Cholesterol Sulfate and Cholesterol Sulfotransferase Inhibit Gluconeogenesis by Targeting Hepatocyte Nuclear Factor 4α

Abstract

Sulfotransferase (SULT)-mediated sulfation represents a critical mechanism in regulating the chemical and functional homeostasis of endogenous and exogenous molecules. The cholesterol sulfotransferase SULT2B1b catalyzes the sulfoconjugation of cholesterol to synthesize cholesterol sulfate (CS). In this study, we showed that the expression of SULT2B1b in the liver was induced in obese mice and during the transition from the fasted to the fed state, suggesting that the regulation of SULT2B1b is physiologically relevant. CS and SULT2B1b inhibited gluconeogenesis by targeting the gluconeogenic factor hepatocyte nuclear factor 4α (HNF4α) in both cell cultures and transgenic mice. Treatment of mice with CS or transgenic overexpression of the CS-generating enzyme SULT2B1b in the liver inhibited hepatic gluconeogenesis and alleviated metabolic abnormalities both in mice with diet-induced obesity (DIO) and in leptin-deficient (ob/ob) mice. Mechanistically, CS and SULT2B1b inhibited gluconeogenesis by suppressing the expression of acetyl coenzyme A (acetyl-CoA) synthetase (Acss), leading to decreased acetylation and nuclear exclusion of HNF4α. Our results also suggested that leptin is a potential effector of SULT2B1b in improving metabolic function. We conclude that SULT2B1b and its enzymatic by-product CS are important metabolic regulators that control glucose metabolism, suggesting CS as a potential therapeutic agent and SULT2B1b as a potential therapeutic target for metabolic disorders.

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ACKNOWLEDGMENTS

This study was supported in part by NIH grants DK083953 and HD073070 (to W.X.). W.X. is the Joseph Koslow Endowed Chair in Pharmaceutical Sciences at University of Pittsburgh School of Pharmacy. 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.

We thank Yanqiao Zhang for the adenovirus expressing shHNF4α, Stephen A. Duncan for the lentivirus expressing HNF4α RNAi, Richard M. O'Brien for the G6pase luciferase reporter gene, and Henry Dong (University of Pittsburgh) for the FoxO1-expressing vector.

Notes

This paper is dedicated to the memory of Victor A. Fung.