title: Paradoxical enhancement of hepatic metabolism of 7-ketocholesterol in sterol 27-hydroxylase-deficient mice.
abstract: 7-Ketocholesterol (7KC) is a major oxysterol found in atherosclerotic plaque and is believed to be derived both endogenously and exogenously (from the diet). Previously, we have demonstrated that subsequent to hepatic lipoprotein uptake, 7KC delivered in a model chylomicron remnant lipid emulsion is metabolised more rapidly and excreted into the intestinal tract and faeces to a much greater extent than simultaneously administered cholesterol. Furthermore, we have shown that human 7KC metabolism is dependent upon sterol 27-hydroxylase (27OHase). In the present work, we utilised a mouse model possessing the null mutation in the sterol 27-hydroxylase gene, Cyp27, to further investigate the metabolism and potential arterial accumulation of 7KC versus cholesterol. Despite the homozygous null mutation in Cyp27 (Cyp27-/-), 7KC was observed to undergo greater metabolism and excretion in the Cyp27-/- animals compared with the wild-type control mice. Six hours post-injection, 7KC levels were greater in aortae from Cyp27-/- mice but by 24 h, there was no significant difference between the knockout and control mice. We conclude that in contrast to humans, mice do not have an absolute requirement for 27OHase in order to metabolise 7KC and must rely on alternative side-chain oxidising pathways.
authors.affiliation: Cell Biology Group, Heart Research Institute, 145 Missenden Road, Camperdown, 2050 Sydney, Australia. mlyons@jax.org
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Lyons
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brown
mesh_terms: D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase; D002914:Chylomicrons / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007653:Ketocholesterols / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D012995:Solubility; D013250:Steroid Hydroxylases / Q000172:deficiency* / Q000235:genetics
chemical_list: D002914:Chylomicrons; D007653:Ketocholesterols; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; C003001:7-ketocholesterol