title: 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.
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, USA.
authors.forename: Xiongjie
authors.initials: X
authors.lastname: Shi
authors.forename: Qiuqiong
authors.initials: Q
authors.lastname: Cheng
authors.forename: Leyuan
authors.initials: L
authors.lastname: Xu
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.forename: Mengxi
authors.initials: M
authors.lastname: Jiang
authors.forename: Jinhan
authors.initials: J
authors.lastname: He
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.forename: Maja
authors.initials: M
authors.lastname: Stefanovic-Racic
authors.forename: Ian
authors.initials: I
authors.lastname: Sipula
authors.forename: Robert Martin
authors.initials: RM
authors.lastname: O'Doherty
authors.forename: Shunlin
authors.initials: S
authors.lastname: Ren
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism / Q000494:pharmacology*; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D002788:Cholesterol Esters; D051557:Hepatocyte Nuclear Factor 4; D005576:Colforsin; C554336:SULT2B1b protein, mouse; D015238:Sulfotransferases; D003066:Coenzyme A Ligases; C101958:acetate-CoA ligase (ADP-forming); D005947:Glucose; C007045:cholesteryl sulfate