Mechanistic Role of MicroRNAs in Coupling Lipid Metabolism and Atherosclerosis

Abstract

MicroRNAs (miRNAs, miRs) represent a group of powerful and versatile posttranscriptional regulators of gene expression being involved in the fine control of a plethora of physiological and pathological processes. Besides their well-established crucial roles in the regulation of cell cycle, embryogenesis or tumorigenesis, these tiny molecules have also been shown to participate in the regulation of lipid metabolism. In particular, miRs orchestrate cholesterol and fatty acids synthesis, transport, and degradation and low-density and high-density lipoprotein (LDL and HDL) formation. It is thus not surprising that they have also been reported to affect the development and progression of several lipid metabolism-related disorders including liver steatosis and atherosclerosis. Mounting evidence suggests that miRs might represent important "posttranscriptional hubs" of lipid metabolism, which means that one miR usually targets 3'-untranslated regions of various mRNAs that are involved in different steps of one precise metabolic/signaling pathway, e.g., one miR targets mRNAs of enzymes important for cholesterol synthesis, degradation, and transport. Therefore, changes in the levels of one key miR affect various steps of one pathway, which is thereby promoted or inhibited. This makes miRs potent future diagnostic and even therapeutic tools for personalized medicine. Within this chapter, the most prominent microRNAs involved in lipid metabolism, e.g., miR-27a/b, miR-33/33*, miR-122, miR-144, or miR-223, and their intracellular and extracellular functions will be extensively discussed, in particular focusing on their mechanistic role in the pathophysiology of atherosclerosis. Special emphasis will be given on miR-122, the first microRNA currently in clinical trials for the treatment of hepatitis C and on miR-223, the most abundant miR in lipoprotein particles.

Keywords: Atherosclerosis; Cholesterol; HDL; LDL; Lipid metabolism; miR-122; miR-223; miR-33.

Fig. 5.1

MicroRNAs in lipid metabolism. The figure summarizes the main miRs involved in lipid metabolism. Blunted arrows represent inhibition, classical arrows represent activation. miRs are marked in circles, their targets are marked in squares. Detailed description is provided in the text. FXR Farnesoid X receptor, SREBP sterol regulatory element binding protein, LXR liver X receptor, RXR retinoid X receptor, miR microRNA, RT reverse transport; ABCA1 ATP-binding cassette transporter A1, ABCG1 ATP-binding cassette transporter G1, ABCB11 ATP-binding cassette, subfamily B member 11, LDLR low density lipoprotein receptor, SR-IB scavenger receptor type I class B, HMGCoA-R hydroxymethylglutaryl coenzyme A reductase, MSMO1 methylsterol monooxygenase 1, FASN fatty acid synthase, NFYH nuclear transcription factor Y, RIP-140 receptor-interacting protein 140, SRC steroid receptor coactivator, CPT1A carnitine palmitoyltransferase 1A, HADBH hydroxyacyl-CoA-dehydrogenase, CROT carnitine O-octaniltransferase, AMPK AMP-activated protein kinase, ACC acyl-CoA carboxylase, GPAM mitochondrial glycerol-3-phosphate, GPC-6 glucose-6-phosphatase, PCK1 phosphoenolpyruvate carboxykinase; IRS-2 insulin receptor substrate 2, ALDO-A aldolase A, ApoE3 apolipoprotein E3, ApoA1 apolipoprotein A1, ANGPTL3 angiopoietin-like 3, PPAR peroxisome proliferator-activated receptor α, CEBP CCAAT/enhancer-binding protein α