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Emerging role of MicroRNAs in the regulation of lipid metabolism

M icroRNAs (miRNAs) are endogenous 22 nucleotide (nt) RNAs that play essential gene-regulatory roles in animals and plants by pairing messenger RNAs (mRNAs) of protein-coding genes to direct their posttranscriptional repression by translational inhibition, deadenylation, and mRNA decay. The human genome is thought to encode over 1,000 miRNAs that regulate the expression of more than 60% of genes. Interestingly, a single miRNA may target multiple genes, potentially providing simultaneous regulation of the genes involved in a physiological pathway. In fact, the complexity in higher organisms is thought to be achieved through sophisticated control and coordinated mechanisms carried out by noncoding RNAs including miRNAs. MiRNAs have recently emerged as key regulators of lipid metabolism, playing major roles in regulating cholesterol and fatty acid metabolism. Among these, miR122 was the most widely studied miRNA and the first described for its role in regulating total serum cholesterol and hepatic metabolism. miR-122 is highly expressed in the liver, and it is estimated to account for 75% of all liver miRNAs. Inhibition of miR-122 using antisense oligonucleotides significantly reduces plasma cholesterol levels and reverses hepatic steatosis in mice fed a high-fat diet. Similarly, silencing of miR-122 in nonhuman primates results in a significant reduction in plasma cholesterol. In addition to miR122, miR-33a/b have recently been discovered as main regulators of lipid homeostasis. miR-33a/b are miRNAs encoded in intron 16 and 17 of the Srebp-2 and Srebp-1 genes, respectively. miR-33a/b are cotranscribed with their host genes and target genes involved in cellular cholesterol export, including the adenosine triphosphate binding cassette (ABC) transporters ABCA1 and ABCG1, and fatty acid metabolism, including carnitine O-acetyltransferase (CROT), carnitine palmitoyltransferase 1a (CPT1a), hydroxyacyl-CoA dehydrogenase beta subunit (HADHB), and AMP-activated protein kinase (AMPK). Notably, inhibition of miR-33 in mice and nonhuman primates using a variety of approaches increases hepatic ABCA1 expression and circulating high-density lipoprotein (HDL) levels. As expected by the significant increase in HDL levels observed in mice treated with anti-miR-33 oligonucleotides, the inhibition of miR-33 expression promotes reverse cholesterol transport and regression of atherosclerosis. Overexpression of miR-33 also represses genes involved in the regulation of fatty acid oxidation. Indeed, endogenous inhibition of miR-33 up-regulates CROT, CPT1a, HADHB, and AMPK expression, leading to an increase in b-oxidation. Later, Temel, Moore and colleagues confirmed the important role of miR-33 in regulating triglyceride metabolism in nonhuman primates. In addition to miR-122 and miR-33, other miRNAs have been shown to play an important role in the posttranscriptional regulation of lipid metabolism, including miR-370, miR-378/378*, miR-335, miR-27, and miR-125a-5p. miR-27b has been shown to regulate human adipocyte differentiation by directly targeting peroxisome proliferator-activated receptor (PPAR) gamma and C/EBPa, two key regulators of adipogenesis. Overexpression of miR-27b represses adipogenic marker gene expression and triglyceride accumulation. Moreover, miR-27b also inhibits PPARa, an important transcription factor that regulates genes encoding lipidrelated genes including lipoprotein lipase (LPL) and ABCA1 and ABCG1 transporters. miR-27b is a member of the miR-27 microRNA family, encoded in chromosome 9 and clustered with other miRNAs such as miR-23b, miR-3074, and miR-24-1. The molecular mechanism that regulates its expression remains poorly understood. In addition to its role in lipid metabolism Abbreviations: ABC, adenosine tri-phosphate binding cassette; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; ANGPTL3, angiopoetin-like 3; CPT1a, carnitine palmitoyltransferase 1a; CROT, carnitine O-acetyltransferase; GPAM, glycerol-3-phosphate acyltransferase 1; HADHB, hydroxyacyl-CoA dehydrogenase beta subunit; HDL, high-density lipoprotein; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; Huh7, human hepatocarcinoma cell line; LPL, lipoprotein lipase; miRNA, microRNA; PPAR, proliferator-activated receptor; TSP-1, thrombospondin-1. The Fern andez-Hernando Lab is supported by grants from the National Institutes of Health (R01HL107953 and R01HL106063). Address reprint requests to: Carlos Fern andez-Hernando, Departments of Medicine, Leon H. Charney Division of Cardiology, and Cell Biology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY 10016. E-mail: carlos. fernandez-hernando@nyumc.org; fax: 212-263-4129. CopyrightVC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.25960 Potential conflict of interest: Nothing to report.