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 products. We show here that increasing the intracellular concentration of cholesterol by a factor of 10 leads to about a twofold increase in the excretion of 27-oxygenated products from cultured macrophages. Inhibition of the sterol 27-hydroxylase caused a significant intracellular accumulation of cholesterol. A direct comparison was made between flux of cholesterol and 27-oxygenated products from macrophages preloaded with [4-14C]cholesterol. Under the specific conditions employed with fetal 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-oxygenated products, which was found to be about 20 mg/24 h. This uptake corresponds to approximately 4% of the bile acid production, assuming quantitative conversion into bile acids. It is concluded that the 27-hydroxylase pathway is of significance for elimination of extrahepatic cholesterol.
Lund
E
E
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge Hospital Sweden, Stockholm, Sweden.
Andersson
O
O
Zhang
J
J
Babiker
A
A
Ahlborg
G
G
Diczfalusy
U
U
Einarsson
K
K
Sjövall
J
J
Björkhem
I
I
D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism
D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase