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

Abstract

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.

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

“…The chronic hyperglycemia characteristic of diabetes has long been established the result of inadequate insulin action making one of the prime directives of the β-cell field to identify genes and mechanisms which contribute to reduced growth and function of this cell type. Since the first gain and loss of function studies on miR-375, several subsequent reports have identified a number of additional miRNAs as negative regulators of β-cell function including miR-7, miR-184, miR-21, miR-29a and miR-33a [5] [12] [8] [17] [18]. Importantly, the role of several miRNAs as negative regulators has been substantiated using specific genetic mouse knockouts [19].…”

A big role for small RNAs in HDL homeostasis

“…Although the anti-miR33 LNA oligonucleotide used in this study increased HDL-C in Ldlr Ϫ / Ϫ mice on a chow diet, it also increased total plasma cholesterol and triglyceride levels ( 38 ), effects not seen in previous studies ( 34,37 ). These effects on HDL-C and total plasma cholesterol were not sustained when the mice were switched to a 1.25% cholesterol-containing Western diet, despite hepatic increases in ABCA1, and no effect on atherosclerotic plaque size was observed ( 39 ). While the reasons for the different outcome observed in this study are unknown, they may relate to the bioavailability and potency of the anti-miR-33 oligonucleotides used, the effects of oligonucleotide treatment concurrent with Western diet feeding, and the cholesterol content of the different Western diets used [1.25% ( 38 ) vs. 0.15% ( 37 )].…”

“…While the reasons for the different outcome observed in this study are unknown, they may relate to the bioavailability and potency of the anti-miR-33 oligonucleotides used, the effects of oligonucleotide treatment concurrent with Western diet feeding, and the cholesterol content of the different Western diets used [1.25% ( 38 ) vs. 0.15% ( 37 )]. In addition to improving arterial health, miR-33 inhibition may also be a viable strategy to treat individuals with combined defects in ␤ -cell function and plasma lipids ( 39 ), as elevated islet cholesterol impairs ␤ -cell function and glucose tolerance ( 39 ). In this setting, miR-33 inhibition in pancreatic islets increased ABCA1 expression, enhanced the removal of excess cholesterol from ␤ -cells and restored normal insulin secretion.…”

HDLs, Diabetes, and Metabolic Syndrome

“…Acute cholesterol depletion rescued the exocytotic defect in beta cells lacking ABCA1, suggesting that elevated islet cholesterol accumulation directly impairs granule fusion and insulin secretion (Kruit et al 2011). Posttranscriptional suppression of ABCA1 in beta cells by adenoviral overexpression of miR33a and miR145 also led to increased cholesterol levels and to decreased glucose-stimulated insulin secretion (Kang et al 2013;Wijesekara et al 2012). This compromised insulin secretion was again rescued by cholesterol depletion.…”