MicroRNAs involved in the lipid metabolism and their possible implications for atherosclerosis development and treatment

Abstract

Hyperlipidemia is a well-accepted risk factor in the development of atherosclerosis. MicroRNAs (miRNAs), a novel class of posttranscriptional regulators of gene expression, are involved in a variety of biological and pathological processes, including the regulation of the lipid metabolism and atherosclerosis. As our knowledge of miRNAs expands, a new class of "circulating miRNAs" has recently been described. It includes miRNAs which may be found in various bodily fluids packaged in microvesicles/exosomes, or bound to specific transporting proteins. High-density lipoprotein (HDL) particles have been identified as one such carrier. As this class of miRNAs likely plays a role in intercellular communication, it may also contribute to the atherosclerosis development and progression. This review aims to provide a comprehensive explanation of the roles of distinct miRNAs involved in the regulation of the lipid metabolism. These microRNAs seem to be promising therapeutic agents, as documented in rodents and African green monkeys. The second part of the review focuses on circulating miRNAs and their involvement in the atherosclerosis, especially as their levels have been described as altered in patients with dyslipidemia/hyperlipidemia. Special emphasis is placed on miRNAs transported in a complex with HDL particles and on those which may be considered potential atherosclerosis biomarkers.

Figure 1

MicroRNA-33/33* effects. MicroRNA-33/33* are transcribed from the intron of the SREBP gene. Statins and low circulating cholesterol levels promote this process. Both miRNAs also target a variety of mRNAs involved in the glucose, fatty acid, and cholesterol metabolism. In the cholesterol metabolism, their targets include molecules involved both in cholesterol transport to HDL/reverse cholesterol transport and the transport of cholesterol to bile. CH: cholesterol; all other abbreviations are explained in the text.

Figure 2

MicroRNAs involved in lipid metabolism. The figure depicts the complex regulation of lipid metabolism by distinct microRNAs. Individual microRNAs are shown together with their confirmed targets (in rectangles); red blunted arrows represent inhibition; green arrows represent stimulation. Figure summarizes the relationships described into greater detail in the text. The abbreviations are also explained in the text.

Figure 3

MicroRNAs targeting ABCA1 mRNA. This figure summarizes all currently validated miRNAs which target ABCA1 mRNA and are thus involved in cholesterol transport. The inhibition of these miRNAs holds great therapeutic potential in increasing circulating HDL cholesterol levels.