Mechanism of accumulation of cholesterol and cholestanol in tendons and the role of sterol 27-hydroxylase (CYP27A1).
OBJECTIVE
Tendon xanthomas are deposits of lipids and connective tissue commonly found in hypercholesterolemic patients. Macrophages are likely to be responsible for the lipid accumulation. Normolipidemic patients with the rare disease cerebrotendinous xanthomatosis, lacking the enzyme sterol 27-hydroxylase (CYP27A1), develop prominent xanthomas in tendons and brain containing both cholestanol and cholesterol, with a cholestanol:cholesterol ratio higher than that in the circulation. Because of its ability to convert cholesterol into polar metabolites that leave the cells faster, CYP27A1 has been suggested to be an antiatherogenic enzyme. The hypothesis was tested that tendons contain CYP27A1 that may be of importance for the normal efflux of both steroids.


RESULTS
Western blotting and combined gas chromatography-mass spectrometry showed that human tendons contain significant amounts of CYP27A1 and its product, 27-hydroxycholesterol. Immunohistochemistry showed that CYP27A1 is present in macrophages and tenocytes. The tendons also contained cholestanol, with a cholestanol:cholesterol ratio slightly higher than that in the circulation. Recombinant human CYP27A1, and cultured human macrophages containing this enzyme, had similar activity toward cholesterol and cholestanol. After loading of macrophages with labeled cholesterol and cholestanol, there was an efflux of these steroids in both unmetabolized and 27-oxygenated form, resulting in a significant cellular accumulation of cholestanol compared with cholesterol.


CONCLUSIONS
The results are consistent with the possibility that CYP27A1 is of importance for the efflux of both cholesterol and cholestanol from tendons.
von Bahr
Sara
S
Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Movin
Tomas
T
Papadogiannakis
Nikos
N
Pikuleva
Irina
I
Rönnow
Per
P
Diczfalusy
Ulf
U
Björkhem
Ingemar
I
D000328:Adult; D000437:Alcoholism / Q000150:complications / Q000201:enzymology; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase; D004083:Cholestanol / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism / Q000502:physiology*; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000201:enzymology; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013250:Steroid Hydroxylases / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity; D019294:Xanthomatosis, Cerebrotendinous / Q000150:complications / Q000201:enzymology / Q000473:pathology
D006888:Hydroxycholesterols; C076996:27-hydroxycholesterol; D004083:Cholestanol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase