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Jiang, Mengxi (2014) THE ROLE OF STEROID SULFATASE IN ENERGY HOMEOSTASIS AND INFLAMMATION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this study, I first showed that the hepatic expression of STS was induced in the high-fat diet (HFD) and ob/ob models of obesity and type 2 diabetes. Over-expression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity and consequently improved the metabolic functions; whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue (WAT) and skeletal muscle, as well as a pattern of skeletal muscle gene expression that favors energy expenditure.

Chronic inflammatory liver diseases are associated with estrogen excess and feminization in men. The estrogen excess was reasoned to be due to liver damage that weakens the liver's ability to breakdown estrogen. In this study, I showed that STS may have mediated the inflammation induced estrogen increase in chronic liver disease. Bioinformatic and IHC analysis demonstrated that STS was induced in liver samples from patients with chronic inflammatory liver diseases. In contrast, several enzymes involved in estrogen inactivation were down-regulated in diseased livers, including the phase I enzymes CYP1A2 and CYP3A4 and the phase II enzyme estrogen sulfotransferase (EST). Mechanistically, I showed that STS is an NF-κB target gene, whose induction facilitates the conversion of inactive estrogen sulfates to estrogens. On the other hand, loss of STS or blocking estrogen signaling increased NF-κB transcriptional activity and inflammation. These elucidated the activation of negative feedback loop, that is, STS induced by NF-κB in hepatocytes enhanced estrogen activity, which in turn suppresses NF-κB-mediated inflammation.

In summary, I have uncovered novel roles and mechanisms of STS in energy homeostasis and inflammation, which may facilitate the development of novel interventions for metabolic syndrome and chronic inflammatory liver disease.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Jiang, Mengximej39@pitt.eduMEJ39
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVollmer , Regisvollm@pitt.eduVOLLM
Committee MemberXie, Wenwex6@pitt.eduWEX6
Committee MemberLi, Songsol4@pitt.eduSOL4
Committee MemberSelcer,
Date: 5 August 2014
Date Type: Publication
Defense Date: 16 July 2014
Approval Date: 5 August 2014
Submission Date: 26 July 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 97
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Date Deposited: 05 Aug 2014 13:17
Last Modified: 15 Nov 2016 14:22


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