HDL as a Biomarker, Potential Therapeutic Target, and Therapy

Emerging evidence suggests that HDL function is not always accurately predicted by HDL cholesterol levels. The functions of HDL include reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of the innate immune system. In healthy individuals, in the absence of systemic oxidative stress and inflammation, HDL is anti-inflammatory. However, in those with chronic illnesses such as diabetes that are characterized by systemic oxidative stress and inflammation, HDL may actually promote the inflammatory response (i.e., it may become proinflammatory). HDL may be thought of as a shuttle. The size of the shuttle can be estimated by HDL cholesterol levels. The shuttle’s cargo can change dramatically from one that efficiently promotes reverse cholesterol transport and is anti-inflammatory to one that is less effective in promoting reverse cholesterol transport and is also proinflammatory without any change in the size of the shuttle (i.e., these changes in HDL cargo can occur without any change in HDL cholesterol levels). Understanding these issues may lead to improved use of HDL as a biomarker and may also lead to new therapeutic targets and therapies. HDL can modulate LDL oxidation. Lipoproteins evolved to facilitate the extracellular transport of lipids in multicellular organisms. The major protein in LDL is apolipoprotein (apo)-B. This protein contains a binding domain that causes LDL to be deposited in the extracellular matrix of many tissues, particularly in arteries that are predisposed to atherosclerosis. As a result of the binding of apoB-containing proteins to extracellular matrix molecules, the concentration of apoB in the subendothelial space of even normal arteries is twofold higher than in plasma (1). The deposition of LDL in the extracellular matrix of the subendothelial space predisposes it to oxidation. The oxidized lipids that result evoke a tissue response similar to that which occurs in response to a Mycobacterium (2,3). Unlike LDL, HDLs do not normally bind to extracellular matrix molecules, and the concentration of the main protein in HDL (apoA-I) in the subendothelial space of normal arteries is only one-fifth the concentration found in plasma (1). Adding LDL to an artery wall model constructed from cultured human aortic endothelial and smooth muscle resulted in LDL being deposited in the subendothelial space where the cells oxidized the LDL lipids. This caused the cells to synthesize and secrete monocyte chemoattractant protein (MCP)-1, which evokes a potent inflammatory response of the type seen in atherosclerosis. Addition of normal HDL abolished this process, indicating that normal HDL is capable of preventing LDL oxidation and the inflammatory response induced by LDL (4). The acute-phase response changes HDL’s ability to inhibit LDL oxidation. Van Lenten et al. (5) were the first to report that HDL loses its ability to inhibit LDL oxidation during the acute-phase response. HDL from normal rabbits and humans prior to elective surgery prevented LDL oxidation and prevented LDL-induced MCP-1 production (measured by a bioassay) in cultures of human artery wall cells. In contrast, HDL from the same rabbits or humans, isolated at the peak of an acute-phase response, was less effective in inhibiting LDL oxidation and actually increased LDL-induced MCP-1 production (5). This change in HDL was paralleled by changes in HDL composition. Among the changes noted at the peak of the acute-phase response was a decrease in activity of two HDL-associated enzymes, paraoxonase-1 (PON1) and platelet-activating factor acetylhydrolase (PAF-AH). Upon resolution of the acute-phase response, these HDL-associated enzyme activities returned toward baseline and the anti-inflammatory properties of the HDL were restored (5). Subsequently, it was found that these enzymes were partly responsible for the ability of normal HDL to inhibit proinflammatory LDL-derived oxidized lipids (6–8). The ability of HDL to prevent the formation of LDL-derived oxidized lipids or to inactivate them was determined to be a major factor in identifying the anti-inflammatory properties of HDL (9,10). The chronic acute-phase response. Gabay and Kushner (11) noted that many chronic disease states are associated with a chronic acute-phase response defined by the persistent presence of acute-phase reactants in the plasma. By this definition, diseases characterized by persistent elevations of acute-phase reactants such as C-reactive protein (CRP) are examples of a chronic acute-phase response. The important clinical implications of the persistent elevations of these plasma biomarkers in chronic disease states have been extensively studied (12–14). HDL in diabetes, the metabolic syndrome, obesity, and familial hypercholesterolemia. Hedrick et al. (15) found that glycation of HDL by incubation under hyperglycemic conditions caused the HDL to lose its ability to inhibit monocyte adhesion to human aortic endothelial cells exposed to oxidized LDL. Glycation of the HDLassociated enzyme PON1 also prevented its ability to inhibit monocyte adhesion to the endothelial cells. In From the Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and the Atherosclerosis Research Unit, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. Corresponding author: Mohamad Navab, [email protected]. Received 11 April 2009 and accepted 3 September 2009. DOI: 10.2337/db09-0538 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. PERSPECTIVES IN DIABETES