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11 beta-hydrosysteroid dehydrogenases in renal allograft donors and patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis

English title 11 beta-hydrosysteroid dehydrogenases in renal allograft donors and patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis
Applicant Frey Felix Julius
Number 122135
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Internal Medicine
Start/End 01.10.2008 - 30.09.2011
Approved amount 678'193.00
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All Disciplines (3)

Discipline
Internal Medicine
Pathophysiology
Endocrinology

Keywords (7)

salt sensitivity; kidney; transplantation; cortisol; NASH; nonalcoholic fatty liver disease; 11beta-hydroxysteroid dehydrogenase

Lay Summary (English)

Lead
Lay summary
A reduced 11beta-HSD2 activity, a novel mechanism of salt sensitivity and hypertension after renal allograft donation?Blood pressure increases after renal allograft donation. The mechanism of this type of hypertension is unknown. Since renin activity and aldosterone concentrations have been found to be low, a mechanism accounting for volume expansion has to be identified. Here we hypothesize that a diminished 11beta-HSD2 activity accounts at least in part for hypertension in kidney donors. This hypothesis is supported first, by our observations in rats after uninephrectomy (UNX) or syngenic transplantation and in humans after UNX for transplantation (only preliminary short term observations so far) and second, the known biology of the 11beta-HSD2 enzyme. 11beta-HSD1 in patients with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)NAFLD comprises a spectrum of changes ranging from steatosis to an inflammatory liver disease entitled NASH, which ultimately might lead to fibrosis or cirrhosis. The development from fatty liver to NASH involves accumulation of triglycerides in hepatocytes, a phenomenon attributed to insulin resistance and obesity with a progression characterized by inflammation. Transgenic mice over-expressing 11beta-HSD1 selectively in the liver develop fatty liver, and an increased activity of 11beta-HSD1 has been associated with insulin resistance. Our group has shown, first, that TNF-alpha, which is increased in liver tissue in patients with NASH, stimulates 11beta-HSD1 activity and second, that the bile acid ursodeoxycholic acid, an agent known for its beneficial therapeutic action in humans with NASH, inhibits 11beta-HSD1. Therefore, we hypothesize that 11beta-HSD1 reductase activity is increased in liver tissue from patients with NAFLD or NASH and contributes by its amplification of local intracellular glucocorticoid action to the development of these entities. For this purpose we propose to investigate healthy humans and patients with NAFLD or NASH with respect to the 11beta-HSD1 activity.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Effect of electroporation-mediated diphtheria toxin A expression on PSA positive human prostate xenograft tumors in SCID mice.
Goepfert Christine, Gazdhar Amiq, Frey Felix J, Frey Brigitte M (2011), Effect of electroporation-mediated diphtheria toxin A expression on PSA positive human prostate xenograft tumors in SCID mice., in The Prostate, 71(8), 872-80.
Nocturnal dipping behaviour in normotensive white children and young adults in response to changes in salt intake.
Simonetti Giacomo D, Farese Stefan, Aregger Fabienne, Uehlinger Dominik, Frey Felix J, Mohaupt Markus G (2010), Nocturnal dipping behaviour in normotensive white children and young adults in response to changes in salt intake., in Journal of hypertension, 28(5), 1027-33.
Urinary proteomics before and after extracorporeal circulation in patients with and without acute kidney injury.
Aregger Fabienne, Pilop Christiane, Uehlinger Dominik E, Brunisholz René, Carrel Thierry P, Frey Felix J, Frey Brigitte M (2010), Urinary proteomics before and after extracorporeal circulation in patients with and without acute kidney injury., in The Journal of thoracic and cardiovascular surgery, 139(3), 692-700.
Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients.
Farese Stefan, Kruse Anja, Pasch Andreas, Dick Bernhard, Frey Brigitte M, Uehlinger Dominik E, Frey Felix J (2009), Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients., in Kidney international, 76(8), 877-84.
Role of CYP27A1 in progesterone metabolism in vitro and in vivo.
Escher Geneviève, Vögeli Isabelle, Escher Robert, Tuckey Robert C, Erickson Sandra, Krozowski Zygmunt, Frey Felix J (2009), Role of CYP27A1 in progesterone metabolism in vitro and in vivo., in American journal of physiology. Endocrinology and metabolism, 297(4), 949-55.
Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms.
Pilop Christiane, Aregger Fabienne, Gorman Robert C, Brunisholz Rene, Gerrits Bertran, Schaffner Thomas, Gorman Joseph H, Matyas Gabor, Carrel Thierry, Frey Brigitte M (2009), Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms., in Circulation, 120(11), 983-91.
Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells.
Ignatova Irena D, Kostadinova Radina M, Goldring Christopher E, Nawrocki Andrea R, Frey Felix J, Frey Brigitte M (2009), Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells., in American journal of physiology. Endocrinology and metabolism, 296(2), 367-77.
Sodium thiosulfate prevents vascular calcifications in uremic rats.
Pasch Andreas, Schaffner Thomas, Huynh-Do Uyen, Frey Brigitte M, Frey Felix J, Farese Stefan (2008), Sodium thiosulfate prevents vascular calcifications in uremic rats., in Kidney international, 74(11), 1444-53.
A novel steroidal antiandrogen targeting wild type and mutant androgen receptors.
Andrieu Thomas, Bertolini Reto, Nichols Sara E, Setoud Raschid, Frey Felix J, Baker Michael E, Frey Brigitte M, A novel steroidal antiandrogen targeting wild type and mutant androgen receptors., in Biochemical pharmacology, 82(11), 1651-62.

Associated projects

Number Title Start Funding scheme
138670 Regulation of 11 betahydroxysteroid dehydrogenase type 2 in health and disease states 01.10.2011 Project funding
102153 Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 in health and disease states. 01.10.2003 Project funding

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