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

Abstract

Cellular cholesterol homeostasis is important for normal β-cell function. Disruption of cholesterol transport by decreased function of the ATP-binding cassette (ABC) transporter ABCA1 results in impaired insulin secretion. Mice lacking β-cell ABCA1 have increased islet expression of ABCG1, another cholesterol transporter implicated in β-cell function. To determine whether ABCA1 and ABCG1 have complementary roles in β-cells, mice lacking ABCG1 and β-cell ABCA1 were generated and glucose tolerance, islet sterol levels, and β-cell function were assessed. Lack of both ABCG1 and β-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 β-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-1β and macrophage infiltration. Thus, lack of both ABCA1 and ABCG1 induces greater defects in β-cell function than deficiency of either transporter individually. These data suggest that ABCA1 and ABCG1 each make complimentary and important contributions to β-cell function by maintaining islet cholesterol homeostasis in vivo.

Chronic exposure to leucine in vitro induces β-cell dysfunction in INS-1E cells and mouse islets

“…described here is coherent with several data obtained in vitro and in vivo in animal models and have recently been put into perspective (Peyot et al 2010, Vergeer et al 2010, Kruit et al 2012. Combined deletion of ATP-binding cassette transporter G subfamily 1 (ABCG1) and the ATP-binding cassette transporter subfamily A member 1 (ABCA1) resulted in increased islet CH levels compared with control, b-cellspecific ABCA1 deficiency, and globally deficient ABCG1; notably, islets lacking both ABCA1 and ABCG1 had an even greater reduction in GSIS compared with islets from mice lacking either ABCA1 or ABCG1 (Kruit et al 2012). Likewise, high-fat induced obese mice were divided into low responders (LDR) and high responders (HDR) according to their body weight (Peyot et al 2010).…”

The E3 Ubiquitin Ligases, HUWE1 and NEDD4-1, Are Involved in the Post-translational Regulation of the ABCG1 and ABCG4 Lipid Transporters

“…Ϫ/Ϫ mouse model, insulin secretion from ABCG1 Ϫ/Ϫ islets was significantly reduced upon glucose challenge (8). One can speculate that the changes observed in the Nedd4 heterozygotes may be associated with increases in ABCG1 transporter levels and activity.…”

“…Although its individual role in the development of atherosclerosis in mouse models has at times been confusing, its important role in conjunction with ABCA1 in maintaining macrophage cholesterol homeostasis has been more evident (7). In addition, ABCG1 (in conjunction with ABCA1) has been implicated in the regulation of ␤-cell function and insulin secretion (8), and more recently in the regulation of triglyceride storage in adipocytes (9).…”

Group X Secretory Phospholipase A2 Regulates Insulin Secretion through a Cyclooxygenase-2-dependent Mechanism

“…Indeed, cellular cholesterol accumulation is an emerging mechanism leading to beta cell dysfunction in T2D (44). Deficiency of either ABCA1 or ABCG1 in beta cells leads to alterations in cellular cholesterol distribution and impaired insulin secretion (45). We assessed whether GX sPLA 2 impacts LXR target gene expression or cholesterol content in primary mouse islets and/or MIN6 cells (data not shown).…”