Role of microRNAs in Metabolic Diseases

Abstract

MicroRNAs regulate a number of processes by controlling the gene expression at the post-transcriptional level. These small, non-coding RNA molecules play an important role in predisposition to metabolic diseases by maintaining glucose, lipid, and cholesterol metabolism. miRNAs are synthesized as double-stranded RNA, the two strands are separated to produce functional single-stranded miRNAs. The miRNAs are part of a large silencing complex called RNA-induced silencing complex (RISC). miRNAs regulate adipogenesis, the accumulation and droplet size of triacylglycerols, and PPAR gene expression. Dysfunction or higher expression of certain miRNAs (e.g., miR-222) silences the glucose transporter mRNAs resulting in a decrease in the surface receptors for glucose uptake hence predisposing to diabetes. miR-222 has also been reported to increase insulin resistance. Certain miRNAs are upregulated in obese mice as well as obese humans including miR143-145, miR29a, etc. The most important regulatory miRNA for lipid metabolism is miR-122, in addition, miR-33a and miR-33b exert their effect through sterol regulatory element binding proteins. The naturally occurring miRNAs can be silenced by chemically modified anti-miRNA oligonucleotides (AMOs) to alter their cellular expression levels. Another therapeutic oligonucleotide type called miRNA sponges compete with miRNAs for binding sites on the target mRNAs. The nuclease-resistant locked nucleic acids (LNAs) can also reduce the expression of certain miRNAs and have been shown to reduce cholesterol levels in mice. In conclusion, miRNAs appear to be faithful therapeutic targets for altering the gene expression of many target genes involved in lipid and fat metabolism in the future.