MicroRNA-33a/b in Lipid Metabolism

miRNAs have been found in acute myocardial infarction,11 acute coronary syndrome,12 stable coronary artery disease (CAD),13 heart failure,14 essential hypertension,15 and stroke.16 miRNAs have many functions in physiological and pathological states, and some miRNAs have been shown to have a significant effect on lipid homeostasis.9,17,18 Dyslipidemia and related metabolic disorders continue to rise at an alarming rate worldwide and are associated with increased cardiovascular disease risk. A high plasma level of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for CAD. Therapy with statins [inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR)], which inhibit cholesterol biosynthesis, effectively reduces the levels of both LDL-C and modified forms of LDL in human plasma,19 and significantly reduces the risk of CAD, as evidenced by primary and secondary clinical intervention studies.20,21 However, patients who are treated with high doses of statins, regardless of their treated LDL-C level, are still at considerable risk for cardiovascular disease.22,23 Thus, we still need other therapeutic options to treat the residual risk.24–26 Elucidation of the function of miRNAs may provide avenues to developing novel treatments of dyslipidemia. In particular, we have intensively investigated the functions of miR-33a/b, in vivo, using genetically modified mice.27–30 In this review, we summarize the functions of miR-33a/b and therapeutic strategies to suppress these functions. icroRNAs (miRNAs; miRs) are endogenous, small (approximately 20–22 nucleotides in length), nonprotein-coding RNAs. miRNAs bind to the 3’ untranslated region (UTR) of specific mRNAs according to the complementarity of their sequences and they either inhibit translation or promote mRNA degradation.1,2 miRNAs were initially discovered in Caenorhabditis elegans3,4 and were later found to be evolutionarily conserved.5,6 More than 60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs, and so far, approximately 2,500 miRNAs have been identified in humans.6,7 miRNAs are usually transcribed as longer primary miRNAs (Pri-miRNAs) by RNA polymerase II (Pol II) and then processed by the Drosha (RNase III)/DGCR8 complex to premature miRNAs (Pre-miRNAs) in the nucleus. Pre-miRNAs are exported to the cytoplasm through exportin 5 and then processed by another ribonuclease enzyme, Dicer, to form mature miRNAs, which typically comprise 20–22 nucleotides. Moreover, it is known that miR-451 does not require Dicer. Instead, the pre-miRNA becomes loaded into Ago and is cleaved by the Ago catalytic center to generate an intermediate 3’ end, which is further trimmed.8 Mature miRNAs are assembled into an RNA-inducing silencing complex and post-transcriptionally inhibit mRNA expression by binding to the 3’ UTR of their target mRNAs.9 In addition to their existence in tissues, recent studies have indicated that miRNAs also exist in serum, plasma, urine, and other body fluids in highly stable forms that are secure from endogenous RNase activity.10 Altered levels of circulating M