Inhibitory effects of HepG2 cell-derived apolipoprotein A-I-containing lipoproteins on cholesteryl ester accumulation in macrophages.
We investigated the mechanisms of inhibitory effects on foam cell formation of apolipoprotein A-I-containing lipoproteins secreted by HepG2 cells (HepG2-HDL) using mouse peritoneal macrophages. When macrophages were incubated with acetylated low-density lipoprotein (acetyl-LDL) in the presence of HepG2-HDL, cholesterol ester (CE) accumulation in cells was reduced by 63%. This inhibitory capacity was almost similar to that of plasma high-density lipoprotein (HDL). When macrophages were converted to foam cells with acetyl-LDL and then reacted with HepG2-HDL or plasma HDL, the HDL-induced CE reduction was 2.2-fold greater than HepG2-HDL. Similar results were obtained using apo E-free HepG2-HDL. Since the inhibitory effect of HDL on acetyl-LDL-induced CE accumulation in macrophages is due largely to its cholesterol efflux capacity, these results suggest the presence of an additional mechanism for the inhibition of CE accumulation by HepG2-HDL. To investigate the mechanism, acetyl-LDL was reisolated from HepG2-HDL by Sephacryl S-300 gel filtration after incubation in a cell-free system. Reisolated acetyl-LDL showed a significant reduction in electrophoretic mobility. The extent of CE accumulation by reisolated acetyl-LDL was reduced by 20% compared with control acetyl-LDL. Moreover, its endocytic degradation by macrophages was reduced by 28%. HepG2-HDL also inhibited macrophage degradation of acetyl-LDL as well as oxidized LDL, a likely atherogenic lipoprotein. This inhibitory effect was ascribed to the HepG2-HDL subfraction containing pre-beta HDL. Our results indicated that apo A-I-containing lipoproteins as a physiological model of nascent HDL may inhibit foam cell formation by reducing ligand activity of atherogenic lipoproteins. These data possibly suggest inhibitory function of nascent HDL for the formation of foam cells in vivo.
Kawano
T
T
Department of Biochemistry, Kumamoto University School of Medicine, Japan.
Hakamata
H
H
Ohta
T
T
Ding
Y
Y
Yoshida
M
M
Ueda
S
S
Horiuchi
S
S
D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000378:metabolism; D005591:Chemical Fractionation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002788:Cholesterol Esters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018197:Hepatoblastoma / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein