Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis

Abstract

Atheroprotective properties of human plasma high-density lipoproteins (HDLs) are determined by their involvement in reverse cholesterol transport (RCT) from the macrophage to the liver. ABCA1, ABCG1, and SR-BI cholesterol transporters are involved in cholesterol efflux from macrophages to lipid-free ApoA-I and HDL as a first RCT step. Molecular determinants of RCT efficiency that may possess diagnostic and therapeutic meaning remain largely unknown. This review summarizes the progress in studying the genomic variants of ABCA1, ABCG1, and SCARB1, and the regulation of their function at transcriptional and post-transcriptional levels in atherosclerosis. Defects in the structure and function of ABCA1, ABCG1, and SR-BI are caused by changes in the gene sequence, such as single nucleotide polymorphism or various mutations. In the transcription initiation of transporter genes, in addition to transcription factors, long noncoding RNA (lncRNA), transcription activators, and repressors are also involved. Furthermore, transcription is substantially influenced by the methylation of gene promoter regions. Post-transcriptional regulation involves microRNAs and lncRNAs, including circular RNAs. The potential biomarkers and targets for atheroprotection, based on molecular mechanisms of expression regulation for three transporter genes, are also discussed in this review.

Keywords: ABCA1; ABCG1; SCARB1; atherosclerosis; cholesterol efflux; gene expression.

Figure 1

The major steps in the reverse cholesterol transport (RCT) pathway. RCT denotes cholesterol movement from peripheral tissue cells, macrophages in particular, to the liver. The dash arrows correspond to cholesterol transport by ABCA1, ABCG1, and SR-B1 transporters to different cholesterol acceptors and solid arrows correspond to the transitions between different lipoprotein structures. Lipid-free/lipid-poor apoA-I is an exclusive acceptor of cholesterol and phospholipid molecules exported by ABCA1, while both nascent discoidal HDL and mature spherical HDL2 and HDL3 particles accept lipid molecules exported by ABCG1 and SR-B1. The initial complex of apoA-I, with a few molecules of cholesterol and phospholipid with pre-β1-mobility at agarose gel electrophoresis, continues to accept more cholesterol and phospholipid molecules and transforms to a discoidal HDL particle with pre-β-mobility. Discoidal HDL is an efficient substrate for cholesterol esterification catalyzed by lecithin-cholesterol acyl transferase (LCAT) with the appearance of HDL3 and HDL2 as the first and the second products with α-mobilities in sequential reactions of HDL maturation. The backward regeneration of HDL3 from HDL2 particles with the concomitant dissociation of lipid-free apoA-I is catalyzed by phospholipid-transfer protein (PLTP). Cholesteryl ester (CE) molecules in both HDL3 and HDL2 particles are selectively removed by the SR-B1 molecule in the hepatocyte membrane (direct RCT) or exchanged with LDL on triglyceride by cholesteryl ester transfer protein (CETP). CE-enriched LDL particles bind to the LDL-receptor (LDLR) in the hepatocyte membrane and internalize (indirect RCT). Finally, cholesterol in both unmodified and modified to bile acid forms enters the intestine for subsequent excretion with feces.