STEROL 27-HYDROXYLASE-MEDIATED AND APOAI PHOSPHOLIPID-MEDIATED EFFLUXOF CHOLESTEROL FROM CHOLESTEROL-LADEN MACROPHAGES - EVIDENCE FOR AN INVERSE RELATION BETWEEN THE 2 MECHANISMS/

Cholesterol-laden, human monocyte-derived macrophages were found to co ntain 27-hydroxycholesterol in proportion to their content of choleste rol ester. In accordance with previous wort; with human lung alveolar macrophages, there was a significant efflux of 27-hydroxycholesterol a nd 3 beta-hydroxy-5-cholestenoic acid from the cultured cells. The eff lux of 27-hydroxycholesterol was proportional to the cellular content of this steroid. Incubation of cholesterol-laden macrophages with reco nstituted discoidal complexes made from apolipoprotein A-I and phospho lipids resulted in a decrease in total cellular cholesterol, an increa se in the efflux of free cholesterol, and a concomitant decrease in th e total production and efflux of 27-oxygenated steroids, in particular , 3 beta-hydroxy-5-cholestenoic acid. Reconstituted discoidal complexe s with the Milano variant of apolipoprotein A-I gave virtually identic al 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, 3 b eta-hydroxy-5-cholestenoic acid. and free cholesterol. In the presence of exogenous cholesterol accepters, export of free cholesterol become s more effective, resulting in less cholesterol exported via the 27-hy droxylase 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.