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THE ROLE OF CONSTITUTIVE ANDROSTANE RECEPTOR AND ESTROGEN SULFOTRANSFERASE IN ENERGY HOMEOSTASIS

Gao, Jie (2012) THE ROLE OF CONSTITUTIVE ANDROSTANE RECEPTOR AND ESTROGEN SULFOTRANSFERASE IN ENERGY HOMEOSTASIS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Obesity and type 2 diabetes are related metabolic disorders of high prevalence. The constitutive androstane receptor (CAR) was initially characterized as a xenobiotic receptor regulating the responses of mammals to xenotoxicants. In this study, I have uncovered an unexpected role of CAR in preventing obesity and alleviating type 2 diabetes. Activation of CAR prevented obesity and improved insulin sensitivity in both the HFD-induced type 2 diabetic model and the ob/ob mice. In contrast, CAR null mice maintained on a chow diet showed spontaneous insulin insensitivity. The metabolic benefits of CAR activation may have resulted from inhibition of hepatic lipogenesis and gluconeogenesis. The molecular mechanism through which CAR activation suppressed hepatic gluconeogenesis might be mediated via peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). CAR can interact with PGC-1α and sequestrate it into promyelocytic leukemia (PML) nuclear bodies, thus preventing the PGC-1α from binding to the promoter region of gluconeogenesis genes.
Estrogen sulfotransferase (EST), the enzyme responsible for the sulfonation and inactivation of estrogens, plays an important role in estrogen homeostasis. Here, I showed that induction of hepatic Est is a common feature of type 2 diabetes. Loss of Est in female mice improved metabolic function in ob/ob, dexamethasone- and high-fat diet-induced mouse models of type 2 diabetes. The metabolic benefit of Est ablation included improved body composition, increased energy expenditure and insulin sensitivity, and decreased hepatic gluconeogenesis and lipogenesis. This metabolic benefit appeared to have resulted from decreased estrogen deprivation and increased estrogenic activity in the liver. Interestingly, the effect of Est was gender specific, as Est ablation in ob/ob males exacerbated the diabetic phenotype, which was accounted for by the decreased islet β cell mass and failure of glucose-stimulated insulin secretion in vivo. The loss of β cell mass in obe males was associated with increased macrophage infiltration and inflammation in white adipose tissue.
In summary, I had uncovered critical roles of CAR and EST in energy metabolism and the pathogenesis of type 2 diabetes. Both of CAR and EST may represent novel therapeutic targets in the management type 2 diabetes.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gao, Jiejiegao426@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorXie, Wenwex6@pitt.eduWEX6
Committee ChairDay, Billybday@pitt.eduBDAY
Committee MemberDefranco, Donalddod1@pitt.eduDOD1
Committee MemberPoloyac, Samuelpoloyac@pitt.eduPOLOYAC
Committee MemberLi, Songsol4@pitt.eduSOL4
Date: 9 February 2012
Date Type: Publication
Defense Date: 18 January 2012
Approval Date: 9 February 2012
Submission Date: 8 February 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 124
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: constitutive androstane receptor; estrogen sulfotransferase; energy homeostasis;
Date Deposited: 09 Feb 2012 15:42
Last Modified: 09 Feb 2017 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/10974

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