miR-33a modulates ABCA1 expression, cholesterol accumulation, and insulin secretion in pancreatic islets

N Wijesekara, L Zhang, MH Kang, T Abraham… - Diabetes, 2012 - Am Diabetes Assoc
N Wijesekara, L Zhang, MH Kang, T Abraham, A Bhattacharjee, GL Warnock, CB Verchere
Diabetes, 2012Am Diabetes Assoc
Changes in cellular cholesterol affect insulin secretion, and β-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 β-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 …
Changes in cellular cholesterol affect insulin secretion, and β-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 β-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-β-cyclodextrin or mevastatin. Inhibition of miR-33a expression in apolipoprotein E knockout islets and ABCA1 overexpression in β-cell–specific ABCA1 knockout islets rescued normal insulin secretion and reduced islet cholesterol. These findings confirm the critical role of β-cell ABCA1 in islet cholesterol homeostasis and β-cell function and highlight modulation of β-cell miR-33a expression as a means to influence insulin secretion.
Am Diabetes Assoc