Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice

• Published in: Diabetologia Vol. 53; no. 6; pp. 1110 - 1119
• Main Authors: Kruit, J. K, Kremer, P. H. C, Dai, L, Tang, R, Ruddle, P, de Haan, W, Brunham, L. R, Verchere, C. B, Hayden, M. R
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.06.2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: ABC transporters; ABCA1; Analysis of Variance; Animals; Apolipoproteins; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Beta cell function; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Cholesterol; Cholesterol - metabolism; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Experiments; Glucose; Homeostasis; Human Physiology; Hypercholesterolemia - metabolism; Insulin - metabolism; Insulin resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; Internal Medicine; Islets; Islets of Langerhans Transplantation; LDL receptor; Low density lipoprotein receptors; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Knockout; Penicillin; Plasma; Receptors, LDL - genetics; Receptors, LDL - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Canada; United States > US; ABCA1; Beta cell function; Islets; Cholesterol; LDL receptor; Endocrinopathy; Diabetes mellitus; Langerhans islet; Rodentia; Lipids; Uptake; Vertebrata; Mammalia; Mouse; Animal; β Cell; ATP; Carrier protein; Endocrine pancreas; Biological receptor
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-1691-2

Aims/hypothesis Cellular cholesterol accumulation is an emerging mechanism for beta cell dysfunction in type 2 diabetes. Absence of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) results in increased islet cholesterol and impaired insulin secretion, indicating that impaired cholesterol efflux leads to beta cell dysfunction. In this study, we aimed to determine the role of the LDL receptor (LDLr) in islet cholesterol uptake and to assess the contributions of cholesterol uptake compared with efflux to islet cholesterol levels. Methods Islet cholesterol and beta cell function were assessed in mice lacking LDLr (Ldlr ⁻/⁻), or apolipoprotein E (Apoe ⁻/⁻), as well as in mice with beta-cell-specific deficiency of Abca1 crossed to Ldlr ⁻/⁻ mice. Results Hypercholesterolaemia resulted in increased islet cholesterol levels and decreased beta cell function in Apoe ⁻/⁻ mice but not in Ldlr ⁻/⁻ mice, suggesting that the LDL receptor is required for cholesterol uptake leading to cholesterol-induced beta cell dysfunction. Interestingly, when wild-type islets with functional LDL receptors were transplanted into diabetic, hypercholesterolaemic mice, islet graft function was normal compared with Ldlr ⁻/⁻ islets, suggesting that compensatory mechanisms can maintain islet cholesterol homeostasis in a hypercholesterolaemic environment. Indeed, transplanted wild-type islets had increased Abca1 expression. However, lack of the Ldlr did not protect Abca1 ⁻/⁻ mice from islet cholesterol accumulation, suggesting that cholesterol efflux is the critical regulator of cholesterol levels in islets. Conclusions/interpretation Our data indicate that islet cholesterol levels and beta cell function are strongly influenced by LDLr-mediated uptake of cholesterol into beta cells. Cholesterol efflux mediated by ABCA1, however, can compensate in hypercholesterolaemia to regulate islet cholesterol levels in vivo.