Abstract 24: MicroRNA-27b Is a Regulatory Hub in Lipid Metabolism and Is Altered in Dyslipidemia

Abstract

Cellular and plasma lipid levels are tightly controlled by complex gene regulatory mechanisms. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and have emerged as important modulators of lipid homeostasis, but the extent of their role has not been systematically investigated. In this study, we performed high-throughput small RNA sequencing and detected approximately n=150 miRNAs in mouse liver. We then employed an unbiased, in silico strategy to identify miRNA regulatory hubs in lipid metabolism, and miR-27b was identified as the strongest such hub in human and mouse liver. In addition, hepatic miR-27b levels were determined to be sensitive to plasma hyperlipidemia, as evidenced by its 3-fold up-regulation in the liver of mice on a high-fat diet (42% calories from fat). Further, we showed in a human hepatocyte cell line (Huh7) that miR-27b regulates the expression (mRNA and protein) of several key lipid-metabolism genes. Finally, hepatic levels of miR-27b and its target genes, which include ANGPTL3 and GPAM , were inversely regulated in a mouse model of severe dyslipidemia and atherosclerosis. Conclusion: miR-27b is responsive to lipid levels, and acts as a “regulatory hub” in lipid metabolism, controlling multiple genes involved in dyslipidemia.