The metabolism and anti-atherogenic properties of HDL

Abstract

Population studies have shown that plasma HDL levels correlate inversely with cardiovascular disease risk. In recent years there has been intense interest in developing strategies for exploiting these cardioprotective properties by increasing HDL levels. While this approach has considerable merit, it is important to recognize that HDL are structurally and functionally diverse and consist of numerous, highly dynamic subpopulations of particles that do not all inhibit atherosclerosis to the same extent. For this reason it is essential to assess HDL subpopulation distribution and functionality when considering therapeutic interventions that raise HDL levels. This review documents what is known about the relationship between the metabolism and function of HDL subpopulations and how this affects their cardioprotective properties.-Rye, K-A., C. A. Bursill, G. Lambert, F. Tabet, and P. J. Barter. The metabolism and anti-atherogenic properties of HDL. J. Lipid Res. 2009. 50: S195-S200.Supplementary key words HDL remodelling • HDL subpopulations • HDL function HDL, the smallest and most dense of all plasma lipoproteins, consist of several distinct subpopulations of particles that vary in size, shape, density, surface charge, and composition. An inverse relationship between HDL levels and premature cardiovascular disease has been observed in many large-scale prospective studies (1, 2). This relationship is also evident in animal studies (3,4).HDL have several potentially anti-atherogenic properties. The best known of these is their ability to remove cholesterol from cells, such as macrophages in the artery wall, in the first step of the reverse cholesterol transport pathway (5). HDL also inhibit LDL oxidation (6), promote endothelial repair (7), improve endothelial function (8), have anti-thrombotic and anti-inflammatory properties (8, 9), and inhibit the binding of monocytes to the endothelium (10). In addition to preventing atherosclerotic lesion progression, HDL also promote lesion regression in animals (11, 12).This review presents evidence that several of the aforementioned anti-atherogenic functions of HDL are mediated by specific subpopulations of particles. To appreciate this functional diversity, it is important to understand something of the origins and heterogeneity of HDL subpopulations. ORIGINS OF HDLHDL originate as discoidal particles that are either secreted from the liver or assembled in the plasma from the individual constituents. Discoidal HDL consist of two or more apolipoprotein molecules complexed with phospholipids and unesterified cholesterol (Fig. 1A). These particles are excellent substrates for LCAT, the enzyme that generates most of the cholesteryl esters in plasma (13). Cholesteryl esters are extremely hydrophobic and partition into the center of the particles as they are formed. This converts discoidal HDL into the large spherical HDL particles that predominate in normal human plasma. It also depletes the HDL surface of cholesterol and establishes a concentration gradient down which ...

Modification in Oxidative Stress, Inflammation, and Lipoprotein Assembly in Response to Hepatocyte Nuclear Factor 4α Knockdown in Intestinal Epithelial Cells

“…The present experiments could demonstrate that HNF4␣ shRNA-infected cells resulted in the reduced capacity of intestinal Caco-2 cells to produce HDL and its major protein component, apoA-I. Various investigations reported that HDL and apoA-I protect against the development of atherosclerosis by mediating reverse cholesterol transport, a pathway by which excess cholesterol is removed from peripheral cells such as plaque macrophages to the liver for excretion (74,75). Subsequently, HDL and apoA-I were shown to inhibit inflammatory and oxidative damage, a situation in concordance with our observations depicting a lower output of HDL and apoA-I along with pro-inflammatory and pro-oxidant events in HNF4␣-depleted Caco-2 cells.…”

Apolipoprotein A-I: A Molecule of Diverse Function

“…Interestingly, a vast number of studies of HDL have suggested a list of expanded activities for the lipoprotein beyond simply contributing as a cholesterol carrier from tissues to liver. This includes anti-inflammatory, anti-parasitic, anti-apoptotic, and innate immune activities [16][17][18]. As an antiinflammatory molecule it mediates its action with the vascular endothelium and circulating inflammatory cells [16][17][18].…”

“…This includes anti-inflammatory, anti-parasitic, anti-apoptotic, and innate immune activities [16][17][18]. As an antiinflammatory molecule it mediates its action with the vascular endothelium and circulating inflammatory cells [16][17][18]. Apo A-I exhibits its anti-parasitic effect function by forming a complex with apolipoprotein L1, a minor apolipoprotein component of HDL, a parasite-specific lysosomal pore forming protein, a trypanosome lytic factor (Fig.…”

Vitamin D status and metabolic syndrome in the elderly: the Rotterdam Study

“…Firstly, vitamin D influences formation of HDL particles (26,27,28,29,30). Secondly, serum 25(OH)D inhibits adipocyte differentiation and may thereby influence the development of adiposity (9).…”