Sterol 27-hydroxylase- and apoAI/phospholipid-mediated efflux of cholesterol from cholesterol-laden macrophages: evidence for an inverse relation between the two mechanisms.
Cholesterol-laden, human monocyte-derived macrophages were found to contain 27-hydroxycholesterol in proportion to their content of cholesterol ester. In accordance with previous work with human lung alveolar macrophages, there was a significant efflux of 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid from the cultured cells. The efflux of 27-hydroxycholesterol was proportional to the cellular content of this steroid. Incubation of cholesterol-laden macrophages with reconstituted discoidal complexes made from apolipoprotein A-I and phospholipids resulted in a decrease in total cellular cholesterol, an increase in the efflux of free cholesterol, and a concomitant decrease in the total production and efflux of 27-oxygenated steroids, in particular, 3beta-hydroxy-5-cholestenoic acid. Reconstituted discoidal complexes with the Milano variant of apolipoprotein A-I gave virtually identical results, whereas high density lipoprotein was less efficient. These results suggest that cultured cholesterol-laden cells can export some of their excess cholesterol in the form of 27-hydroxycholesterol, 3beta-hydroxy-5-cholestenoic acid, and free cholesterol. In the presence of exogenous cholesterol acceptors, export of free cholesterol becomes more effective, resulting in less cholesterol exported via the 27-hydroxylase pathway. The balance between the two mechanisms for removal of cholesterol from macrophages may be of importance for formation of foam cells and development of atherosclerosis.
Westman
J
J
King Gustav V Research Institute, Karolinska Hospital, Stockholm, Sweden.
Kallin
B
B
Björkhem
I
I
Nilsson
J
J
Diczfalusy
U
U
D016632:Apolipoprotein A-I / Q000378:metabolism*; D001692:Biological Transport; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism*; D017077:Culture Media, Conditioned; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism*
D016632:Apolipoprotein A-I; D017077:Culture Media, Conditioned; D006888:Hydroxycholesterols; D010743:Phospholipids; C029435:3-hydroxy-5-cholestenoic acid; C076996:27-hydroxycholesterol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase