Serum cholestenoic acid as a potential marker of pulmonary cholesterol homeostasis: increased levels in patients with pulmonary alveolar proteinosis.
The conversion of cholesterol into the more polar metabolites 27-hydroxycholesterol (27-OH) and cholestenoic acid by the cytochrome P450 sterol 27-hydroxylase is a cholesterol-removal mechanism used by almost all cells. Most of the cholestenoic acid present in the circulation originates from the lung, and it has been suggested that sterol 27-hydroxylase is of particular importance for cholesterol homeostasis in this organ. As an example of pulmonary cholesterol accumulation, a known disorder of surfactant homeostasis, pulmonary alveolar proteinosis (PAP), was studied. Analysis of bronchoalveolar lavage fluid from PAP patients revealed a significant accumulation of the cholesterol metabolites cholestenoic acid and 27-OH. This pattern was recapitulated in serum, with a significant increase in the levels of both cholestenoic acid (P=0.003) and 27-OH (P=0.017) in PAP patients compared with healthy controls. Analysis of PAP alveolar macrophages did not reveal a significant change in mRNA expression levels of either sterol 27-hydroxylase or the cholesterol-esterifying enzyme acyl-CoA:cholesterol acyltransferase-1. These results are consistent with the contention that substrate availability, rather than enzyme expression, is the key factor in regulating the production of cholestenoic acid by the lung and that serum cholestenoic acid may be a marker of pulmonary cholesterol homeostasis.
Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden. steve.meaney@labmed.ki.se
Steve
S
Meaney
Tracey L
TL
Bonfield
Magnus
M
Hansson
Amir
A
Babiker
Mani S
MS
Kavuru
Mary Jane
MJ
Thomassen
D000328:Adult; D015415:Biomarkers / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D011649:Pulmonary Alveolar Proteinosis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1