Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Zaufel, A.
Effects of cholestasis, bile acids and FXR on the adrenal glands
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2015. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Wagner Martin
- Zollner Gernot
- Altmetrics:
- Abstract:
- Introduction: Cholestasis is a condition with abnormal high bile acid levels. There is evidence that cholestasis induces remission in patients with rheumatoid arthritis. Furthermore, patients with alcoholic hepatitis, who are jaundiced have increased cortisol levels. Also, in animal experiments cholestasis alters adrenocortical function. The link between cholestasis and adrenocortical function has not been investigated in detail so far. Therefore, we hypothesized that systemic accumulation of bile acids during cholestasis affects adrenocortical function and glucocorticoid output. We assessed adrenocortical function in mice with obstructive cholestasis and in response to bile acid feeding to determine the role of bile acids and tested the impact of the major bile acid receptor FXR in mice with genetic depletion of FXR. Methods: Mice either underwent common bile duct ligation (CBDL) for 3 weeks (w) or were fed a chenodeoxycholic acid (CDCA)-enriched diet for 4 days (d). The role of FXR was assessed in 7d CBDL FXR wildtype (WT) and knockout (KO) mice. We assessed serum levels of corticosterone (rodent homologue to human cortisol), determined mRNA expression levels of enzymes involved in adrenal cholesterol metabolism, steroid synthesis, and hepatic steroid breakdown and visualized adrenal lipid content with oil red O staining. Results: 3w CBDL and 4d CDCA-feeding resulted in two fold elevated serum corticosterone levels. SR-BI (adrenal cholesterol uptake), HMG-CoA reductase and lanosterol-14¿-demethylase (Cyp51) (cholesterol de novo synthesis) mRNA levels were increased in adrenal glands after CBDL and CDCA feeding while Abca1 mRNA (cholesterol export) was decreased after CBDL. Enzymes mediating adrenal corticosterone synthesis remained unchanged after CBDL and CDCA feeding. Hepatic corticosterone breakdown (5ß-reductase, 3¿-hydroxysteroid dehydrogenase mRNA) was reduced in both treatment groups. Genetic loss of FXR had no impact on serum corticosterone levels or mRNA expression levels in 7d BDL mice. We observed FXR independent loss of neutral adrenal lipids. Discussion: Obstructive cholestasis and bile acid feeding lead to hypercorticosteronemia in mice via increased adrenal cholesterol uptake and biosynthesis (as substrate for adrenal steroid synthesis) as well as decreased hepatic corticosterone breakdown. These alterations are independent of FXR.