Regulation of Cholesterol Sulfotransferase SULT2B1b by Hepatocyte Nuclear Factor 4α Constitutes a Negative Feedback Control of Hepatic Gluconeogenesis

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 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, downregulation 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 sirtuin 1 (Sirt1). The expression of Sult2B1b was also induced by HNF4α 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 HNF4α-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 HNF4α-SULT2B1b-CS axis represents a key endogenous mechanism to prevent uncontrolled gluconeogenesis. Thiocholesterol may be used as a therapeutic agent to manage hyperglycemia.

KEYWORDS:

• sulfotransferase
• HNF4α
• gluconeogenesis
• cholesterol sulfate
• thiocholesterol

ACKNOWLEDGMENTS

This study was supported in part by NIH grants DK083952 and HD073070 (to Wen Xie). Normal human hepatocytes were obtained through the Liver Tissue Procurement and Distribution System, Pittsburgh, PA, which was funded by NIH contract N01-DK-7-0004/HHSN267200700004C. Wen Xie is also supported in part by the Joseph Koslow Endowed Professorship in Pharmaceutical Sciences from the University of Pittsburgh School of Pharmacy and the Chinese Ministry of Education 111 Project grant no. B16047.

Yuhan Bi and Wen Xie participated in research design. Yuhan Bi, Xiongjie Shi, Xiudong Guan, Junjie Zhu, Wojciech G. Garbacz, Yixian Huang, Li Gao, Meishu Xu, and Songrong Ren conducted the experiments. Yuhan Bi and Wen Xie performed data analysis. Yuhan Bi, Xiudong Guan, Jiong Yan, Shunlin Ren, Yulan Liu, Xiaochao Ma, Song Li, and Wen Xie wrote or contributed to the writing of the manuscript. Wen Xie acquired funding.

We declare that no conflict of interest exists.