol Sulfotransferase SULT2B1b by Hepatocyte Nuclear Factor 4 alpha Constitutes a Negative Feedback Control of Hepatic Gluconeogenesis |
| Authors | Bi, Yuhan Shi, Xiongjie Zhu, Junjie Guan, Xiudong Garbacz, Wojciech G. Huang, Yixian Gao, Li Yan, Jiong Xu, Meishu Ren, Songrong Ren, Shunlin Liu, Yulan Ma, Xiaochao Li, Song Xie, Wen |
| Affiliation | Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA. Capital Med Univ, Beijing Tiantan Hosp, Dept Neurosurg, Beijing, Peoples R China. Peking Univ, Peoples Hosp, Dept Gastroenterol, Beijing, Peoples R China. Virginia Commonwealth Univ, Dept Med, Vet Affairs McGuire Med Ctr, Med Coll Virginia Campus, Richmond, VA 23298 USA. Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15260 USA. Xie, W (reprint author), Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA. Xie, W (reprint author), Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15260 USA. |
| Keywords | sulfotransferase HNF4 alpha gluconeogenesis cholesterol sulfate thiocholesterol FATTY LIVER-DISEASE GENE-EXPRESSION MOUSE MODELS X-RECEPTOR IN-VIVO HNF4-ALPHA TRANSCRIPTION DEPRIVATION METABOLISM ACTIVATION |
| Issue Date | 2018 |
| Publisher | MOLECULAR AND CELLULAR BIOLOGY |
| Citation | MOLECULAR AND CELLULAR BIOLOGY. 2018, 38(7). |
| Abstract | 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 4 alpha (HNF4 alpha). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4 alpha, which led to our hypothesis that the induction of SULT2B1b by HNF4(alpha) represents a negative feedback to limit the gluconeogenic activity of HNF4 alpha. Indeed, downregulation of Sult2B1b enhanced the gluconeogenic activity of HNF4 alpha, which may have been accounted for by the increased acetylation of HNF4 alpha as a result of decreased expression of the HNF4 alpha deacetylase sirtuin 1 (Sirt1). The expression of Sult2B1b was also induced by HNF4 alpha 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 HNF4 alpha-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 HNF4 alpha-SULT2B1b-CS axis represents a key endogenous mechanism to prevent uncontrolled gluconeogenesis. Thiocholesterol may be used as a therapeutic agent to manage hyperglycemia. |
| URI | http://hdl.handle.net/20.500.11897/510438 |
| ISSN | 0270-7306 |
| DOI | 10.1128/MCB.00654-17 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 人民医院 |
