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

Abstract

e 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 4␣ (HNF4␣) in both cell cultures and transgenic mice. Treatment of mice with CS or transgenic overexpression of the CSgenerating 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 HNF4␣. 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.

A MALDI-MSI Approach to the Characterization of Radiation-Induced Lung Injury and Medical Countermeasure Development

“…In addition to stabilizing cell membranes, cholesterol sulfate has been proven to play a significant regulatory role in a plethora of processes, whose activity includes the regulation of serine proteases, specific protein kinase C isoforms, as well as the modulation of phosphatidylinositol-3-kinase activity(Strott and Higashi 2003). In addition to its enzyme-like properties, cholesterol sulfate is a regulator of gene expression, as demonstrated by a number of publications over the past two decades(Kawabe et al 1998, Hanyu et al 2012, Zenri et al 2012, Shi et al 2014). Of key importance was the publication by Okano et al , 2001, showing cholesterol sulfate induces a conformational change in high-mobility group protein 1 (HMG1), a step thought to be essential for its phosphorylation.…”

Deciphering the roles of the constitutive androstane receptor in energy metabolism

“…Acetylation of HNF4α is an essential event for HNF4α translocation into the nucleus. Indeed, cholesterol sulfate and Sult2B1b were recently reported to inhibit gluconeogenesis through the deacetylation of HNF4α [85] . Therefore, up-regulation of Sult2B1b by CAR may have also played a role in the suppression of gluconeogenesis.…”

“…Consistently, the TCPOBOPinduced reduction of lipogenic genes is abolished in Sult2B1b knockout mice [78] . Liver-specific overexpression of Sult2B1b, either by adenoviral delivery or transgenic strategy, ameliorates dyslipidemia in a diabetic mouse model [84,85] . In addition to deactivating LXR ligands, the products of sulfonation, such as 25-hydroxycholesterol-3-sulfate, have been reported to decrease lipid accumulation and inflammation [86][87][88][89] .…”

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

“…and lipids (5,6). HNF4␣ promotes gluconeogenesis through its positive regulation of PEPCK and G6Pase genes (7,8).…”