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ROLE OF CHOLESTEROL SULFOTANSFERASE AND STEROID SULFATASE IN NUCLEAR RECEPTOR MEDIATED ENERGY HOMEOSTASIS

Bi, Yuhan (2018) ROLE OF CHOLESTEROL SULFOTANSFERASE AND STEROID SULFATASE IN NUCLEAR RECEPTOR MEDIATED ENERGY HOMEOSTASIS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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 4 (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 HNF4 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 HNF4 as a result of decreased expression of the HNF4 deacetylase sirtuin 1 (Sirt1). The expression of Sult2B1b was also induced by HNF4 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 HNF4 -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.

Steroid sulfatase (STS), a desulfating enzyme that converts steroid sulfates to hormonally active steroids, plays an important role in the homeostasis of sex hormones. STS is expressed in the adipose tissue of both male and female mice, but the role of STS in the development and function of adipose tissue remains largely unknown. In this report, we first showed that the adipose expression of Sts was induced in the high-fat diet (HFD) and ob/ob models of obesity and type 2 diabetes. Transgenic overexpression of the human STS in the adipose tissue of male mice exacerbated the HFD induced metabolic phenotypes, including increased body weight gain and fat mass, and worsened insulin sensitivity, glucose tolerance and energy expenditure, which were accounted for by adipocyte hypertrophy, increased adipose inflammation, and dysregulation of adipogenesis. The metabolic harm of the STS transgene appeared to have resulted from increased androgen activity in the adipose tissue, and castration abolished most of the phenotypes. Interestingly, the transgenic effects were sex-specific, because the HFD-fed female STS transgenic mice exhibited improved metabolic functions, which were associated with attenuated adipose inflammation. The metabolic benefit of the STS transgene in female mice was accounted for by increased estrogenic activity in the adipose tissue, whereas such benefit was abolished upon ovariectomy. Our results revealed an essential role of the adipose STS in energy homeostasis in sex- and sex hormone-dependent manner. The adipose STS may represent a novel therapeutic target for the management of obesity and type 2 diabetes.

In summary, I have uncovered novel roles and mechanisms of SULT2B1b and STS in HNF4α mediated hepatic gluconeonenesis and in estrogen receptor (ER)/ androgen receptor (AR) mediated energy homeostasis of adipose tissue respectively, which may facilitate the development of novel interventions for metabolic syndromes.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bi, Yuhanyub10@pitt.eduyub100000-0002-7728-1504
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairXie, Wenwex6@pitt.eduwex6
Committee MemberRohan, LisaROHANL@pitt.eduROHANL
Committee MemberMa, XiaochaoMXIAOCHA@pitt.eduMXIAOCHA
Committee MemberYang, Dadyang@pitt.eduDYANG0000-0002-8336-9457
Committee MemberSelcer, Kyleselcer@duq.edu
Date: 12 July 2018
Date Type: Publication
Defense Date: 13 March 2018
Approval Date: 12 July 2018
Submission Date: 24 June 2018
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 98
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Cholesterol sulfotransferase (SULT2B1b) Hepatocyte nuclear factor 4 (HNF4α)Gluconeogenesis Steroid sulfatase (STS) Estrogen Androgen Diabetes Obesity Cholesterol sulfate Thiocholesterol
Date Deposited: 12 Jul 2018 16:13
Last Modified: 12 Jul 2018 16:13
URI: http://d-scholarship.pitt.edu/id/eprint/34673

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