Enzyme inhibitor may help lower cholesterol and unclog arteriesAtherosclerosis, the accumulation of cholesterol in the arteries that clogs the circulation and results in heart attacks and strokes, is a leading cause of death. One strategy for preventing heart disease and stroke is to clear out clogged arteries, restoring circulation. This process, known as reverse cholesterol transport is accomplished by the high-density lipoproteins (HDLs) in the blood. HDL transports excess cholesterol from the artery wall and macrophages and delivers it to the liver, where it is excreted as bile salts and cholesterol. In a study appearing in the May issue of the Journal of Clinical Investigation, Fumihiko Matsuura and colleagues from Columbia University, New York, reveal new features of this pathway that suggest an enzyme inhibitor currently in phase III clinical trials may help reduce cholesterol levels and atherosclerosis in humans.
One proposal for boosting reverse cholesterol transport has been to elevate plasma HDL levels by inhibiting a protein called CETP that transfers cholesterol esters from HDL to lower-density lipoproteins. However, there has been controversy in the medical literature as to whether CETP deficiency is pro- or anti-atherogenic. Matsuura and colleagues assessed the ability of HDL-2 from individuals deficient in CETP to promote cholesterol removal from macrophages. They observed a 2–3-fold increase in cholesterol efflux in these individuals compared to controls and they demonstrated that this was dependent on a molecule known as ABCG1, which is present on macrophages and contributes to the formation of HDL. They also found that the enhanced ability to promote cholesterol removal in these CETP-deficient individuals was due to increased amounts of the enzyme LCAT and apolipoprotein E in HDL-2, which allow the inner cholesterol ester–rich core of HDL-2 to expand to carry greater amounts of cholesterol. In an accompanying commentary, Robert Mahley and colleagues from the University of California, San Francisco, comment that as CETP does not appear to be essential for reverse cholesterol transport in humans, this raises the hope of using a CETP inhibitor to elevate HDL levels and therefore reduce the incidence of atherosclerosis.
TITLE: HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway
Osaka University, Osaka, Japan.
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TITLE: Putting cholesterol in its place: apoE and reverse cholesterol transport
Robert W. Mahley
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
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