An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells
Jeffrey M. Sturek, … , Raghavendra G. Mirmira, Catherine C. Hedrick
Jeffrey M. Sturek, … , Raghavendra G. Mirmira, Catherine C. Hedrick
Published June 7, 2010
Citation Information: J Clin Invest. 2010;120(7):2575-2589. https://doi.org/10.1172/JCI41280.
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An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells

Abstract

Cholesterol is a critical component of cell membranes, and cellular cholesterol levels and distribution are tightly regulated in mammals. Recent evidence has revealed a critical role for pancreatic β cell–specific cholesterol homeostasis in insulin secretion as well as in β cell dysfunction in diabetes and the metabolic response to thiazolidinediones (TZDs), which are antidiabetic drugs. The ATP-binding cassette transporter G1 (ABCG1) has been shown to play a role in cholesterol efflux, but its role in β cells is currently unknown. In other cell types, ABCG1 expression is downregulated in diabetes and upregulated by TZDs. Here we have demonstrated an intracellular role for ABCG1 in β cells. Loss of ABCG1 expression impaired insulin secretion both in vivo and in vitro, but it had no effect on cellular cholesterol content or efflux. Subcellular localization studies showed the bulk of ABCG1 protein to be present in insulin granules. Loss of ABCG1 led to altered granule morphology and reduced granule cholesterol levels. Administration of exogenous cholesterol restored granule morphology and cholesterol content and rescued insulin secretion in ABCG1-deficient islets. These findings suggest that ABCG1 acts primarily to regulate subcellular cholesterol distribution in mouse β cells. Furthermore, islet ABCG1 expression was reduced in diabetic mice and restored by TZDs, implicating a role for regulation of islet ABCG1 expression in diabetes pathogenesis and treatment.

Authors

Jeffrey M. Sturek, J. David Castle, Anthony P. Trace, Laura C. Page, Anna M. Castle, Carmella Evans-Molina, John S. Parks, Raghavendra G. Mirmira, Catherine C. Hedrick

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Figure 8

Proposed model of ABCG1 localization and action in the regulation of granule cholesterol content and insulin secretion.

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Proposed model of ABCG1 localization and action in the regulation of gra...
ABCG1 localizes to the regulated secretory pathway and acts to maintain secretory granule cholesterol, perhaps by redistributing granule membrane cholesterol to the inner leaflet, thereby regulating membrane curvature and restricting cholesterol exit via carrier-mediated diffusion to other cellular sites. This activity is analogous to that of other intracellular ABC transporters, which move their respective substrates into the lumen of the organelles in which they reside. In ABCG1 deficiency, cholesterol redistributes out of the granules; the granules are subsequently enlarged, and their release is impaired. SG, secretory granule; ISG, immature secretory granule, TGN, trans-Golgi network; CMD, carrier-mediated diffusion.