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Team spots key regulator for cholesterol production

Oct. 2, 2014, 9:17 AM

A Vanderbilt University-led research team has discovered a “master regulator” for cholesterol production and transport in the liver — a tiny piece of RNA called microRNA-223.

The liver produces most of the body’s supply of cholesterol, an essential constituent of cell membranes. But too much cholesterol can lead to atherosclerosis, the accumulation of fatty deposits along blood vessel walls.

By regulating the “translation” of genetic instructions in the liver, microRNA-223 provides another level of control over cholesterol levels, and is a potential new target for treating and preventing cardiovascular disease, the researchers reported recently in the Proceedings of the National Academy of Sciences.

Cholesterol synthesis and transport were thought to be regulated primarily by proteins called transcription factors that control the “transcription” of cholesterol-regulating genes from the DNA into messenger RNAs.

MicroRNA-223 ups the ante. It suppresses the translation of messenger RNA into proteins, the workhorses of the cell.

“It’s a new level of regulation for cholesterol,” said Kasey Vickers, Ph.D., assistant professor of Medicine and of Molecular Physiology and Biophysics at Vanderbilt, and the paper’s first author.

Kasey Vickers, Ph.D.

In studies in cells and mice at Vanderbilt and the National Heart, Lung and Blood Institute (NHLBI), the researchers found that microRNA-223 served as a feedback “repressor,” preventing the accumulation of excess cholesterol in liver cells, and falling quickly when cholesterol levels dropped and more cholesterol was needed.

In mice without the gene for microRNA-223, “plasma cholesterol levels skyrocketed,” he said.

MicroRNA regulation is a burgeoning field, said Vickers, who did his postdoctoral work at NHLBI in the lab of Alan Remaley, M.D., Ph.D., a leader in the lipid metabolism field and the paper’s senior author, before coming to Vanderbilt in 2012.

Small non-coding RNAs, namely microRNAs, can each regulate hundreds of genes and, in turn, each gene may be repressed, or turned down, by many microRNAs. This creates a complex network of direct and indirect metabolic gene regulation.

Because MicroRNA-223 also is involved in regulating inflammation, it “provides an interface between inflammation and cholesterol, which ultimately is a hallmark of atherosclerosis,” Vickers said.

Dyslipidemia, dysregulated cholesterol or lipid levels, contributes not only to heart disease but is associated with chronic kidney disease, diabetes, metabolic syndrome and obesity. “MicroRNA-223 may help improve our understanding and treatment of these disorders as well,” Vickers said.

“Kasey’s discovery of the wide-ranging effects miR-223 in regulating cholesterol metabolism is truly groundbreaking work that has the potential to open new avenues for the prevention of cardiovascular disease,” said MacRae Linton, M.D., Stephen and Mary Schillig Professor of Medicine and director of the Atherosclerosis Research Unit at Vanderbilt.

The research was supported in part by National Institutes of Health grants HL113039, DK020593 and HL116263.

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