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Treating Obesity and Type 2 Diabetes by Targeting a Phase II Sulfotransferase

Young, Gregory (2022) Treating Obesity and Type 2 Diabetes by Targeting a Phase II Sulfotransferase. Master's Thesis, University of Pittsburgh. (Unpublished)

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Obesity and Type II Diabetes Mellitus and their related comorbidities are one of the leading causes of loss of life and disability globally. Current first-line therapies seem to be inefficient in reducing global trends. The need to find potential therapeutic targets to help curb growing insulin resistance and obesity rates will be vital to stop this health crisis. Given these metabolic diseases involve dysregulated cholesterol levels, examining proteins involved in cholesterol regulation may prove fruitful. SULT2B1b is a sulfotransferase that preferentially conjugates a sulfate group onto cholesterol. Generally, sulfonation by a sulfotransferase is a part of phase II metabolism in which the liver attempts to clear metabolites from the body. However, sulfonation also plays a significant role in modulating the effects of certain endogenous compounds by deactivating their biological effects. In a previous study, cholesterol sulfate, the product of SULT2B1b, was shown to reduce lipogenesis through inhibition of the nuclear receptor Liver X Receptor (LXR). Furthermore, cholesterol sulfate inhibited Hepatic Nuclear Factor 4α (HNF4α), which caused downregulation of gluconeogenesis. Overexpression of SULT2B1b shows protection against diet-induced obesity given its inhibitory roles on excessive glucose and lipid production. However, in this study, we investigated the SULT2B1b genetic knockout to examine whether loss of SULT2B1b in mice challenged with a high-fat diet would worsen outcomes. Surprisingly, SULT2B1b knockout protected mice against fat accumulation and insulin resistance. This may be due to the downregulation of CD36 in SULT2B1b null mice. Given the protection provided through genetic ablation, inhibiting SULT2B1b may be a promising target to combat obesity and T2DM.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Young, GregoryGMY7@pitt.eduGMY7
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberYang, Dadyang@pitt.edudyang
Committee MemberGibbs, Robertgibbsr@pitt.edugibbsr
Thesis AdvisorXie, Wenwex6@pitt.eduwex6
Date: 25 January 2022
Date Type: Publication
Defense Date: 1 December 2021
Approval Date: 25 January 2022
Submission Date: 17 December 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 37
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: sulfotransferase, type 2 diabetes, obesity, liver, cd36
Date Deposited: 25 Jan 2022 20:54
Last Modified: 25 Jan 2022 20:54

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