Structure Of HDL Cholesterol Determined

May 24, 1999

Using novel methods for performing infrared spectroscopy recently developed in his laboratory, assistant professor of pharmacology Paul H. Axelsen, MD, and his colleagues have resolved a contentious scientific debate over the structure of high-density lipoproteins, or HDL particles, the so-called "good" cholesterol.

The team's findings are reported in the May 21 issue of the Journal of Biological Chemistry. HDL is thought to be responsible for ferrying cholesterol from various body tissues to the liver for reprocessing or elimination. In this way, HDL particles are thought to play a crucial role in reducing the risk of atherosclerotic cardiovascular disease. Prior to this study, many scientists thought HDL particles consisted of two-layered disks of fatty molecules, or lipids, surrounded by a "picket fence" of proteins at the disk's edge. A smaller number of investigators also believed that the lipid molecules comprised a two-layered disk, but that the proteins surrounding the disk were wrapped around the disk's perimeter in a "belt" formation. Existing tools for determining molecular structure were technically limited, leaving advocates for the competing models of HDL's structure at odds and without means to resolve the controversy. The best known tool for determining molecular structure,

X-ray crystallography, could not be employed because no one knows how to form HDL particles into the requisite crystals. NMR and older forms of infrared spectroscopy both require samples to be dried at one point in their preparation.

However, lipoprotein structures are disrupted in the drying process, because they are held together by their mutual repulsion from water, a phenomenon known as the hydrophobic effect. The novel infrared spectroscopy methodology developed by Axelsen and his coworkers enabled them to study HDL particles in water and in their native state. Their results verify the lipid bilayer structure in the particles, presumed in both the "picket fence" and "belt" models, and point unambiguously to the belt model for the orientation of the surrounding proteins.

"These findings turn our understanding of HDL structure, not on its head but on its side," Axelsen says. "It's now clear that the proteins in HDL are rotated 90 degrees from what had been the prevailing view."

University of Pennsylvania School of Medicine

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