The cholesterol sulfotransferase SULT2B1b is a cytosolic sulfotransferase best known for its activity in sulfonating cholesterol and oxysterols. Metabolic syndrome, often manifested as obesity and insulin resistant type 2 diabetes, is a major health concern. The dysregulation of glucose and lipid metabolism plays an important pathogenic role in obesity and type 2 diabetes. Although the activity of SULT2B1b in catalyzing the sulfation of cholesterol has been documented, the role of SULT2B1b and its enzymatic byproduct cholesterol sulfate (CS) in energy metabolism and metabolic syndrome remains largely unknown. Our preliminary results showed that: 1) SULT2B1b was induced in obese mice and during the transition from the fasted to the fed state;2) SULT2B1b and CS inhibited gluconeogenesis in hepatic cells;3) SULT2B1b and CS specifically inhibited the gluconeogenic activity of HNF4?;4) Treatment with CS inhibited gluconeogenesis and improved insulin sensitivity in both HFD and ob/ob models;5) Transgenic overexpression of SULT2B1b improved metabolic functions in the HFD model;6) Leptin is a potential effector for the metabolic benefit of SULT2B1b;7) SULT2B1b and CS suppressed the expression of acetyl-coenzyme A synthetase 2 (Acss2), decreased the acetylation of HNF4?, and caused the nuclear exclusion of HNF4?;whereas a forced expression of Acss2 abolished the inhibitory effect of CS on HNF4?;8) Down-regulation of HNF4? abolished the inhibitory effect of CS on gluconeogenesis in vitro;and 9) SULT2B1b is a potential HNF4? target gene, providing a possible mechanism of negative feedback regulation of gluconeogenesis. Based on our preliminary data, we hypothesize that the cholesterol sulfotransferase SULT2B1b has a previously unrecognized role in inhibiting gluconeogenesis and alleviating metabolic disease. Mechanistically, the metabolic benefit of SULT2B1b may have been achieved through its enzymatic byproduct cholesterol sulfate (CS) and by targeting the acetylation and nuclear translocation of the gluconeogenic transcriptional factor HNF4?. We also hypothesize that the SULT2B1 is a HNF4? target gene, which represents a negative feedback mechanism to limit the gluconeogenic activity of HNF4?. We anticipate that leptin is a potential effector of SULT2B1b in improving metabolic functions. By using the liver-specific SULT2B1b transgenic mice, in conjunction with HFD and ob/ob models of obesity and type 2 diabetes, we propose three Specific Aims to test our hypotheses: 1) To determine whether the liver-specific overexpression of SULT2B1b inhibits the ob/ob model of obesity and type 2 diabetes;2) To determine the molecular mechanism by which SULT2B1b and CS inhibit gluconeogenesis;and 3) To determine whether the induction of SULT2B1b by HNF4? represents a potential mechanism of negative feedback regulation of gluconeogenesis. To our knowledge, this study represents the first attempt to comprehensively evaluate the endobiotic and hepatic function of SULT2B1b and its enzymatic byproduct CS in energy metabolism in vivo. Results from this study may establish SULT2B1b as a novel therapeutic target and CS as a therapeutic agent to manage metabolic disease.

Public Health Relevance

The cholesterol sulfotransferase SULT2B1b is a cytosolic sulfotransferase best known for its activity in sulfonating cholesterol and oxysterols. The goal of this study is to determine the role of SULT2B1b and its enzymatic byproduct cholesterol sulfate in energy metabolism and metabolic syndrome. We hypothesize that the cholesterol sulfotransferase SULT2B1b has a previously unrecognized role in inhibiting gluconeogenesis and alleviating metabolic disease. Results from this study may establish SULT2B1b as a novel therapeutic target and cholesterol sulfate as a therapeutic agent to manage metabolic disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01DK099232-01A1
Application #
8754531
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Maruvada, Padma
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ou, Zhimin; Jiang, Mengxi; Hu, Bingfang et al. (2014) Transcriptional regulation of human hydroxysteroid sulfotransferase SULT2A1 by LXR?. Drug Metab Dispos 42:1684-9