HEART
June 15, 2011

From Bad Cholesterol to Worse

LDL, is the bad artery-clogging lipoprotein. Now researchers have found something that makes it even stickier: sugar.

How can you make bad cholesterol worse? By adding sugar to it.

Researchers at the University of Warwick have found that when sugar binds to the protein LDL, it makes it stickier and more likely to attach to artery walls, an essential step in plaque formation. Plaque buildup on artery walls is a major cause of heart disease.

The findings may help explain why diabetics have such a high risk of heart disease.

The binding of sugar to LDL changes its shape, making it smaller and denser. It also changes which parts of the protein are at its surface--much stickier parts than in normal, sugar-free LDL.

Technically, bad cholesterol is cholesterol that's bound to the protein LDL. But sometimes LDL itself is called bad cholesterol. Current usage of the term varies and is inconsistent.

When sugar binds to substances in the blood that it normally would not bind to, the process is called glycation. People with Type 2 diabetes and the elderly are known to have a higher than average amount of glycated substances in their blood (mainly proteins), including glycated LDL. Some seem relatively benign, such as hemoglobin A1c, whose blood level is used as a yardstick of how high a person's blood sugar has been recently. Other glycated substances are more toxic.

Glycated LDL appears to be among the worst of them.

The Warwick researchers have been studying various aspects of glycation for many years. Here, they took normal human LDL and glycated it, using methylglyoxal, a substance known to form glycated LDL in diabetics. They then studied the modified LDL: its physical properties, effects on cells in culture and on rats when injected into the bloodstream.

They found that the binding of sugar to LDL changes its shape, making it smaller and denser. It also changes which parts of the protein are at its surface — much stickier parts than in normal, sugar-free LDL. Experiments with cultured cells showed that glycated LDL was much less likely to be scavenged — transported out of a cell once inside of it. And when injected into rats, glycated LDL had a higher tendency to stick to the rat aortal wall than normal LDL.

These results suggest that glycated LDL is not at all healthy. It's been dubbed "ultra-bad cholesterol."

The results also offer a possible explanation for why the diabetes drug metformin seems to lower the risk of heart disease. Because metformin lowers blood sugar, it should lead to lower amounts of glycated LDL being formed.

The researchers hope this study is a first step towards finding treatments that will neutralize the harmful effects of glycated LDL or prevent its formation in the first place.

An ahead-of-print article on the study was published online by the journal Diabetes on May 26, 2011. This article will also appear in a future print edition of the journal.

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