IMPORTANCE OF A NOVEL OXIDATIVE MECHANISM FOR ELIMINATION OF INTRACELLULAR CHOLESTEROL IN HUMANS

We have recently demonstrated that cultured human alveolar macrophages efficiently convert cholesterol into excretable 27-oxygenated product s. We show here that increasing the intracellular concentration of cho lesterol by a factor of 10 leads to about a twofold increase in the ex cretion of 27-oxygenated products from cultured macrophages. Inhibitio n of the sterol 27-hydroxylase caused a significant intracellular accu mulation of cholesterol. A direct comparison was made between flux of cholesterol and 27-oxygenated products from macrophages preloaded with [4-C-14]cholesterol. Under the specific conditions employed with feta l calf serum in the culture medium, the flux of 27-oxygenated products was about 10% of that of cholesterol. Since the sterol 27-hydroxylase , which converts cholesterol to 27-oxygenated products, is present in many cell types, we suggest that 27-oxygenation is a general mechanism for removal of intracellular cholesterol. To evaluate this hypothesis , we measured the net uptake by the human liver of circulating 27-oxyg enated products, which was found to be about 20 mg/24 h. This uptake c orresponds to approximate to 4% of the bile acid production, assuming quantitative conversion into bile acids. It is concluded that the 27-h ydroxylase pathway is of significance for elimination of extrahepatic cholesterol.