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

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 3; pp. 653 - 658
• Main Authors: WIJESEKARA, Nadeeja, ZHANG, Lin-Hua, KANG, Martin H, ABRAHAM, Thomas, BHATTACHARJEE, Alpana, WARNOCK, Garth L, VERCHERE, C. Bruce, HAYDEN, Michael R
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2012
• Subjects: Animals; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - analysis; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - physiology; beta-Cyclodextrins - pharmacology; Biological and medical sciences; Cholesterol - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose - pharmacology; Humans; Insulin - metabolism; Insulin Secretion; Islands of Langerhans; Islet Studies; Islets of Langerhans; Islets of Langerhans - metabolism; Medical sciences; Messenger RNA; Mice; MicroRNAs - physiology; Physiological aspects; Endocrinopathy; Pancreatic hormone; Secretion; Diabetes mellitus; Lipids; Pancreas; Insulin; Accumulation; Cholesterol
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db11-0944

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.