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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Geier, A; Dietrich, CG; Voigt, S; Ananthanarayanan, M; Lammert, F; Schmitz, A; Trauner, M; Wasmuth, HE; Boraschi, D; Balasubramaniyan, N; Suchy, FJ; Matern, S; Gartung, C.
Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver.
Am J Physiol Gastrointest Liver Physiol. 2005; 289(5):G831-G841 Doi: 10.1152/ajpgi.00307.2004 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Trauner Michael
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Abstract:
Proinflammatory cytokines such as TNF-alpha and IL-1beta lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF-alpha or IL-1beta for up to 16 h. Transporter mRNA expression was determined by Northern blot analysis, nuclear activity, and protein-expression of transactivators by EMSA and Western blotting. TNF-alpha induces a sustained decrease in Ntcp, Oatp1/Oatp1a1, and Bsep mRNA expression but exerts only transient [multidrug resistance-associated protein 2 (Mrp2)] or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1, IL-1beta also downregulates Bsep, Mrp2, and Mrp3 mRNAs to some extent. To study transcriptional regulation, Ntcp and Bsep promoters were first cloned from mice revealing a new distal Ntcp hepatocyte nuclear factor 1 (HNF-1) element but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by a reduction in binding activities at IR-1, ER-8, DR-5, and HNF-1alpha sites after 4 h by either cytokine, which remained more sustained by TNF-alpha in the case of nuclear receptors. Nuclear protein levels of retinoid X receptor (RXR)-alpha are significantly decreased by TNF-alpha but only transiently affected by IL-1beta. Minor reductions of retinoic acid receptor, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor nuclear proteins are restricted to 4 h after cytokine application and paralleled by a decrease in mRNA levels. Basolateral and canalicular transporter systems are downregulated by both cytokines, TNF-alpha and IL-1beta. Activity of HNF-1alpha as regulator of mNtcp is suppressed by both cytokines. Decreased binding activities of nuclear receptor heterodimers may be explained by a reduction of the ubiquitous heterodimerization partner RXR-alpha.
Find related publications in this database (using NLM MeSH Indexing)
5' Untranslated Regions - genetics
Animals -
Base Sequence -
Gene Expression Regulation - drug effects
Interleukin-1 - pharmacology Interleukin-1 - physiology
Liver - drug effects Liver - metabolism
Male -
Mice -
Mice, Inbred C57BL -
Organic Anion Transporters - genetics Organic Anion Transporters - metabolism
Promoter Regions, Genetic - genetics
Protein Binding -
RNA, Messenger - biosynthesis RNA, Messenger - genetics
Trans-Activators - metabolism
Tumor Necrosis Factor-alpha - pharmacology Tumor Necrosis Factor-alpha - physiology

Find related publications in this database (Keywords)
cholestasis
tumor necrosis factor-alpha
interleukin-1 beta
nuclear hormone receptors
gene expression
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