WASHINGTON: Researchers at Washington University School of Medicine in St Louis have found a way to significantly reduce atherosclerosis in mice without lowering cholesterol levels or eliminating other obesity-related problems.
Atherosclerosis is the process through which fatty substances, such as cholesterol and cellular waste products accumulate in the lining of arteries.
Those buildups, called plaques, reduce blood flow through the artery and can contribute to heart attack, stroke and even gangrene. It is common in individuals with obesity-related problems such as high blood pressure, high cholesterol and diabetes.
Atherosclerosis is the process through which fatty substances, such as cholesterol and cellular waste products accumulate in the lining of arteries.
Those buildups, called plaques, reduce blood flow through the artery and can contribute to heart attack, stroke and even gangrene. It is common in individuals with obesity-related problems such as high blood pressure, high cholesterol and diabetes.
In the study, researchers inhibited atherosclerosis in mice by interfering with production of a substance called fatty acid synthase.
This enzyme converts dietary sugars into fatty acids in the liver, where it plays an important role in energy metabolism.
But fatty acids also are involved in atherosclerosis.
"The plaques that clog arteries contain large amounts of fatty acids. We engineered mice that are unable to make fatty acid synthase in one of the major cell types that contribute to plaque formation. On a standard Western diet high in fat, the mice had less atherosclerosis than their normal littermates," said senior investigator Dr. Clay F. Semenkovich.
Animals can't survive without fatty acid synthase, so mice in this study were able to make the substance in most of their tissues.
They couldn't manufacture it, however, in macrophages, a type of white blood cell that surrounds and kills invading microorganisms, removes dead cells from the body and stimulates the action of other immune cells.
These mouse experiments suggest targeting fatty acid synthase in macrophages may provide a potential treatment strategy for humans.
The researchers identified factors in the fatty acid pathway that seem to be capable of preventing plaques from blocking arteries in mice.
He says those substances - LXR-alpha and ABCA1 - eventually may become drug targets.
"It may be possible, for example, to take macrophages out of humans, inhibit fatty acid synthase in those cells, and then infuse the macrophages back into the same personFrom what we've observed in mice, we would hypothesize that approach might prevent or interfere with plaque buildup in people," he said.
Inhibiting fatty acid synthase in macrophages may not keep blood vessels clean forever, according to Semenkovich, but he says it could lower the risk of heart attacks and strokes while people are making lifestyle changes in order to lose weight, gain control of blood sugar levels or lower triglycerides and cholesterol.
"This discovery allows us to separate atherosclerosis from associated conditions such as diabetes and high cholesterol," he said.
The study has been published in the issue of the Journal of Biological Chemistry.
This enzyme converts dietary sugars into fatty acids in the liver, where it plays an important role in energy metabolism.
But fatty acids also are involved in atherosclerosis.
"The plaques that clog arteries contain large amounts of fatty acids. We engineered mice that are unable to make fatty acid synthase in one of the major cell types that contribute to plaque formation. On a standard Western diet high in fat, the mice had less atherosclerosis than their normal littermates," said senior investigator Dr. Clay F. Semenkovich.
Animals can't survive without fatty acid synthase, so mice in this study were able to make the substance in most of their tissues.
They couldn't manufacture it, however, in macrophages, a type of white blood cell that surrounds and kills invading microorganisms, removes dead cells from the body and stimulates the action of other immune cells.
These mouse experiments suggest targeting fatty acid synthase in macrophages may provide a potential treatment strategy for humans.
The researchers identified factors in the fatty acid pathway that seem to be capable of preventing plaques from blocking arteries in mice.
He says those substances - LXR-alpha and ABCA1 - eventually may become drug targets.
"It may be possible, for example, to take macrophages out of humans, inhibit fatty acid synthase in those cells, and then infuse the macrophages back into the same personFrom what we've observed in mice, we would hypothesize that approach might prevent or interfere with plaque buildup in people," he said.
Inhibiting fatty acid synthase in macrophages may not keep blood vessels clean forever, according to Semenkovich, but he says it could lower the risk of heart attacks and strokes while people are making lifestyle changes in order to lose weight, gain control of blood sugar levels or lower triglycerides and cholesterol.
"This discovery allows us to separate atherosclerosis from associated conditions such as diabetes and high cholesterol," he said.
The study has been published in the issue of the Journal of Biological Chemistry.
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