The 67-year-old woman had sky-high high-density lipoprotein (HDL) cholesterol to form long considered as protective against heart disease, yet his arteries were lined plate. His paradoxical cases helped motivate a team of scientists to show how high HDL can sometimes be a signal not of heart health, but the opposite :. A system incapable of siphoning fatty particles from circulation cholesterol
In the past 10 years, HDL particles have confounded scientists. The normal role of these beams of protein and lipid is to transport cholesterol in the liver rest of the body, which eliminates from the body. More something good should mean better health, and people naturally have higher HDL levels are usually better. But drugs that increase HDL cholesterol have flopped in clinical trials, and the genes that help raise does not seem to follow with less heart disease. "Nothing ever single HDL" said Jay Heinecke, a biochemist at the University of Washington, Seattle, who has studied for years.
In this week's issue of Science Daniel Rader, a geneticist and lipidologist at the University of Pennsylvania, and colleagues suggest that the amount of HDL is less important than the way it is effectively moved the arteries in the liver. the inspiration of Rader was a model mouse developed by Monty Krieger at the Massachusetts Institute of Technology in Cambridge there about 20 years. the mouse developers had deleted a gene called SCARB1 , resulting in animals with surprisingly high HDL and, just amazingly arteries severely blocked. "the mice actually receive heart attacks," said Heinecke. Indeed, the cholesterol displacement system outside the body is broken in these mice.
particles Normally HDL cholesterol gather immune cells that line the arteries, then deposit their load in the liver so that the cycle can begin again. The protein made by the SCARB1 gene, known as SR-B1, helps make this deposit occurs. Mice without SR-B1 have HDL particles swollen with cholesterol, struggling to attract more away from the arterial wall.
Rader wondered if the same could occur in some people. He and his colleagues began by sequencing the gene in 852 people with high HDL and 1,000 controls. They found a person of 67 years, women who had no copies of operation of SCARB1 gene and had more plaque on the arteries mean that a woman of her age. His HDL was 152 mg / dL, well above the average of about 62 mg / dl in women in her age group. Eighteen others were just a functional copy SCARB1 instead of the usual two, and most of them also had higher HDL. Detailed studies of nine people with SCARB1 mutations, including women, have suggested that in mice, their abundant HDL failed to effectively carry cholesterol throughout the body.
Rader then spread to his colleagues who had collected the DNA of hundreds of thousands of people for studies of lipids and heart disease. Among them, he found another 284 people who have had a single copy operation SCARB1 . (No one else was like the first woman with two missing copies.) Most of these people were also higher than average HDL. They were also 80% more likely than the witnesses CHD-roughly the same increase in risk seen traditional risk factors such as diabetes and hypertension.
"This is a key indication of what people have suspected from animal studies," says Alan Tall, an HDL researcher at Columbia University. It seems that HDL is higher "because the flow is blocked, "not because HDL excels in maintaining cholesterol on arteries.
Yet because Rader could find so few people without fully operational SCARB- 1 and because the potential effects of mutations on heart health appeared modest, the link between transport defective HDL and heart disease is still fragile, he and others say. and HDL behavior in a box Petri does not necessarily reflect what it does to the body, suggests Kuivenhoven Jan Albert, who studies the genetics of lipid metabolism at the University Medical Center Groningen in the Netherlands. "We have no good ways do the tests with HDL that can really say what happens "in a person, said Kuivenhoven.
HDL remains extraordinarily complex, and Rader Kuivenhoven say. It is possible that the collection of HDL drugs failed in clinical trials because of the type of HDL-products detected drugs doctors larger HDL particles than expected. Overall, however, there is little doubt that high HDL always follows with a healthier heart for most people, except, Rader said, when it does not.
Ultimately, he said, we would be able to say, "Your HDL is high because X which is good," and someone else, "Your HDL is high because of Y, which is a bad thing. "now, he and others want to nail down exactly what these factors might be and, potentially, how to run them off.
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