title: Human and rodent type 1 11beta-hydroxysteroid dehydrogenases are 7beta-hydroxycholesterol dehydrogenases involved in oxysterol metabolism.
abstract: Interconversion between cortisone and the glucocorticoid receptor ligand cortisol is carried out by 11beta-hydroxysteroid dehydrogenase (11beta-HSD)isozymes and constitutes a medically important example of pre-receptor control of steroid hormones. The enzyme 11beta-HSD type 1 (11beta-HSD1) catalyzes the conversion of cortisone to its active receptor-binding derivative cortisol, whereas 11beta-HSD type 2 performs the reverse reaction. Specific inhibitors against the type 1 enzyme lower intracellular levels of glucocorticoid hormone, with an important clinical application in insulin resistance and other metabolic disorders. We report here on the in vitro oxysterol-metabolizing properties of human and rodent 11beta-HSD1. The enzyme, either as full-length, membrane-attached, or as a transmembrane domain-deleted, soluble form, mediates exclusively conversion between 7-ketocholesterol and 7beta-hydroxycholesterol with similar k(cat) values as observed with glucocorticoid hormones. Thus, human, rat, and mouse 11beta-HSD1 have dual enzyme activities like the recently described 7alpha-hydroxysteroid dehydrogenase/11beta-hydroxysteroid dehydrogenase from hamster liver, but differ fundamentally from the latter in that 7beta-OH rather than 7alpha-OH dehydrogenase constitutes the second activity. These results demonstrate an enzymatic origin of species differences in 7-oxysterol metabolism, establish the origin of endogenous 7beta-OH cholesterol in humans, and point to a possible involvement of 11beta-HSD1 in atherosclerosis.
authors.affiliation: Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Hult
authors.forename: B
authors.initials: B
authors.lastname: Elleby
authors.forename: N
authors.initials: N
authors.lastname: Shafqat
authors.forename: S
authors.initials: S
authors.lastname: Svensson
authors.forename: A
authors.initials: A
authors.lastname: Rane
authors.forename: H
authors.initials: H
authors.lastname: Jörnvall
authors.forename: L
authors.initials: L
authors.lastname: Abrahmsen
authors.forename: U
authors.initials: U
authors.lastname: Oppermann
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D003348:Cortisone / Q000378:metabolism*; D006224:Cricetinae; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats
chemical_list: D000893:Anti-Inflammatory Agents; D007527:Isoenzymes; D002784:Cholesterol; D006913:Hydroxysteroid Dehydrogenases; C031932:7 beta-hydroxysteroid dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D003348:Cortisone; D006854:Hydrocortisone