Modulation of microRNA Expression in Subjects with Metabolic Syndrome and Decrease of Cholesterol Efflux from Macrophages via microRNA-33-Mediated Attenuation of ATP-Binding Cassette Transporter A1 Expression by Statins

• Published in: PloS one Vol. 11; no. 5; p. e0154672
• Main Authors: Chen, Wei-Ming, Sheu, Wayne H-H, Tseng, Pei-Chi, Lee, Tzong-Shyuan, Lee, Wen-Jane, Chang, Pey-Jium, Chiang, An-Na
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.05.2016; Public Library of Science (PLoS)
• Subjects: 3' Untranslated regions; ABC transporters; ABCA1 protein; Abnormalities; Analysis; Animals; Atherosclerosis; Atorvastatin; ATP; ATP Binding Cassette Transporter 1 - genetics; ATP-binding protein; Biochemistry; Biological Transport - drug effects; Biology and Life Sciences; Bone marrow; Cardiovascular disease; Cholesterol; Cholesterol - metabolism; Complications and side effects; Development and progression; Diabetes; Dosage and administration; Down-Regulation - drug effects; Down-Regulation - genetics; Drugs; Efflux; Endocrinology; Federal regulation; Female; Gastroenterology; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene regulation; Genetic aspects; Glucose; Glucose - pharmacology; Hemoglobin; Hepatology; High density lipoprotein; Homeostasis; Homeostasis - drug effects; Hospitals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hyperglycemia; Internal medicine; Low density lipoprotein; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Medicine; Medicine and Health Sciences; Metabolic disorders; Metabolic syndrome; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Metabolic syndrome X; Mice; MicroRNA; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; Modulation; Molecular biology; Physical Sciences; Physiological aspects; Post-transcription; Proteins; RAW 264.7 Cells; Ribonucleic acid; RNA; Statins; Systemic diseases; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0154672

Metabolic syndrome (MetS) is a complicated health problem that encompasses a variety of metabolic disorders. In this study, we analyzed the relationship between the major biochemical parameters associated with MetS and circulating levels of microRNA (miR)-33, miR-103, and miR-155. We found that miRNA-33 levels were positively correlated with levels of fasting blood glucose, glycosylated hemoglobin A1c, total cholesterol, LDL-cholesterol, and triacylglycerol, but negatively correlated with HDL-cholesterol levels. In the cellular study, miR-33 levels were increased in macrophages treated with high glucose and cholesterol-lowering drugs atorvastatin and pitavastatin. miR-33 has been reported to play an essential role in cholesterol homeostasis through ATP-binding cassette transporter A1 (ABCA1) regulation and reverse cholesterol transport. However, the molecular mechanism underlying the linkage between miR-33 and statin treatment remains unclear. In the present study, we investigated whether atorvastatin and pitavastatin exert their functions through the modulation of miR-33 and ABCA1-mediated cholesterol efflux from macrophages. The results showed that treatment of the statins up-regulated miR-33 expression, but down-regulated ABCA1 mRNA levels in RAW264.7 cells and bone marrow-derived macrophages. Statin-mediated ABCA1 regulation occurs at the post-transcriptional level through targeting of the 3'-UTR of the ABCA1 transcript by miR-33. Additionally, we found significant down-regulation of ABCA1 protein expression in macrophages treated with statins. Finally, we showed that high glucose and statin treatment significantly suppressed cholesterol efflux from macrophages. These findings have highlighted the complexity of statins, which may exert detrimental effects on metabolic abnormalities through regulation of miR-33 target genes.