MicroRNA and host gene play key role in regulating cholesterol pathways

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MicroRNA and host gene play key role in regulating cholesterol pathways

http://www.eurekalert.org/pub_releases/2010-05/mgh-mah051110.php

Study identifies potential new strategy for raising 'good' cholesterol levels

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 Gerszten, MD, director

of Clinical and Translational Research, MGH Heart Center, a co-author of the

Science paper.

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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 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.

Massachusetts General Hospital, established in 1811, is the original and largest

teaching hospital of Harvard Medical School. The MGH conducts the largest

hospital-based research program in the United States, with an annual research

budget of more than $600 million and major research centers in AIDS,

cardiovascular research, cancer, computational and integrative biology,

cutaneous biology, human genetics, medical imaging, neurodegenerative disorders,

regenerative medicine, systems biology, transplantation biology and

photomedicine.