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|Title:||A novel sec7-domain-containing protein BIG3 and its role in regulated secretory pathway||Authors:||LI HONGYU||Keywords:||secretory pathway, Sec7, BIG3, insulin, beta cell||Issue Date:||26-Mar-2010||Citation:||LI HONGYU (2010-03-26). A novel sec7-domain-containing protein BIG3 and its role in regulated secretory pathway. ScholarBank@NUS Repository.||Abstract:||The beta cell dysfunction in insulin secretion is one of the key factors in the pathophysiology of diabetes (Bell and Polonsky, 2001). However the mechanisms that underline the development of the beta cell dysfunction in humans still remain elusive. Arf-GEFs are a family of Sec7 domain proteins that regulate intracellular vesicle trafficking. BIG3 is identified as a putative member of the Sec7 protein family and distantly related to BIG/Sec7p subfamily. BIG3 mRNA expression profile shows it is selectively expressed with high levels in the brain and islet. This study therefore investigates the function of endogenous BIG3 in islet cells. BIG3 protein was found highly expressed in beta cells, and predominantly localized to the secretory granules. Investigations on BIG3 knockdown and knockout beta cells demonstrated that the deficiency of BIG3 caused increased amount of secretory granules and secretory proteins in the cells, and elevated secretion upon stimulation. The study on BIG3 knockout mice revealed that in absence of BIG3, the mice exhibited relatively elevated blood insulin level, disturbed glucose homeostasis, impaired glucose tolerance, reduced insulin sensitivity, fatty liver disease, disturbed energy expenditure and activity, and reduced testosterone level. Up-regulated insulin storage and secretion in beta cells may account for the elevated blood insulin level. The metabolic abnormalities could be in part due to the excessively secreted insulin. These data demonstrate for the first time that BIG3 has a functional role in the regulated secretory pathway to modulate the insulin secretion, and therefore to affect the whole body metabolic homeostasis.||URI:||http://scholarbank.nus.edu.sg/handle/10635/18227|
|Appears in Collections:||Ph.D Theses (Open)|
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