When HDL cholesterol doesn’t protect against heart disease

NIH | MARCH 27, 2016

High-density lipoproteins (HDL) is thought to remove cholesterol from arteries and carry it to the liver for removal from the body. Higher levels of HDL have been associated with a lower risk of cardiovascular disease. However, pharmaceutical approaches to reduce heart disease risk by raising HDL levels have had disappointing results.

An international research team led by Dr. Daniel J. Rader at the University of Pennsylvania found a genetic variant within the gene SCARB1, which codes for the major HDL receptor on liver cells, scavenger receptor class BI (SR-BI). In mice, genetic manipulations of this gene had effects opposite from those expected if HDL-C were protective. Overexpression of the gene lowered HDL-C levels but reduced atherosclerosis. Deletion raised HDL-C levels but increased atherosclerosis.

Genetic analyses of well over 300,000 people confirmed that the variant, called SCARB1 P376L, was associated with elevated HDL-C levels. The researchers found that people with the variant had unusually high levels of large HDL-C particles in their blood.

Experiments in cell cultures and mice revealed that the P376L SR-BI protein wasn’t processed properly by the cell and often failed to reach the cell surface. As a result, liver cells became incapable of taking up HDL cholesterol from the blood.

The work demonstrates that the protective effects of HDL are more dependent upon how it functions than merely how much of it is present.

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