March 28, 2011

“Good Cholesterol” Comes Into Focus

Illustration of spherical cage-like structure ApoA-I molecules—each a different color—form a cage-like structure that surrounds the HDL particleW. Sean Davidson, University of Cincinnati.

Scientists have created a 3-D model of cholesterol carriers. The accomplishment could help explain why "good cholesterol" might be so good.

Cholesterol is transported in the blood in 2 forms: LDL and HDL. When there’s too much cholesterol in your bloodstream, the cholesterol from LDL (low-density lipoproteins, or “bad cholesterol”) can begin to coat the walls of your arteries, causing them to harden. Over time, this can increase your risk for developing cardiovascular diseases such as heart attack and stroke.

Studies suggest that the cholesterol from HDL (high-density lipoproteins or “good cholesterol”) may have the opposite effect. HDL particles are packages of protein and fat that pick up excess cholesterol in the blood and carry it to other parts of the body to be removed. Higher HDL levels may actually protect you from developing cardiovascular diseases. Because of this, researchers have been working to create drugs that help to raise levels of HDL. So far though, scientists don't have a clear explanation for why HDL might have a protective effect, which makes it difficult to mimic or enhance that effect with drugs.

For over 30 years, scientists have relied on synthetic HDL made in test tubes to study its structure and biology. However, according to Dr. W. Sean Davidson, professor at the University of Cincinnati, scientists could more fully understand the protective effects of HDL if they knew what naturally-occurring HDL looks like. This could help them discover how HDL interacts with other factors in human blood. Taking a step in the right direction, Davidson and team members have created the first ever 3-D model of HDL isolated from human blood.

In a study featured online on March 13, 2011, in Nature Structural and Molecular Biology, the researchers describe how they used cross-linking chemistry and mass spectrometry techniques to analyze the geometric configuration of human HDL proteins. They were able to model the structure of the abundant HDL protein, apolipoprotein A-I (apoA-I), which is known to play a key role in HDL's positive effect on cardiovascular health. The work was funded in part by NIH's National Heart, Lung and Blood Institute (NHLBI).

Davidson says the ApoA-I proteins surround the HDL particle much like the black lines of a basketball. This cage-like structure holds fats inside while also making them accessible to other proteins. The researchers found evidence that strands of apoA-I use a twisting motion to expand and contract as HDL particles take in and release fat.

The newly proposed model of human HDL is actually quite similar to the model suggested by studies done with synthetic HDL. Davidson and his team were surprised, however, to discover how much of the surface of HDL particles is dominated by apoA-I. This monopolization of the particle surface, Davidson says, suggests that other proteins have very little room to bind to HDL and instead interact directly with apoA-I. This could help explain apoA-I's protective effect.

"By isolating human HDL, we were able to focus on the broad range of HDL particles actually circulating in humans," says Davidson. The work has important implications for understanding the interactions between HDL and other molecules that help prevent cardiovascular disease.

— by Amy Alabaster

Related Links