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.

GRP78 overproduction in pancreatic beta cells protects against high-fat-diet-induced diabetes in mice

“…Indeed, the cell-surface GLUT2 level is maintained in transgenic mice despite the HFD, which likely contributes to improved pancreatic beta cell function in GRP78 transgenic mice. However, other factors may also contribute to improved beta cell function, such as maintenance of proper proinsulin folding [20] or, indeed, maintenance of other proteins that are synthesised in the ER that have an impact on beta cell function, such as the glucagon-like peptide-1 (GLP-1) receptor [37] and/or the ATP-binding cassette transporter (ABCG1) that are essential for normal beta cell function [38].…”

HDLs, Diabetes, and Metabolic Syndrome

“…ABCG1 knockout mice also show glucose intolerance due to reduced insulin secretion (Sturek et al 2010). In contrast to ABCA1 knockout, this defect was rescued by the addition of cholesterol rather than by depletion of cholesterol (Sturek et al 2010). These studies show that a delicate balance of cholesterol concentrations between different subcellular compartments must be achieved to allow optimal beta cell functionality.…”

“…Inhibition of miR33a expression in apolipoprotein E knockout islets and ABCA1 overexpression in beta cell-specific ABCA1 knockout islets rescued normal insulin secretion and reduced islet cholesterol . ABCG1 knockout mice also show glucose intolerance due to reduced insulin secretion (Sturek et al 2010). In contrast to ABCA1 knockout, this defect was rescued by the addition of cholesterol rather than by depletion of cholesterol (Sturek et al 2010).…”

Adipose ABCG1: A potential therapeutic target in obesity?

“…Indeed, Sturek et al elegantly showed that loss of Abcg1 expression impaired insulin secretion both in vitro and in vivo by altering granule cholesterol content and morphology in mouse b-cells. 7 Thus, decreased insulin secretion as well as impaired glucose tolerance were observed in Abcg1 -/-mice fed a normal chow diet as compared to control Abcg1 C/ C mice, whereas Abcg1 deficiency was without effect on insulin sensitivity. 7 Interestingly, a recent epigenome-wide association study among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study suggested that cytosine guanine dinucleotide (CpG) methylation at CpG sites in ABCG1 locus in CD4C T cells was significantly associated with insulin levels and HOMA-IR.…”

“…7 Thus, decreased insulin secretion as well as impaired glucose tolerance were observed in Abcg1 -/-mice fed a normal chow diet as compared to control Abcg1 C/ C mice, whereas Abcg1 deficiency was without effect on insulin sensitivity. 7 Interestingly, a recent epigenome-wide association study among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study suggested that cytosine guanine dinucleotide (CpG) methylation at CpG sites in ABCG1 locus in CD4C T cells was significantly associated with insulin levels and HOMA-IR. 8 Those latter studies would suggest that pharmacological inhibition of ABCG1 could exert potentially deleterious effects on insulin resistance (IR), This possibility is however weakened by the observation that Abcg1 -/-mice fed a highfat diet did not exhibit glucose intolerance or liver steatosis, in contrast to control Abcg1 C/C littermates 4 , suggesting that total Abcg1 deficiency should rather protect against IR rather than deteriorate it.…”