MicroRNAs Shown to Control Lipid and Cholesterol Metabolism in Mouse Models

A group of microRNAs was identified as modulators of lipid and cholesterol metabolism in two mouse models and may serve as targets for drugs designed to protect against cardiovascular diseases.

MicroRNAs (miRNAs) are fragments of RNA about 20 nucleotides long that block gene expression by attaching to molecules of messenger RNA (mRNA) in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA.

Investigators at the Harvard Medical School (Boston, MA, USA) had found previously that the microRNA miR-33 suppressed production of beneficial HDL cholesterol and that antisense blocking of miR-33 increased HDL levels in an animal model.

In the current study, which was published in the October 26, 2015, online edition of the journal Nature Medicine, the investigators reviewed genome-wide association studies involving more than 188,000 individuals. This review yielded 69 microRNAs that were coded by gene loci known to be associated with lipid abnormalities.

Using a tool that predicted the targets of microRNAs based on matches between their nucleotide sequences and those of protein-coding genes and a database of identified gene functions, the investigators identified four microRNAs that appeared to control genes involved in cholesterol and triglyceride levels and in other metabolic functions, such as glucose metabolism.

Two of the microRNAs, miR-128-1 and miR-148a, were found to control the expression of proteins essential to the regulation of cholesterol/lipid levels in cells growing in culture and in high-fat diet-fed C57BL/6J and Apoe-null mouse models. The microRNA miR-128-1 was also found to regulate fatty liver deposits, insulin signaling, and maintenance of blood sugar levels.

"While we and others have recently identified microRNAs that control cholesterol and fat metabolism and trafficking, no studies to date have systematically looked at all non-coding factors, such as microRNAs, in genetic studies of human diseases and other traits," said senior author Dr. Anders Naar, professor of cell biology at Harvard Medical School. "Using human genetic data from almost 190,000 individuals, we have linked 69 microRNAs to increased genetic risk for abnormal cholesterol and triglyceride levels, and showed that four of these act to control proteins we know are involved in those metabolic activities. We are following up these findings with studies to address whether antisense blocking of these microRNAs could decrease atherosclerosis, cardiovascular disease, and inflammatory fatty liver diseases in animals. We hope these findings will lead to new, more effective ways of treating or even preventing cardiovascular disease and other metabolic disorders."

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