3 years ago

Regulation of Cholesterol Sulfotransferase SULT2B1b by HNF4α Constitutes a Negative Feedback Control of Hepatic Gluconeogenesis.

Wen Xie, Junjie Zhu, Wojciech G Garbacz, Jiong Yan, Xiaochao Ma, Meishu Xu, Yulan Liu, Yixian Huang, Songrong Ren, Shunlin Ren, Li Gao, Yuhan Bi, Song Li, Xiudong Guan, Xiongjie Shi
The cholesterol sulfotransferase SULT2B1b converses cholesterol to cholesterol sulfate (CS). We previously reported that SULT2B1b inhibits hepatic gluconeogenesis by antagonizing the gluconeogenic activity of hepatocyte nuclear factor 4α (HNF4α). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4α, which led to our hypothesis that the induction of SULT2B1b by HNF4α represents a negative feedback to limit the gluconeogenic activity of HNF4α. Indeed, down-regulation of Sult2B1b enhanced the gluconeogenic activity of HNF4α, which may have been accounted for by the increased acetylation of HNF4α as a result of decreased expression of the HNF4α deacetylase Sirt1. The expression of Sult2B1b was also induced by HNF4α upon fasting and the Sult2B1b null (Sult2B1b-/-) mice showed increased gluconeogenic gene expression and elevated fasting glucose level, suggesting that SULT2B1b also plays a restrictive role in HNF4α mediated fasting responsive gluconeogenesis. We also developed thiocholesterol, a hydrolysis-resistant derivative of CS, which showed more superior activity than the native CS in inhibiting gluconeogenesis and improving insulin sensitivity in high-fat diet induced diabetic mice. We conclude that the HNF4α-SULT2B1b-CS axis represents a key endogenous mechanism to prevent uncontrolled gluconeogenesis. Thiocholesterol may be used as a therapeutic agent to manage hyperglycemia.

Publisher URL: http://doi.org/10.1128/MCB.00654-17

DOI: 10.1128/MCB.00654-17

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