Determinants of Plasma HDL Cholesterol Levels

Twin studies have indicated that genetic and environmental parameters equally contribute to the levels of cholesterol in HDL in the blood (Goode et al. 2007). This paragraph only shortly describes the major primary and secondary regulators of HDL cholesterol. It is important to underscore, however, that changes in HDL cholesterol without changes in other plasma lipid traits are very rare. They are mostly seen in the context of changes in plasma triglycerides. At the population level, genome-wide association (GWA) studies have recently confirmed that in many cases, genetic variation is associated with changes in more than one lipid trait (Teslovich et al. 2010; Willer et al. 2013).

Established Primary Regulators of Plasma HDL Cholesterol

For the de novo production of HDL, the small intestine and liver need to produce apolipoprotein (apo) A-I, ATP-binding cassette protein A1, and lecithin–cholesterol acyltransferase encoded by the APOAI, ABCA1, and LCAT genes, respectively. When the production of any of these proteins is attenuated (through functional large-impact mutations), it immediately translates into a reduction of HDL cholesterol in the circulation. Other established modulators of HDL are cholesteryl ester transfer protein (encoded by CETP) and scavenger receptor class B member 1 (SRB1, encoded by SCARB1). While CETP mediates the transfer of cholesterol ester from HDL to triglyceride-rich lipoproteins in exchange for triglycerides (thereby controlling the levels of cholesteryl ester in HDL), SRB1 mediates the selective cellular uptake of cholesteryl ester in the liver and steroidogenic organs. Figure 1 gives a schematic representation of how the above genes relate to HDL biology.

Fig. 1 A schematic presentation of factors that control HDL synthesis/binding and/or HDL-mediated cellular cholesterol homeostasis. The genes in the white boxes encode for key HDL proteins and enzymes, while the genes in the blue boxes encode for less established (new) factors that affect HDL metabolism. The roles of the genes in the gray boxes are addressed but solid evidence has not yet been provided. Abbreviations (proteins encoded by the gene names): ABCA1 ATP-binding cassette A1, ABCG1 ATP-binding cassette G1, APOAI apolipoprotein A-I, APOF apolipoprotein F, APOM apolipoprotein M, BMP1 bone morphogenetic protein-1, GLCE glucuronic acid epimerase, LCAT lecithin–cholesterol acyltransferase, PCPE2 procollagen C-proteinase enhancer 2, PCYT1 CTP:phosphocholine cytidylyltransferase alpha, SCARB1 encoding for scavenger receptor class B member 1

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