Cytokine-independent repression of rodentNtcp in obstructive cholestasis

Geier, Andreas; Zollner, Gernot; Dietrich, Christoph G.; Wagner, Martin; Fickert, Peter; Denk, Helmut; Rooijen, Nico van; Matern, Siegfried; Gartung, Carsten; Trauner, Michael

doi:10.1002/hep.20594

Cited by 40 publications

(28 citation statements)

References 45 publications

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“…It has recently been shown that complement C3 expression is inducible by BAs and their nuclear receptor FXR [20]. Furthermore, BA overload causes adaptive changes in hepatocellular transporter expression as observed by decreased basolateral Ntcp [24] and the induction of the retrograde basolateral salvage transporters Mrp3 and 4 [29] which can observed in our study.…”

Section: Discussionsupporting

confidence: 80%

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Complement factor C5 deficiency significantly delays the progression of biliary fibrosis in bile duct-ligated mice

Schmitt¹,

Roderfeld²,

Sabrane³

et al. 2012

Biochemical and Biophysical Research Communications

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Fibrogenesis represents the universal response of the liver to chronic liver injury. Complement factor C5 has been linked to fibrosis in murine toxic liver injury and human chronic hepatitis C. C5 may also play a central role in chronic cholestatic disorders, since the BA receptor FXR has been characterized as an activator of the C3 gene. We aimed to investigate, whether C5 deficiency is able to prevent biliary fibrosis in the mouse bile-duct-ligation model. BDL for 1-4weeks was performed in either Hc(0)/Hc(0) mice (deficient for C5) or WT controls. BA levels were measured by RIA. Histological examination included HE, sirius-red and immunohistochemistry. mRNA expression was quantified by RT-PCR. Protein expression levels were determined by Western blotting or ELISA. Enzymatic MMP-activity was analysed by zymography. One week BDL leads to fibrosis in WT (F2.0±0), while it is almost absent in Hc(0)/Hc(0) mice (F0.5±0.5). No differences in fibrosis can be detected at week-4. Together with delayed fibrogenesis at week-1, fibrotic markers are decreased in Hc(0)/Hc(0) mice. Expression of the inflammatory cytokine TNF-is decreased in Hc(0)/Hc(0) mice. In parallel C5 deficiency leads to an attenuated peribiliary infiltration of CD45(+) cells in fibrotic areas together with decreased MMP-9 expression and gelatinase activity. The present study proves a functional role of C5 during biliary fibrogenesis. C5 deficiency leads to attenuated inflammation and normalized MMP-9 activity concomitantly with a significant reduction of fibrosis. C5 appears to be an attractive target for future therapeutic intervention in chronic cholestatic liver disease. The present study proves a functional role of C5 during biliary fibrogenesis. C5 deficiency leads to attenuated inflammation and normalized MMP-9 activity concomitantly with a significant reduction of fibrosis. C5 appears to be an attractive target for future therapeutic intervention in chronic cholestatic liver disease.

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Section: Discussionsupporting

confidence: 80%

“…BDL or sham-laparatomy was performed in either C5-deficient mice (n=4, each group) or WT controls (n=5, each group) as described previously [24]. After 1 and 4 weeks the mice were sacrificed and liver tissue and blood samples were harvested.…”

Section: Animalsmentioning

confidence: 99%

Complement factor C5 deficiency significantly delays the progression of biliary fibrosis in bile duct-ligated mice

Schmitt¹,

Roderfeld²,

Sabrane³

et al. 2012

Biochemical and Biophysical Research Communications

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“…27,54 Fxr and Hnf1a are implicated broadly in cholestatic liver injury. [55][56][57][58] Reports that Sp1 plays a role in liver injury are more anecdotal. [59][60][61] To confirm the role of these four factors, we performed ChIP-seq on liver samples 1 and 14 days after ligation.…”

Section: Resultsmentioning

confidence: 99%

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

et al. 2017

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Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

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“…In the early stages of obstructive cholestasis, NTCP transcription is downregulated by SHP-dependent mechanisms similar to those involved in the regulation by bile acids ( 90,91,99 ). At later stages, proinfl ammatory cytokines may contribute to the sustained downregulation of NTCP expression via RXR ␣ :RAR ␣ -dependent mechanisms ( 91 ).…”

Section: Hepatocellular Transport Of Bile Acidsmentioning

confidence: 99%