A Novel Role for ABCG1 in Pancreatic b Cell Function
Sturek, Jeffrey Michael, Department of Pharmacology, University of Virginia
Hedrick, Catherine, Department of Pharmacology, University of Virginia
Cholesterol is a critical component of cell membranes, and cellular cholesterol levels and distribution are tightly regulated. Recent evidence has revealed a critical role for pancreatic cell-specific cholesterol homeostasis in insulin secretion, as well as in cell dysfunction in diabetes and the metabolic response to the anti-diabetic thiazolidinediones (TZDs). The ATP-binding-cassette transporter G1 (ABCG1) has been shown to play a role in cholesterol efflux, but its role in the cell is unexplored. Interestingly, in other cell-types, ABCG1 expression is down-regulated in diabetes and up-regulated by TZDs. Using both genetic knock-out and transient knock-down studies, we investigated the role of ABCG1 in pancreatic cells using a variety of techniques, including in vivo and in vitro measures of insulin secretion, cholesterol content and efflux assays, assessments of subcellular localization and morphology, and regulation of expression in disease. Results from these studies establish a new intracellular role for ABCG1 in cells. Loss of ABCG1 impaired insulin secretion in vivo and in vitro, but had no effect on cellular cholesterol content or efflux. Instead, subcellular localization studies placed the bulk of ABCG1 protein in insulin granules. Interestingly, insulin granules are known to have high membrane cholesterol content, which is important for their function. Loss of ABCG1 led to altered granule morphology and reduced granule cholesterol, while exogenous cholesterol restored granule morphology and cholesterol content, and rescued insulin secretion in ABCG1 deficiency. These findings suggest that ABCG1 acts primarily within the regulated secretory pathway to maintain granule cholesterol levels. Furthermore, islet ABCG1 expression was reduced by chronic high iii glucose in vitro and in diabetic mice, while TZDs increased islet ABCG1 expression in vitro, and restored islet ABCG1 expression to normal levels in TZD-treated diabetic mice, implicating a role for regulation of islet ABCG1 expression in diabetes pathogenesis and treatment.
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PHD (Doctor of Philosophy)
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