Loss of Both ABCA1 and ABCG1 Results in Increased Disturbances in Islet Sterol Homeostasis, Inflammation, and Impaired β-Cell Function

Cellular cholesterol homeostasis is important for normal beta-cell function. Disruption of cholesterol transport by decreased function of the ATP-binding cassette (ABC) transporter ABCA1 results in impaired insulin secretion. Mice lacking beta-cell ABCA1 have increased islet expression of ABCG1, another cholesterol transporter implicated in beta-cell function. To determine whether ABCA1 and ABCG1 have complementary roles in beta-cells, mice lacking ABCG1 and beta-cell ABCA1 were generated and glucose tolerance, islet sterol levels, and beta-cell function were assessed. Lack of both ABCG1 and beta-cell ABCA1 resulted in increased fasting glucose levels and a greater impairment in glucose tolerance compared with either ABCG1 deletion or loss of ABCA1 in beta-cells alone. In addition, glucose-stimulated insulin secretion was decreased and sterol accumulation increased in islets lacking both transporters compared with those isolated from knockout mice with each gene alone. Combined deficiency of ABCA1 and ABCG1 also resulted in significant islet inflammation as indicated by increased expression of interleukin-1 beta and macrophage infiltration. Thus, lack of both ABCA1 and ABCG1 induces greater defects in beta-cell function than deficiency of either transporter individually. These data suggest that ABCA1 and ABCG1 each make complimentary and important contributions to beta-cell function by maintaining islet cholesterol homeostasis in vivo. Diabetes 61:659-664, 2012