ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice

Aims/hypothesis Islet amyloid, a pathological feature of type 2 diabetes, forms from the aggregation of islet amyloid polypeptide (IAPP), a beta cell peptide that is produced and co-secreted with insulin. Cholesterol regulates amyloid-beta processing, deposition and clearance, promoting amyloidogenesis in the brain. ATP-binding cassette transporter 1 (ABCA1) is a cholesterol efflux transporter that when absent increases and when overexpressed reduces brain amyloid-beta deposition in mouse models of Alzheimer's disease. We examined whether alterations in ABCA1 expression and islet cholesterol content could also modulate islet amyloidogenesis. Methods Thioflavin S staining for amyloid was performed in islets isolated from mice with beta cell expression of human IAPP (hIAPP(Tg/o)) and cultured for 8 days following cholesterol loading, microRNA-33 overexpression (to reduce ABCA1 expression) or palmitate treatment in the presence or absence of ABCA1 overexpression or mevastatin treatment (to reduce cholesterol synthesis). hIAPP(Tg/o) mice were crossed with beta cell-specific Abca1-knockout mice (hIAPP(Tg/o)Abca1(beta KO)) and glucose tolerance and amyloid formation were assessed. Results Cholesterol loading and microRNA-33-induced reduction in islet ABCA1 expression increased Thioflavin S-positive amyloid in hIAPP(Tg/o) islets. Palmitate treatment also increased amyloid formation and this was reduced by both ABCA1 overexpression and mevastatin treatment. hIAPP(Tg/o)Abca1(beta KO) mice had increased islet cholesterol, accompanied by fasting hyperglycaemia, glucose intolerance, impaired in vivo insulin secretion and an increased islet proinsulin: insulin ratio. Amyloid area was increased in cultured hIAPP(Tg/o)Abca1(beta KO) islets compared with hIAPP(Tg/o) controls. Conclusions/interpretation These data suggest that elevations in islet cholesterol may lead to increases in IAPP aggregation and islet amyloid formation, further worsening beta cell function and glucose homeostasis.