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Receptor cross talk in arsenic-impaired fat metabolism

Garciafigueroa, Diana (2014) Receptor cross talk in arsenic-impaired fat metabolism. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Metabolic syndrome is a major public health concern that increases cardiovascular risk from dysfunctional lipid and glucose metabolism. Many factors, including genetics and environmental factors, such as inorganic arsenic, contribute to increase the risk for the disease. However, the mechanisms for this correlation are not well understood. This study tested the main hypothesis that arsenic alters proper lipid storage, remodeling and metabolic changes in adipose tissue through specific activation of membrane receptors in adipocytes. Mice exposed to arsenic through drinking water demonstrated that circulating levels of insulin and tryacylglycerides were affected. Moreover, arsenic stimulated adipose tissue remodeling and angiogenesis in epididymal fat pads, as well as redistribution of fat in ectopic tissues.
In a model of cultured adipocytes, arsenic induced loss of lipid droplets and expression of lipid-coated protein perilipin (PLIN-1).Lipolytic activity was also stimulated by arsenic within 24 hour of exposure and sustained after 3 days, which was indicative of aberrant lipid storage. The prevention of arsenic effects through pertussis toxin sensitive pathways strongly suggested that a Gi –linked receptors mediates arsenic toxicity. Further investigation revealed that the G-protein coupled receptors (GPCR) endothelin-1 receptor A (EDNRA) and B (EDNRB) were activated by arsenic. The selective blocking of EDNRA with BQ610, but not EDNRB with BQ788, partially prevented the loss of fat droplets. In contrast, both, blocking EDNRA and EDNRB prevented the increase in glycerol release by arsenic. Activation of the receptor tyrosine kinase (RTK) EGFR in response to arsenic was not mediated by Src family or oxidant stress. However, arsenic exposure induced a transient association of Gαi protein- EGFR. These results indicated a novel mechanism through which arsenic stimulates cross talk between EDNRA-EGFR.
In conclusion, these studies demonstrated that arsenic impairs proper functionality and metabolism of adipose tissue by stimulation of GPCR-RTK cross communication. The result of this dissertation contributes to better understand the etiology and pathophysiology of metabolic diseases. The advanced understanding of the role of environmental exposure in the etiology of diseases, such as diabetes mellitus, atherosclerosis and hypertension, seen the large population exposed to arsenic will aid in developing strategies to greatly reduce the burden of disease.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Garciafigueroa, Dianadyg1@pitt.eduDYG1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPitt, Bruce Rbrucep@pitt.eduBRUCEP
Committee MemberSt Croix, Claudette Mcls13@pitt.eduCLS13
Committee MemberO'Doherty, Robert Mrmo1@pitt.eduRMO1
Thesis AdvisorBarchowsky, Aaronaab20@pitt.eduAAB20
Date: 29 January 2014
Date Type: Publication
Defense Date: 9 December 2013
Approval Date: 29 January 2014
Submission Date: 5 January 2014
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 153
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Arsenic, metabolic syndrome, adipocyte dysfunction
Date Deposited: 29 Jan 2014 17:34
Last Modified: 15 Nov 2016 14:16
URI: http://d-scholarship.pitt.edu/id/eprint/20345

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