Why is 11beta-hydroxysteroid dehydrogenase type 1 facing the endoplasmic reticulum lumen? Physiological relevance of the membrane topology of 11beta-HSD1

Odermatt, Alex; Atanasov, Atanas G; Balazs, Zoltan; Schweizer, Roberto A S; Nashev, Lyubomir G; Schuster, Daniela; Langer, Thierry (2006). Why is 11beta-hydroxysteroid dehydrogenase type 1 facing the endoplasmic reticulum lumen? Physiological relevance of the membrane topology of 11beta-HSD1. Molecular and cellular endocrinology, 248(1-2), pp. 15-23. Shannon: Elsevier Ireland 10.1016/j.mce.2005.11.040

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11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is essential for the local activation of glucocorticoid receptors (GR). Unlike unliganded cytoplasmic GR, 11beta-HSD1 is an endoplasmic reticulum (ER)-membrane protein with lumenal orientation. Cortisone might gain direct access to 11beta-HSD1 by free diffusion across membranes, indirectly via intracellular binding proteins or, alternatively, by insertion into membranes. Membranous cortisol, formed by 11beta-HSD1 at the ER-lumenal side, might then activate cytoplasmic GR or bind to ER-lumenal secretory proteins. Compartmentalization of 11beta-HSD1 is important for its regulation by hexose-6-phosphate dehydrogenase (H6PDH), which regenerates cofactor NADPH in the ER lumen and stimulates oxoreductase activity. ER-lumenal orientation of 11beta-HSD1 is also essential for the metabolism of the alternative substrate 7-ketocholesterol (7KC), a major cholesterol oxidation product found in atherosclerotic plaques and taken up from processed cholesterol-rich food. An 11beta-HSD1 mutant adopting cytoplasmic orientation efficiently catalyzed the oxoreduction of cortisone but not 7KC, indicating access to cortisone from both sides of the ER-membrane but to 7KC only from the lumenal side. These aspects may be relevant for understanding the physiological role of 11beta-HSD1 and for developing therapeutic interventions to control glucocorticoid reactivation.

Item Type:	Journal Article (Further Contribution)
Division/Institute:	04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
UniBE Contributor:	Odermatt, Alexander
ISSN:	0303-7207
ISBN:	16412558
Publisher:	Elsevier Ireland
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:47
Last Modified:	05 Dec 2022 14:14
Publisher DOI:	10.1016/j.mce.2005.11.040
PubMed ID:	16412558
Web of Science ID:	000236691100004
URI:	https://boris.unibe.ch/id/eprint/19823 (FactScience: 2805)