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SHR Neuro Cancer Cardio Lipid Metab Microb

Geier, A; Zollner, G; Dietrich, CG; Wagner, M; Fickert, P; Denk, H; van Rooijen, N; Matern, S; Gartung, C; Trauner, M.
Cytokine-independent repression of rodent Ntcp in obstructive cholestasis.
Hepatology. 2005; 41(3):470-477 Doi: 10.1002/hep.20594 [OPEN ACCESS]
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Co-authors Med Uni Graz

Denk Helmut

Fickert Peter

Trauner Michael

Wagner Martin

Zollner Gernot

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Abstract:

Cholestatic liver injury is associated not only with accumulation of bile acids but also with activation of proinflammatory cytokines. Common bile duct ligation (CBDL) induces sustained downregulation of the Na(+)/taurocholate cotransporter (Ntcp) in rodent liver. Although repression of Ntcp during endotoxemia is cytokine mediated, it is unclear whether inflammatory cytokines contribute to this downregulation in obstructive cholestasis. Cytokine inactivation in CBDL rats and mice was either performed directly with tumor necrosis factor alpha (etanercept) or interleukin 1 beta inactivation (anakinra/AMG 719) or indirectly Kupffer cell depletion via intraperitoneal administration of liposome-encapsulated dichloromethylene bisphosphonate. Protein and messenger RNA (mRNA) expression of Ntcp and short heterodimer partner (SHP) were analyzed via Western and Northern blotting. Key regulators of Ntcp (hepatocyte nuclear factor 1 alpha [HNF-1alpha], HNF-4alpha, retinoid X receptor alpha [RXRalpha]:retinoic acid receptor alpha [RARalpha]) were studied via electrophoretic mobility shift analysis and nuclear Western blot analysis. Both methods of cytokine inactivation failed to maintain Ntcp protein or mRNA expression within 3 days after CBDL in either rats or mice (20%-40% of sham controls), while SHP mRNA expression increased three- to five-fold. Decreased nuclear HNF-1alpha and HNF-4alpha protein levels (45% and 60% of sham controls, respectively) and HNF-1alpha binding activity (32% of sham controls) were not restored during cytokine inactivation after CBDL, indicating cytokine-independent mechanisms of Ntcp regulation. RXRalpha:RARalpha binding remained unchanged in all experimental conditions. In conclusion, during obstructive cholestasis accumulating bile acids per se, without major contribution of cytokines, leads to downregulation of Ntcp via repression of HNF-1alpha and HNF-4alpha.

Find related publications in this database (using NLM MeSH Indexing)

Animals -

Cholestasis - metabolism

Cytokines - physiology

DNA-Binding Proteins - genetics

Gene Expression Regulation -

Hepatocyte Nuclear Factor 1 -

Hepatocyte Nuclear Factor 1-alpha -

Hepatocyte Nuclear Factor 4 -

Kupffer Cells - physiology

Male -

Membrane Transport Proteins - genetics

Mice -

Nuclear Proteins - genetics

Organic Anion Transporters, Sodium-Dependent -

Phosphoproteins - genetics

RNA, Messenger - analysis

Rats -

Rats, Sprague-Dawley -

Receptors, Cytoplasmic and Nuclear - genetics

Symporters -

Transcription Factors - genetics

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