Massachusetts General Hospital (MGH) researchers have identified tiny segments of RNA that may play an important role in the body's regulation of cholesterol and lipids. Their study found that the miR-33 family of microRNAs suppress a protein known to be important for generation of HDL -- the "good cholesterol" that transports lipids to the liver for disposal -- and for the removal of cholesterol from peripheral tissues, including cells that form atherosclerotic plaques. The findings -- which will appear in Science and are receiving early online publication -- suggest that the miR-33-mediated pathway could be a new treatment target for cardiovascular diseases.
"Our study shows that miR-33a and -33b -- microRNAs embedded in the genes of the SREBP family of cholesterol/lipid-regulators -- work together with their host genes to control cellular cholesterol levels," says Anders Näär, PhD, of the MGH Center for Cancer Research, who led the study. "Importantly, miR-33 is also the first microRNA found to modulate cholesterol export from cells and to inhibit HDL production in animals. This new understanding of cholesterol regulation could inform ongoing efforts to boost HDL levels in heart disease patients." Näär is an associate professor of Cell Biology at Harvard Medical School.
Cholesterol is an essential component of all cells and several important hormones, but cholesterol levels that are out of balance or too high overall lead to the formation of atherosclerotic plaques that cause heart attacks or strokes. Excessive particles of low-density lipoprotein (LDL, often called "bad cholesterol") can be taken up by macrophages in the bloodstream, which transforms the immune cells into the lipid-laden "foam cells" that make up plaques. High-density lipoprotein (HDL or "good cholesterol") transports lipids away from cells back to the liver for disposal, and low HDL levels are associated with increased cardiovascular risk.
Among the mechanisms known to regulate production of cholesterol are SREBPs (sterol regulatory element-binding proteins) that control the expression of several genes. While these proteins' role in cholesterol generation is well understood, little is known about the part they play in the removal and clearance of cholesterol and other lipids. Unexpectedly, the MGH/HMS team discovered the presence of a family of microRNAs -- tiny RNA segments that can control gene expression -- in non-coding segments of SREBP genes in animals from fruit flies to humans. The researchers then sought to determine the function of two forms of this microRNA family -- called miR-33a and -33b -- and whether they were related to the functions of the SREBP host genes.
A series of experiments indicated that miR-33a and -33b inhibit ABCA1 (ATP-binding cassette transporter A1), a protein known to be important for both the generation of HDL and for transport of cholesterol from peripheral tissues -- including foam cells -- back to the liver for disposal. Particular variants and mutations in the ABCA1 gene have been associated with increased risk of heart disease. The researchers also found that treating cholesterol-laden mouse macrophages with antisense RNA strands that block miR-33 activity increased levels of ABCA1 and reduced cellular cholesterol levels. Injecting the same miR-33-antisense molecules into mice fed a high-fat diet led to significant increases in the animals' HDL levels but had no effects on levels of LDL, triglycerides or glucose.
"Our discovery that miR-33 acts in concert with its SREBP host to maintain cholesterol levels appears to be the first known example of cooperative regulation of a physiological pathway by a microRNA and its host gene," explains Näär. "These studies also provide the impetus to investigate whether this novel cholesterol-regulatory mechanism might serve as a therapeutic target to treat cardiovascular disease."
"These studies are particularly timely since the development of drugs targeting the 'good' HDL pathway has been challenging," adds Robert Gerszten, MD, director of Clinical and Translational Research, MGH Heart Center, a co-author of the Science paper.
The study was supported by grants from the National Institute of General Medical Sciences, the National Institute for Diabetes and Digestive and Kidney Diseases, the American Heart Association, the Fondation Leducq, and Massachusetts General Hospital. Hani Najafi-Shoushtari, PhD, of the MGH Cancer Center, is lead author of the Science article. Additional co-authors are Fjoralba Kristo and Toshi Shioda, MD, PhD, MGH; and Yingxia Li and David Cohen, MD, PhD, Brigham and Women's Hospital. The MGH has a patent pending that covers the use miR-33 microRNAs to regulate cholesterol levels.
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