Regulation of LTP-I secretion from human monocyte-derived macrophages by differentiation and cholesterol accumulation in vitro.
Human macrophages in vitro synthesize and secrete the cholesteryl ester (CE) transfer protein, LTP-I. The effect of differentiation of monocyte-to-macrophage on the synthesis and secretion of LTP-I cholesteryl ester transfer activity was investigated. One marker of macrophage differentiation is expression of the 'scavenger' receptor, which mediates macrophage uptake and degradation of acetylated low-density lipoprotein. Monocytes secreted very little detectable CE transfer activity in the first 24 h following cell isolation. Both CE transfer activity and scavenger receptor activity increased with time in culture. Thus, although circulating monocytes probably do not secrete CE transfer activity, tissue macrophages such as hepatic Kupffer cells may contribute to plasma CE transfer activity. Resident macrophages of the arterial wall are derived from circulating monocytes which enter the vessel wall where they differentiate into macrophages. Such macrophages are the principal source of lipid-laden foam cells of the atherosclerotic plaque. Cholesterol accumulation results when uptake of lipoprotein cholesterol overwhelms the capacity of macrophages to excrete cholesterol. Since LTP-I is postulated to function in reverse cholesterol transport, the effect on LTP-I secretion of loading macrophages with cholesterol was determined after exposure of macrophages to acetylated-LDL or free cholesterol (FC). Cholesterol loading by both these maneuvers resulted in dose-dependent increases in macrophage secretion of CE transfer activity, and there was a significant positive correlation between CE transfer activity secreted and accumulation of CE. Thus, LTP-I may function at the cellular level in maintenance of lipid homeostasis: macrophage LTP-I secretion may be a protective mechanism in response to excess cholesterol accumulation in resident macrophages of the arterial wall.
Faust
R A
RA
Department of Medicine, University of Washington School of Medicine, Seattle.
Tollefson
J H
JH
Chait
A
A
Albers
J J
JJ
D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism*; D006023:Glycoproteins; D006801:Humans; D008071:Lipoprotein Lipase / Q000032:analysis; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000502:physiology
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D006023:Glycoproteins; D002784:Cholesterol; D008071:Lipoprotein Lipase