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. Elevated plasma lipid content, or hyperlipidemia, is a significant risk factor for cardiovascular morbidity and mortality. MicroRNAs (miRNAs) are posttranscriptional 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 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, including Angptl3 and Gpam. Finally, we demonstrated that hepatic miR-27b and its target genes are inversely altered in a mouse model of dyslipidemia and atherosclerosis. Conclusion miR-27b is responsive to lipid levels, and controls multiple genes critical to dyslipidemia.

MicroRNA-223 coordinates cholesterol homeostasis

“…In summary, we have described a small, but powerful regulator of metabolism because miR-223 likely coordinates cholesterol homeostasis through multiple direct and indirect mechanisms controlling cholesterol biosynthesis, uptake, and efflux. Results from this and other recent studies on miRNAs (13,18) highlight the potential importance of miRNAs in the etiology of dyslipidemias and cardiovascular disease. As such, miR-223 has great potential as a therapeutic target to control systemic cholesterol levels in the prevention and treatment of cardiovascular disease.…”

“…1 D and E). Recently, we confirmed that Apoe −/− mice on a cocoa butter diet (CBD) are severely hypercholesterolemic after 4 wk (13). Here, we present that this mouse model (Apoe −/− CBD, 4 wk) also has markedly elevated hepatic cholesterol (P = 0.02) and miR-223 levels (fivefold, P = 0.02) (Fig.…”

“…Collectively, loss of miR-223 resulted in profound changes to hepatic gene expression and cholesterol homeostasis. To identify genes, in addition to SR-BI, that may contribute to the observed hypercholesterolemia, we systematically filtered the 972 hepatic genes that were significantly altered in miR-223 −/− livers for genes previously reported to be associated with cholesterol and lipid metabolism (13). Strikingly, we found 11 genes that were previously reported to be significantly associated with complex lipid traits in a large-scale genome-wide association study and 18 genes that were previously identified to be targets of sterol response element binding proteins (SREBP) (SI Appendix, Table S7) (38,39).…”

“…Likewise, cholesterol and lipid accumulation in the liver are driving forces in nonalcoholic fatty liver disease and hepatic inflammation (10). MicroRNA-223 (miR-223) was previously found to control monocyte differentiation and regulate multiple inflammatory genes in monocytes and macrophages (11,12); however, bioinformatics suggest that miR-223 likely also regulates many genes associated with lipid and cholesterol metabolism (13).…”

MicroRNA-27a promotes porcine myoblast proliferation by downregulating myostatin expression

“…It has been reported that miR-27 enhances differentiation of osteoblasts and strongly inhibits adipogenesis (Lin et al, 2009;Wang and Xu, 2010). MiR-27b is a regulatory hub in lipid metabolism through repressing critical regulators of lipid homeostasis, such as PPARα, HMGCR (Kida et al, 2011, Vickers et al, 2013. In a recent study, miR-27b was reported to specifically target to bovine myostatin (Miretti et al, 2013).…”