Hyperalphalipoproteinemia and Beyond: The Role of HDL in Cardiovascular Diseases

Abstract

Hyperalphalipoproteinemia (HALP) is a lipid disorder characterized by elevated plasma high-density lipoprotein cholesterol (HDL-C) levels above the 90th percentile of the distribution of HDL-C values in the general population. Secondary non-genetic factors such as drugs, pregnancy, alcohol intake, and liver diseases might induce HDL increases. Primary forms of HALP are caused by mutations in the genes coding for cholesteryl ester transfer protein (CETP), hepatic lipase (HL), apolipoprotein C-III (apo C-III), scavenger receptor class B type I (SR-BI) and endothelial lipase (EL). However, in the last decades, genome-wide association studies (GWAS) have also suggested a polygenic inheritance of hyperalphalipoproteinemia. Epidemiological studies have suggested that HDL-C is inversely correlated with cardiovascular (CV) risk, but recent Mendelian randomization data have shown a lack of atheroprotective causal effects of HDL-C. This review will focus on primary forms of HALP, the role of polygenic inheritance on HDL-C, associated risk for cardiovascular diseases and possible treatment options.

Keywords: CETP; HDL; cardiovascular disease; hyperalphalipoproteinemia; polymorphisms.

Figure 1

Schematic representation of the biogenesis of HDL. The first step in HDL biogenesis begins with the secretion of Apo-A1 by the liver and the intestine. The lipid-poor Apo-A1 then interacts with ABCA1 and progressively gains phospholipids (PL) and free cholesterol (FC) from the cells. The lipidated apoA-I is gradually converted to discoidal particles composed of unesterified cholesterol. Then, the enzyme lecithin/cholesterol acyltransferase (LCAT) esterifies the FC and the discoidal HDLs are finally converted to spherical HDL particles containing Apo-A1, Apo-E or Apo-A4: secondary causes of hyperalphalipoproteinemia.

Figure 2

Schematic representation of the Reverse Cholesterol Transport (RCT) mechanism. In the RCT process, the ApoA-I receives the cholesterol from the foam cells (macrophages) through the ATP-binding cassette transporter member 1 (ABCA1) (1), leading HDL to become mature in a mechanism mediated by the transporter ABCG1 (2). The Lecitin:cholesterol acyltransferase (LCAT) (3) esterifies the free cholesterol (FC) thus contributing to form mature and spherical HDLs formed of a cholesteryl ester (CE) core. Finally, HDLs bind to the scavenger receptor class B type-1 (SR-B1) in the liver (4) and are selectively removed from the blood stream.