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Controlling ‘good cholesterol’
By Ruth SoRelle, MPH

Lawrence Chan, ScD, MBBS

First, there was fat. Then there was cholesterol. Now there is high density lipoprotein (‘good cholesterol’), low density lipoprotein and very low density lipoprotein, both of which are considered ‘bad cholesterol.’

As understanding of these fats increases, researchers are looking at what controls their levels in the blood stream as the first step to manipulating them to improve the health of individuals. In a recent publication in the Proceedings of the National Academy of Sciences, Lawrence Chan, ScD, MBBS, chief of the division of endocrinology at Baylor College of Medicine, and members of his laboratory have determined that a newly described enzyme called endothelial lipase controls the structure, metabolism and concentration of high density lipoprotein (HDL) in the blood.

When normal endothelial lipase is altered, the structure of the resulting HDL particles changes. For example, said Chan, when mice are bred to lack the enzyme, the HDL particles they produce are much larger. Because they are larger, they can carry more cholesterol in each particle.

“We don’t know if it is good or bad that the HDL becomes larger,” said Chan. “We were always taught that high levels of HDL are good for you because it (HDL) carries cholesterol from the outer areas of the body back to the liver where it is excreted as bile.”

High levels of HDL may also inhibit inflammation, a newly accepted factor in coronary heart disease, said Chan.

“It also protects the vascular wall,” he said. “It may slow down the oxidation of low density lipoprotein (the so-called bad cholesterol). Oxidized LDL is very bad.”

A variant of the enzyme, found in approximately 26 percent of people, is associated with high levels of HDL, Chan said. He and his colleagues are following the medical progress of these people in hopes that they will be able to determine whether the variant form is beneficial or not.

Just finding the variants is important because they could explain why some people have high HDL levels and others have levels that are lower, even when other factors are constant.

Endothelial lipase belongs to a family of lipase enzymes. Lipoprotein lipase is found mainly in the fat cells, heart and muscle. Hepatic lipase, as its name implies, is mainly in the liver. All the lipases are anchored on the surface of the endothelium of blood vessels. When lipoproteins pass through the blood vessels, these enzymes act on them.

“Endothelial lipase is the only one actually made in the endothelium,” said Chan. The others are made by heart or fat cells and migrate from those tissues to the endothelium.

Without the endothelial lipase, metabolism of HDL is a lot slower.

“That’s also why it accumulates and the levels of HDL are higher,” said Chan.

He and his colleagues tested metabolism by injecting HDL attached to a chemical that ‘labels’ it into mice. They could then watch what happened to the HDL.

“Under normal circumstances, it disappears over time because it is metabolized,” he said. However, when HDL is bigger, it appears that it is metabolized more slowly.

Because HDL has several different effects, it is not clear that just affecting one – the size of the particle and slower metabolism – is necessarily negative, he said.

“High HDL could have all these vascular protective functions,” he said. “On the other hand, will not having the endothelial lipase interrupt reverse transport (of cholesterol from the periphery of the body back to the liver)? It might at least slow it down. If it does, then whether it is good or bad will be a balance among all these other actions. These actions (that protect vascular health) are still there and are good, but if you cannot transfer cholesterol back to the liver for excretion, that’s probably not good. The question is which one is more important.”

When that question is answered and it is determined which of the variants are good for people, “then we can design drugs to increase or decrease activity, depending on what is better for you,” said Chan.

This work was supported by the National Institutes of Health, the Betty Rutherford Chair for Diabetes and Endocrinology Research (L.C.), a grant from Novartis Pharmaceuticals Corporation and Nijad Fares and Jeff Hines.

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