Effect of 17 beta-estradiol on metabolism of acetylated low-density lipoprotein by THP-1 macrophages in culture.
Evidence from numerous epidemiological and animal studies has shown a protective effect of estrogens on the development of atherosclerosis. Since not all of the beneficial effects of estrogen can be explained by alterations in plasma lipoprotein profiles, estrogens may have a direct effect on the arterial wall on one or more of the key steps in the pathogenesis of atherosclerosis. In the present study we tested the hypothesis that estrogens decrease macrophage foam cell formation by reducing lipoprotein uptake via the scavenger receptor pathway. Incubation of the human THP-1 macrophage cell line with 17 beta-estradiol reduced the uptake and metabolism of 125 I-labeled human acetylated LDL (acLDL) in a concentration-dependent manner (from 10(-9) to 10(-5) mol/L) by 30% to 40% at the highest concentrations used. This decrease was accompanied by a reduction in cholesterol accumulation and esterification. When chloroquine was used to block lysosomal degradation, 17 beta-estradiol retained its ability to decrease accumulation of acLDL. This finding suggested that the effect of estrogen occurs before degradation of acLDL by lysosomes. 17 beta-Estradiol had no effect on binding of 125I-acLDL at 4 degrees C. When 125I-acLDL was bound at 4 degrees C and warmed to 37 degrees C, less acLDL was internalized and degraded in cells treated with 17 beta-estradiol, due to greater dissociation of the bound acLDL from the surface of estrogen-treated cells during internalization. We conclude that as a result of the estrogen-induced increase in dissociation of acLDL, less lipoprotein cholesterol is delivered to macrophages, resulting in a reduced rate of foam cell formation. This may be one mechanism by which estrogens reduce the development of atherosclerosis.
Sulistiyani
Department of Pathology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1072, USA.
St Clair
R W
RW
D000818:Animals; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004951:Esterification / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D009994:Osmolar Concentration; D011817:Rabbits; D013696:Temperature
D008077:Lipoproteins, LDL; C032629:acetyl-LDL; D004958:Estradiol; D002738:Chloroquine; D002784:Cholesterol