Serum, but not monocyte macrophage foam cells derived from low HDL-C subjects, displays reduced cholesterol efflux capacity

The main antiatherogenic function of HDL is to promote the efflux of cholesterol from peripheral cells and transport it to the liver for excretion in a process termed reverse cholesterol transport. The aim of this study was to evaluate the cholesterol efflux capacity in low- and high-HDL subjects by utilizing monocytes and serum from 18 low-HDL and 15 high-HDL subjects. Low and high HDL levels were defined, respectively, as HDL ≤10th and HDL ≥90th Finnish age/sex-specific percentile. Cholesterol efflux from [3H]cholesterol-oleate-acetyl-LDL-loaded monocyte-derived macrophages to standard apolipoprotein A-I (apoA-I), HDL2, and serum was measured. In addition, cholesterol efflux from acetyl-LDL-loaded human THP-1 macrophages to individual sera (0.5%) derived from the study subjects was evaluated. Cholesterol efflux to apoA-I, HDL2, and serum from macrophage foam cells derived from low- and high-HDL subjects was similar. The relative ABCA1 and ABCG1 mRNA expression levels in unloaded macrophages, as well as their protein levels in loaded macrophage foam cells, were similar in the two study groups. Cholesterol efflux from THP-1 foam cells to serum recovered from high-HDL subjects was slightly higher than that to serum from low-HDL subjects (P = 0.046). Cholesterol efflux from THP-1 macrophages to serum from study subjects correlated with serum apoB (P = 0.033), apoA-I (P = 0.004), apoA-II (P < 0.0001), and the percentage of apoA-I present in the form of preβ-HDL (P = 0.0001). Our data reveal that macrophages isolated from either low- or high-HDL subjects display similar cholesterol efflux capacity to exogenous acceptors. However, sera from low-HDL subjects have poorer cholesterol acceptor ability as compared with sera from high-HDL subjects. The main antiatherogenic function of HDL is to promote the efflux of cholesterol from peripheral cells and transport it to the liver for excretion in a process termed reverse cholesterol transport. The aim of this study was to evaluate the cholesterol efflux capacity in low- and high-HDL subjects by utilizing monocytes and serum from 18 low-HDL and 15 high-HDL subjects. Low and high HDL levels were defined, respectively, as HDL ≤10th and HDL ≥90th Finnish age/sex-specific percentile. Cholesterol efflux from [3H]cholesterol-oleate-acetyl-LDL-loaded monocyte-derived macrophages to standard apolipoprotein A-I (apoA-I), HDL2, and serum was measured. In addition, cholesterol efflux from acetyl-LDL-loaded human THP-1 macrophages to individual sera (0.5%) derived from the study subjects was evaluated. Cholesterol efflux to apoA-I, HDL2, and serum from macrophage foam cells derived from low- and high-HDL subjects was similar. The relative ABCA1 and ABCG1 mRNA expression levels in unloaded macrophages, as well as their protein levels in loaded macrophage foam cells, were similar in the two study groups. Cholesterol efflux from THP-1 foam cells to serum recovered from high-HDL subjects was slightly higher than that to serum from low-HDL subjects (P = 0.046). Cholesterol efflux from THP-1 macrophages to serum from study subjects correlated with serum apoB (P = 0.033), apoA-I (P = 0.004), apoA-II (P < 0.0001), and the percentage of apoA-I present in the form of preβ-HDL (P = 0.0001). Our data reveal that macrophages isolated from either low- or high-HDL subjects display similar cholesterol efflux capacity to exogenous acceptors. However, sera from low-HDL subjects have poorer cholesterol acceptor ability as compared with sera from high-HDL subjects. Epidemiological and observational studies have clearly demonstrated an inverse relationship between the risk of premature coronary heart disease (CHD) and the level of HLD-cholesterol (HDL-C) (1Gordon D.J. Probstfield J.L. Garrison R.J. Neaton J.D. Castelli W.P. Knoke J.D. Jacobs Jr., D.R. Bangdiwala S. Tyroler H.A. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.Circulation. 1989; 79: 8-15Crossref PubMed Scopus (2680) Google Scholar, 2Gordon T.W.P. Castelli M.C. Hjortland M.C. Kannel W.B. Dawber T.R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study.Am. J. Med. 1977; 62: 707-714Abstract Full Text PDF PubMed Scopus (4105) Google Scholar). The increased CHD risk associated with low HDL-C is apparent at all concentrations of LDL-cholesterol (LDL-C) (3Barter P. Gotto A.M. LaRosa J.C. Maroni J. Szarek M. Grundy S.M. Kastelein J.J. Bittner V. Fruchart J.C. 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Full Text PDF PubMed Google as a of protein from was loaded for of ABCA1 and for of were to and and were for of ABCA1 and and were for macrophages from low- and high-HDL subjects were to mRNA cholesterol mRNA was and as P. R.M. A.J. M. A. J. J. is associated with factor 2004; 36: PubMed Scopus Google Scholar). the was to the relative of was the the relative ABCA1 and ABCG1 expression levels between monocyte-derived macrophages isolated from low- and high-HDL the relative mRNA expression in was against the expression of the to in cells A. J. M. S. A. M. L. ABCA1 HDL and cellular cholesterol efflux in subjects with low HDL.J. Lipid Res. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, mRNA as well as expression levels of and were in unloaded monocyte-derived macrophages a similar to that THP-1 monocytes were from the American The monocytes were and in and at and the the monocytes into macrophages, the cells were and with in the for to the The macrophages were with and loaded by in the of of in with lipoprotein and for the cells were with and to cholesterol the THP-1 macrophages were in with and with the serum (0.5%) from the study subjects as a cholesterol for at the was and at for to remove cells. in the and cells and the protein of the were and cholesterol efflux was as in of and were with are as for and as or for with were the and were compared between by the in and are as < was The of the was compared between with the The of and were by and as and of the study subjects are The was similar in the two groups. apoA-I, and apoA-II were higher in the high-HDL the low-HDL subjects higher levels of and a and than high-HDL subjects. and were similar in the two and of the study heart disease cholesterol cholesterol cholesterol are as or The two from the are in a are as or The two from the are The of = and recovered by are In the low-HDL of their cholesterol was recovered in the in the high-HDL of the HDL cholesterol level of preβ-HDL particles in the two study was similar However, in the of the sera from low-HDL subjects higher levels of preβ-HDL percentage of as compared with the high-HDL = of HDL particles of the study are as in a are as the HDL in low- and high-HDL in low-HDL the particles were in high-HDL the large particles the of HDL and of all HDL particles in high-HDL subjects. low-HDL subjects HDL than high-HDL subjects. The of and of in the low-HDL subjects study macrophage foam cells derived from low- or high-HDL subjects display in cholesterol efflux to apoA-I and macrophage foam cells in the of acceptors Cholesterol efflux was similar from macrophages from low- = or = HDL subjects to apoA-I = to = and serum = The of ABCA1 and ABCG1 were in unloaded monocyte-derived of mRNA for the of ABCA1 were from low- and high-HDL subjects and for the of ABCG1 from low- and high-HDL subjects. The relative ABCA1 and ABCG1 mRNA expression levels in between low- and high-HDL subjects relative expression of ABCA1 low-HDL = high-HDL = = the relative expression of ABCG1 low-HDL = high-HDL = = In addition, expression of ABCA1 and ABCG1 protein in macrophage foam cells between low- and high-HDL subjects as by low-HDL = high-HDL = low HDL = low-HDL = high-HDL = low HDL = ABCA1 and ABCG1 are in the In addition, of the isolated macrophages by expression levels of the and The expression levels of were similar in low-HDL and high-HDL subjects. in between low-HDL subjects with or CHD the ability of sera from low- and high-HDL subjects to function as cholesterol human THP-1 macrophage foam cells Cholesterol efflux from THP-1 foam cells to serum from high-HDL subjects = was slightly higher than that to sera from low-HDL subjects = = 0.046). In addition, cholesterol efflux from THP-1 foam cells to individual sera a with serum apoB = = 0.033), apoA-I = = 0.004), and apoA-II = < as well as = = = = cholesterol = = = = percentage of preβ-HDL = = 0.0001), preβ-HDL = < 0.0001), preβ-HDL at = = and HDL-C = = between plasma concentrations of apoA-I and apoA-II and cholesterol efflux from THP-1 macrophage foam cells. The and the data from low-HDL subjects low-HDL subjects with and high-HDL In the low-HDL between apoA-I and apoA-II and cholesterol efflux from human THP-1 macrophages were (P = and (P = In the high-HDL between apoA-I and apoA-II and cholesterol efflux from human THP-1 macrophages were (P = and (P < 0.0001), The for apoA-I and apoA-II were between the low- and high-HDL (P = and serum and as well as to into of HDL between the low- and high-HDL subjects. and were similar between the two groups. low-HDL subjects higher and in serum in and their The slightly between the two the high-HDL subjects higher levels of mRNA expression levels in unloaded monocyte-derived macrophages, as well as serum were similar between low-HDL and high-HDL subjects. In this from low- and subjects display to cholesterol efflux or the sera derived from subjects as cholesterol acceptors. in the present that cholesterol efflux to apoA-I, HDL2, and standard serum was similar from macrophage foam cells derived from low- and high-HDL subjects. However, cholesterol efflux from THP-1 macrophage foam cells to serum recovered from high-HDL subjects was higher than that to serum from low-HDL subjects. The present data that macrophages derived from low-HDL subjects cholesterol efflux to apoA-I similar to isolated from the subjects A. J. M. S. A. M. L. ABCA1 HDL and cellular cholesterol efflux in subjects with low HDL.J. Lipid Res. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, of cholesterol efflux to or data that the ABCA1 the ABCG1 is were in cholesterol efflux levels in the low-HDL subjects with CHD = compared with CHD = ABCA1 or ABCG1 mRNA expression their protein levels in macrophages data in cholesterol efflux between the macrophages derived from low-HDL and high-HDL subjects. the in plasma HDL-C this is HDL levels and the of HDL-C is M. N. F. A. Fruchart J.C. and ABCA1 have and in the of plasma high-density lipoprotein cholesterol levels in 2006; PubMed Scopus Google Scholar). In with N. K. S. of isolated low HDL and of efflux Thromb. Vasc. Biol. 2007; PubMed Scopus Google the of low-HDL that a large of low-HDL subjects cholesterol efflux from isolated to apoA-I and of low-HDL subjects cellular cholesterol efflux the of subjects in that the of the monocytes and macrophages in low-HDL subjects may to the of low HDL to for this in L. N. M. M. K. M.R. D. of a in monocyte-derived macrophages from subjects with low plasma Thromb. Vasc. 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Biol. 2007; PubMed Scopus Google was and this factor in the in cholesterol efflux between low-HDL subjects. studies with a higher of study subjects are to the of the function of macrophages in cholesterol Another that is the that the study of of from Finnish low-HDL the of the present study of subjects from the and their or In to macrophage studies have the cholesterol efflux capacity to individual serum (4Fielding C.J Fielding P.E. Molecular physiology of reverse cholesterol transport.J. Lipid Res. 1995; 36: 211-228Abstract Full Text PDF PubMed Google Scholar). Cholesterol efflux from THP-1 macrophages to the individual sera a with serum apoA-I, relative and of and ABCG1 mediates cholesterol efflux to HDL to a to N. Lan D. Chen W. Matsuura F. Tall A.R. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins.Proc. Natl. Acad. Sci. USA. 2004; 101: 9774-9779Crossref PubMed Scopus (889) Google Scholar). 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Matsuura F. Tall A.R. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins.Proc. Natl. Acad. Sci. USA. 2004; 101: 9774-9779Crossref PubMed Scopus (889) Google Scholar, I.C Harris M. Rye K.A. Quinn C. Brown A.J. Kockx M. Cartland S. Packianathan M. Kritharides L. Jessup W. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I..Arterioscler. Thromb. Vasc. Biol. 2006; 26: 534-540Crossref PubMed Scopus (344) Google Scholar, N. J.L. V. A. M. N. HDL and as a factor cholesterol efflux capacity from cells to human Thromb. Vasc. Biol. PubMed Scopus Google Scholar). In with studies S. A. C. M. M.R. is associated with concentrations in subjects with low HDL.J. Lipid Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. A. C. C. M. high-density lipoprotein and large HDL in Finnish low-HDL relationship with Thromb. Vasc. 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S. apolipoprotein atherosclerosis and premature in apolipoprotein and Thromb. Vasc. Biol. 2006; 26: PubMed Scopus Google Scholar). The in cholesterol efflux between sera from the two by in the serum levels of and the level between the low- and high-HDL subjects. was increased in the high-HDL of the of the of has associated with is the relationship between and disease. an inverse relationship between serum and CHD risk was K. K. M. C. protein as a protective factor for coronary heart J. 2004; PubMed Scopus Google Scholar). However, the role of are to the present the of low-HDL and high-HDL subjects for the cholesterol efflux the macrophages from isolated monocytes may represent cells in the the of cholesterol data higher cholesterol efflux to serum from high-HDL it have to cholesterol efflux to HDL isolated from the study subjects. In isolated from either low- or high-HDL subjects in their ability to cholesterol efflux to exogenous apoA-I, HDL2, and However, serum from high-HDL subjects higher cholesterol efflux from THP-1 macrophage foam cells than serum from low-HDL to the higher of and preβ-HDL The low levels of and preβ-HDL particles may the efflux capacity and promote atherosclerosis in low-HDL subjects. it is very to that HDL level as HDL-C level is a to the of HDL-C coronary disease higher HDL-C levels may a protective Our study that the of the of HDL is antiatherogenic of serum and ability to function as a cholesterol this is an and has to HDL levels are The the and the subjects for in the and are for their