Abstract
Human alveolar macrophages have exceptionally high capacity to convert cholesterol into 27-hydroxycholesterol and cholestenoic acid by the sterol 27-hydroxylase mechanism. It is shown here that the human lung has a higher content of 27-hydroxycholesterol relative to cholesterol than any other organ. In order to evaluate the importance of the sterol 27-hydroxylase mechanism for cholesterol homeostasis in the lung, the production of cholestenoic acid by human lung was investigated. Removal of one lung reduced the level of cholestenoic acid in the circulation by 48 ± 4% (P < 0.005). The levels of cholestenoic acid in the pulmonary artery and in the pulmonary vein showed significant differences (P < 0.002) with higher levels in the pulmonary vein (108 ± 16 and 104 ± 16 ng/mL, respectively). This corresponds to a net flux of cholestenoic acid from the lung of about 14 mg/day, which is more than 80% of the reported removal of this oxysterol and its metabolites from the circulation by the liver per day. Bypassing the lung for 60 min led to a reduction in circulating cholestenoic acid (30%) that fits with a pulmonary origin when taking into account the half-life of cholestenoic acid. The level of circulating cholestenoic acid was found to be less in patients with different lung diseases. It is evident that most of the cholestenoic acid in the circulation is of pulmonary origin.▪The present results suggest that the sterol 27-hydroxylase in the lung is responsible for at least half of the total flux of 27-oxygenated cholesterol metabolites to the liver and that this enzyme system may be of importance for cholesterol homeostasis in the lung.—Babiker, A., O. Andersson, D. Lindblom, J. van der Linden, B. Wiklund, D. Lütjohann, U. Diczfalusy, and I. Björkhem. Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin. J. Lipid Res. 1999. 40: 1417–1425.
Highlights
Human alveolar macrophages have exceptionally high capacity to convert cholesterol into 27-hydroxycholesterol and cholestenoic acid by the sterol 27-hydroxylase mechanism
In the present work we present evidence that this is the case, and that the sterol 27-hydroxylase may be of importance for cholesterol homeostasis in the lung
With determination by mass spectrometry of the product as the methyl ester trimethylsilyl derivative, it was found that saturation of the double bond with deuterium gas under these catalytic conditions with PtO2 as catalyst was associated with introduction of 2H in some other undefined positions, yielding cholestenoic acid containing a mixture of mono, di, tri, tetra, penta, and hexa-deuterium labeled species
Summary
Human alveolar macrophages have exceptionally high capacity to convert cholesterol into 27-hydroxycholesterol and cholestenoic acid by the sterol 27-hydroxylase mechanism. The levels of cholestenoic acid in the pulmonary artery and in the pulmonary vein showed significant differences (P Ͻ 0.002) with higher levels in the pulmonary vein (108 ؎ 16 and 104 ؎ 16 ng/mL, respectively) This corresponds to a net flux of cholestenoic acid from the lung of about 14 mg/day, which is more than 80% of the reported removal of this oxysterol and its metabolites from the circulation by the liver per day. Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin. A new oxidative mechanism for elimination of intracellular cholesterol in macrophages and endothelial cells by the enzyme sterol 27-hydroxylase was described [2,3,4] This mechanism involves conversion of cholesterol into 27-hydroxycholesterol and 3-hydroxy-5-cholestenoic acid (cholestenoic acid). The exceptionally high capacity of alveolar macrophages to produce cholestenoic acid and the high content of sterol 27-hydroxylase mRNA in the lung led us to specu-
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