Relation of High‐Density Lipoprotein Charge Heterogeneity, Cholesterol Efflux Capacity, and the Expression of High‐Density Lipoprotein‐Related Genes in Mononuclear Cells to the HDL‐Cholesterol Level

Abstract

The heterogeneity and content of human plasma high‐density lipoprotein (HDL) related to their atheroprotective properties determined by various molecular and cellular mechanisms still remain to be completely clarified. For 29 atherosclerosis‐free male subjects, we studied the relationship of plasma lipid levels and the content of apolipoprotein A‐I (apoA‐I)‐containing HDL with preβ‐electrophoretic mobility, the efficiency of BODIPY‐cholesterol efflux from RAW 264.7 macrophages to apolipoprotein B (apoB)‐deficient plasma, and the expression level of 22 genes related to HDL metabolism in mononuclear cells. A significant decrease in the absolute content of apoA‐I in preβ‐HDL was found in subjects with hypoalphalipoproteinemia compared with the subjects with hyperalphalipoproteinemia. The preβ‐to‐α‐ratio of the apoA‐I content was constant within the HDL‐cholesterol (HDL‐C) range 0.59 to 2.24 mM. However, this ratio was significantly increased with an increase in the plasma triacylglycerol (TAG) content from 0.59 to 3.42 mM. A correlation of the level of preβ‐HDL with the basal and ABCA1‐mediated efflux of cholesterol is shown. The transcript levels for six HDL‐metabolizing genes (LDLR, LCAT, ABCA1, SCARB1, ZDHHC8, and BMP1) were decreased, while the transcript level of APOA1 gene was increased in mononuclear cells of subjects with hyperalphalipoproteinemia as compared with subjects with hypoalphalipoproteinemia. A reduction of the intracellular cholesterol level and inhibition of the expression of cholesterol transporters by nascent HDL in mononuclear cells from subjects with hyperalphalipoproteinemia are suggested. Hyperalphalipoproteinemia can be a driving force of the decreased flux of cholesteryl ester to the liver and the increased TAG hydrolysis. The atheroprotective effect of preβ‐HDL in hypertriglyceridemia is proposed.

HDL cholesterol is associated with pbmc expression of genes involved in HDL metabolism and atherogenesis

“…Four gene transcripts (CUBN, HDLBP, PRKACB, and PRKACG) negatively correlated with HDL-C in the present study. The significant decrease of HDLBP which expression is upregulated by intracellular cholesterol loading (27), thus confirms our earlier suggestion (14) on the decreased level of cholesterol in PBMC at hyperalphalipoproteinemia. Additionally, the decrease of the CUBN transcript, which codes the receptor for apoA-I and HDL (25), may result in an increase of HDL level.…”

“…The positive correlation between HDL-C and APOA1 transcript existed among 22 HDL-related genes, while ten gene transcripts (ABCA1, BMP1, CUBN, HDLBP, LCAT, LDLR, PRKACB, PRKACG, SCARB1 and ZDHHC8) correlated negatively; they included six genes mentioned earlier (14). Four gene transcripts (CUBN, HDLBP, PRKACB, and PRKACG) negatively correlated with HDL-C in the present study.…”

“…Primer structures and coordinates according to mRNA for forty-one genes involved in atherogenesis and for two HDL-related LDLR and LIPC genes are given in Table II. We described earlier the primers for three housekeeping GAPDH, RPL3 and LDHA genes and for twenty HDLrelated genes ABCA1, ABCG1, SCARB1, CETP, PRKACA, PRKACB, PRKACG, LCAT, HDLBP, ZDHHC8, A2M, AMN, ALB, CUBN, BMP1, LPL, PLTP, APOA1, APOE and APOC2 (14). Analysis of primer specificity and protocol of real-time quantitative polymerase chain reaction (qPCR) were performed as previously described (14).…”

“…In addition, 41 genes involved in inflammation and other atherogenesisprone processes (atherogene cluster) were included based on the GWAS data on differentially expressed genes in PBMC in atherosclerosis versus control and RT-PCR data (13). In a pilot study with a small group of patients without coronary atherosclerosis, we com-pared the expression of HDL cluster genes in PBMC, HDL charge heterogeneity and cholesterol acceptor capacity of patient HDL in cholesterol efflux assay (14). The expression of several HDL-related genes, cholesterol efflux efficiency and concentration of preb-HDL significantly differed between hypo-and hyperalphalipoproteinemics (14).…”

“…In a pilot study with a small group of patients without coronary atherosclerosis, we com-pared the expression of HDL cluster genes in PBMC, HDL charge heterogeneity and cholesterol acceptor capacity of patient HDL in cholesterol efflux assay (14). The expression of several HDL-related genes, cholesterol efflux efficiency and concentration of preb-HDL significantly differed between hypo-and hyperalphalipoproteinemics (14). However, the joint consideration of the expression of atheroprotective and pro-atherogenic genes in relation to HDL-C level in the same group of patients is still lacking.…”