Sterol 27-hydroxylase acts on 7-ketocholesterol in human atherosclerotic lesions and macrophages in culture

A.J. Brown, Gerald Watts, John Burnett, R.T. Dean, W. Jessup

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

Abstract

27-Hydroxycholesterol (27OH) is the major oxysterol in human atherosclerotic lesions, followed by 7-ketocholesterol (7K), Whereas 7K probably originates nonenzymically, 27OH arises by the action of sterol 27-hydroxylase, a cytochrome P450 enzyme expressed at particularly high levels in the macrophage and proposed to represent an important pathway by which macrophages eliminate excess cholesterol, We hypothesized and here show that 27-hydroxylated 7-ketocholesterol (27OH-7K) is present in human lesions, probably generated by the action of sterol 27-hydroxylase on 7K. Moreover, [SH]27OH-7K was produced by human monocyte-derived macrophages (HMDMs) supplied with [H-3]7K but not in HMDMs from a patient with cerebrotendinous xanthomatosis (CTX) shown to have a splice-junction mutation of sterol 27-hydroxylase. Whereas [H-3]27OH-7K was predominantly secreted into the medium, [H-3]-27OH formed from [H-3] cholesterol was mostly cell-associated. The majority of supplied [H-3]7K was metabolized beyond 27OH-7K to aqueous-soluble products (apparently bile acids derived from the sterol 27-hydroxylase pathway). Metabolism to aqueous-soluble products was ablated by a sterol 27-hydroxylase inhibitor and absent in CTX cells. Sterol 27-hydroxylase therefore appears to represent an important pathway by which macrophages eliminate not only cholesterol but also oxysterols such as 7K, The fact that 7K (and cholesterol) still accumulates in lesions and foam cells indicates that this pathway may be perturbed in atherosclerosis and affords a new opportunity for the development of therapeutic strategies to regress atherosclerotic lesions.
Original languageEnglish
Pages (from-to)27627-27633
JournalJournal of Biological Chemistry
Volume275
Issue number36
Publication statusPublished - 2000

Fingerprint

Dive into the research topics of 'Sterol 27-hydroxylase acts on 7-ketocholesterol in human atherosclerotic lesions and macrophages in culture'. Together they form a unique fingerprint.

Cite this