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.
OBJECTIVE
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
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.
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, 950 West 28th Ave, Vancouver, BC, Canada V5Z 4H4.
J K
JK
Kruit
P H C
PH
Kremer
L
L
Dai
R
R
Tang
P
P
Ruddle
W
W
de Haan
L R
LR
Brunham
C B
CB
Verchere
M R
MR
Hayden
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D006937:Hypercholesterolemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol