Study Title:

The New World of HDL Cholesterol

Study Abstract

Clinical and epidemiological studies have shown that HDLs, a class of plasma lipoproteins, heterogeneous in size and density, have an atheroprotective role attributed, for years, to their capacity to promote the efflux of cholesterol from activated cholesterol-loaded arterial macrophages. Recent studies, however, have recognized that the physical heterogeneity of HDLs is associated with multiple functions that involve both the protein and the lipid components of these particles. ApoA-I, quantitatively the major protein constituent, has an amphipathic structure suited for transport of lipids. It readily interacts with the ATP-binding cassette transporter ABCA1, the SR-B1 scavenger receptor; activates the enzyme lecithin-cholesterol acyl transferase (LCAT), which is critical for HDL maturation. It also has antioxidant and antiinflammatory properties, along with the HDL-associated enzymes paraoxonase, platelet activating factor acetylhydrolase (PAF), and glutathione peroxidase. Regarding the lipid moiety, an atheroprotective role has been recognized for lysosphingolipids, particularly sphingosine-1-phosphate (S1P). All of these atheroprotective functions are lost in the post-translational dependent dysfunctional plasma HDLs of subjects with systemic inflammation, coronary heart disease, diabetes, and chronic renal disease. The emerging notion that particle quality has more predictive power than quantity has stimulated further exploration of the HDL proteome, already revealing unsuspected pro- or antiatherogenic proteins/peptides associated with HDL.

For a number of years, HDL has been identified as serving an atheroprotective role by promoting reverse cholesterol transport, a process facilitating the efflux of cholesterol from cholesterol-loaded macrophages in the artery wall. This notion has been in keeping with the information derived from epidemiological studies indicating an inverse relationship between low plasma HDL cholesterol levels and coronary disease. Subsequent structural-functional studies have drawn attention to the critical role played by the unique helical make up of the two constitutive protein components of HDL, ApoA-I and ApoA-II. In particular, ApoA-I has been the most abundant and most extensively studied of the two, having besides its ready tendency to undergo delipidation/relipidation both in vitro and in vivo, the ability to interact with the ATP-binding cassette transporter ABC1 and the SR-B1 hepatic receptor as well as activate LCAT. Besides these lipid-related functions, apoA-I has gained increasing recognition for its antioxidant and antiinflammatory properties and even as a modulator of innate immunity. With the introduction of advanced MS techniques, quantitatively 100 "minor" proteins, some related and some unrelated to lipoprotein metabolism, have been identified in addition to special HDL associated lysosphingolipids with an atheroprotective role. We have now come to view the various subclasses of HDL as "dynamic platforms" harboring at their surface, proteins/peptides, mobilized from tissues likely via the ubiquitous ATP-binding cassette transporters Fig. 5 . We have also come to recognize that in the presence of systemic inflammatory settings, apolipoproteins and lipids may lose their atheroprotective role so that, for instance, high plasma levels of HDL rather than protective may be proatherogenic. Conversely, low plasma levels such as in familial hypoalphalipoproteinemia, the loss of protectiveness will result in a proatherogenic profile. From the therapeutic viewpoint, we have seen the promising entry into the clinical arena of ApoA-I mimetic peptides properly designed to favor the redistribution of HDL into atheroprotective prebeta migrating species. Clearly, the HDL field is ripe for systems biology studies in which interdisciplinary approaches lead to a clarification of the many unknowns that still surround this complex lipoprotein class.

From press release:

If you think your levels of "good cholesterol" are good enough, a new study published in the December 2008 issue of The FASEB Journal suggests that you may want to think again. In the report, researchers from the University of Chicago challenge the conventional wisdom that simply having high levels of good cholesterol (HDL) and low levels of bad cholesterol (LDL) is necessary for good heath.

Instead, they show that the good cholesterol has varying degrees of quality and that poor quality HDL is actually bad for you.

"For many years, HDL has been viewed as good cholesterol and has generated a false perception that the more HDL in the blood, the better," said Angelo Scanu, M.D., a pioneer in blood lipid chemistry from University of Chicago and first author of the study. "It is now apparent that subjects with high HDL are not necessarily protected from heart problems and should ask their doctor to find out whether their HDL is good or bad."

The researchers came to this conclusion after reviewing published research on this subject. In their review, they found that the HDL from people with chronic diseases such as rheumatoid arthritis, kidney disease, and diabetes is different from the HDL in healthy individuals, even when blood levels of HDL are comparable. They observed that normal, "good," HDL reduces inflammation, while the dysfunctional, "bad," HDL does not.

"This is yet one more line of research that explains why some people can have perfect cholesterol levels, but still develop cardiovascular disease," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Just as the discovery of good and bad cholesterol rewrote the book on cholesterol management, the realization that some of the 'good cholesterol' is actually bad will do the same."

High Cholesterol

According to the U.S. Centers for Disease Control and Prevention, approximately 17 percent of all American adults have high total cholesterol, putting them at risk for heart disease. Cholesterol is a waxy, fat-like substance used by the body to maintain the proper function of cell membranes and is encapsulated within two types of proteins as it travels in the body—low density lipoproteins (LDL) and high density lipoproteins (HDL). High levels of LDL or total cholesterol are an indicator of increased risk for heart disease. High blood cholesterol elicits no physical symptoms, making medical screenings necessary for detection.

Study Information

Angelo M. Scanu and Celina Edelstein.
HDL: bridging past and present with a look at the future.
The FASEB Journal.
2008 December
University of Chicago.

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