Phytosterols differentially influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells.
Phytosterol supplements lower low-density lipoprotein (LDL) cholesterol, but accumulate in vascular lesions of patients and limit the anti-atherosclerotic effects of LDL lowering in apolipoprotein E (Apo E)-deficient mice, suggesting that the cholesterol-lowering benefit of phytosterol supplementation may not be fully realized. Individual phytosterols have cell-type specific effects that may be either beneficial or deleterious with respect to atherosclerosis, but little is known concerning their effects on macrophage function. The effects of phytosterols on ABCA1 and ABCG1 abundance, cholesterol efflux and inflammatory cytokine secretion were determined in cultured macrophage foam cells. Among the commonly consumed phytosterols, stigmasterol increased expression of ABCA1 and ABCG1 and increased efflux of cholesterol to apolipoprotein (Apo) AI and high-density lipoprotein (HDL). Campesterol and sitosterol had no effect on ABCA1 or ABCG1 levels. Sitosterol had no effect on cholesterol efflux to Apo AI or HDL, whereas campesterol had a modest but significant reduction in cholesterol efflux to HDL in THP-1 macrophages. Whereas stigmasterol blunted aggregated LDL (agLDL) induced increases in tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β secretion, sitosterol exacerbated these effects. The presence of campesterol had no effect on agLDL-induced inflammatory cytokine secretion from THP-1 macrophages. In conclusion, the presence of stigmasterol in modified lipoproteins promoted cholesterol efflux and suppressed inflammatory cytokine secretion in response to lipid loading in macrophage foam cells. While campesterol was largely inert, the presence of sitosterol increased the proinflammatory cytokine secretion.
Pharmaceutical Sciences, College of Pharmacy, Cardiovascular Research Center and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536-0082, USA.
Nadezhda S
NS
Sabeva
Christopher M
CM
McPhaul
Xiangan
X
Li
Theodore J
TJ
Cory
David J
DJ
Feola
Gregory A
GA
Graf
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives / Q000494:pharmacology; D005487:Foam Cells / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008074:Lipoproteins / Q000187:drug effects / Q000235:genetics; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010840:Phytosterols / Q000494:pharmacology; D012855:Sitosterols / Q000494:pharmacology*; D013265:Stigmasterol / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010840:Phytosterols; D012855:Sitosterols; D014409:Tumor Necrosis Factor-alpha; C021273:campesterol; C025473:gamma-sitosterol; D002784:Cholesterol; D013265:Stigmasterol