HDL as a biomarker, potential therapeutic target, and therapy.

Abstract

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, …