miR-33a Modulates ABCA1 Expression, Cholesterol Accumulation, and Insulin Secretion in Pancreatic Islets

Changes in cellular cholesterol affect insulin secretion, and beta-cell-specific deletion or loss-of-function mutations in the cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) result in impaired glucose tolerance and beta-cell dysfunction. Upregulation of ABCA1 expression may therefore be beneficial for the maintenance of normal islet function in diabetes. Studies suggest that microRNA-33a (miR-33a) expression inversely correlates with ABCA1 expression in hepatocytes and macrophages. We examined whether miR-33a regulates ABCA1 expression in pancreatic islets, thereby affecting cholesterol accumulation and insulin secretion. Adenoviral miR-33a overexpression in human or mouse islets reduced ABCA1 expression, decreased glucose-stimulated insulin secretion, and increased cholesterol levels. The miR-33a-induced reduction in insulin secretion was rescued by cholesterol depletion by methyl-beta-cyclodextrin or mevastatin. Inhibition of miR-33a expression in apolipoprotein E knockout islets and ABCA1 overexpression in beta-cell-specific ABCA1 knockout islets rescued normal insulin secretion and reduced islet cholesterol. These findings confirm the critical role of beta-cell ABCA1 in islet cholesterol homeostasis and beta-cell function and highlight modulation of beta-cell miR-33a expression as a means to influence insulin secretion. Diabetes 61:653-658, 2012