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Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis
  1. Naiara Beraza1,2,
  2. Lisa Ofner-Ziegenfuss3,
  3. Haksier Ehedego1,
  4. Mark Boekschoten4,
  5. Stephan C Bischoff5,
  6. Michael Mueller4,
  7. Michael Trauner3,
  8. Christian Trautwein1
  1. 1Department of Internal Medicine, University Hospital (RWTH) Pauwelstrasse, Aachen, Germany
  2. 2Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberedh), Technology Park of Bizkaia, Bizkaia, Spain
  3. 3Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Auenbruggerplatz, Austria
  4. 4Department for Nutrition, Metabolism & Genomics, Wageningen University, Nutrigenomics Consortium, Top Institute Food & Nutrition, Wageningen, The Netherlands
  5. 5Institute of Nutrition, University of Hohenheim, Fruwirthstr, Stuttgart, Germany
  6. 6Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna Waehringer Guertel 18-20, Vienna, Austria
  1. Correspondence to Professor Christian Trautwein, Department of Internal Medicine, University Hospital Aachen (RWTH), Pauwelsstr. 30, 52074 Aachen, Germany; ctrautwein{at}ukaachen.de

Abstract

Background Hepatocyte-specific NEMO/NF-κB deleted mice (NEMOΔhepa) develop spontaneous non-alcoholic steatohepatitis (NASH). Free fatty acids and bile acids promote DR5 expression. TRAIL/NK cell-mediated activation of TRAIL-R2/DR5 plays an important role during acute injury in NEMOΔhepa mice.

Aim To inhibit the progression of NASH in the absence of hepatocyte-NEMO/NF-kB signaling.

Methods NEMOf/f and NEMOΔhepa mice were fed with a low-fat diet, and with two anticholestatic diets; UDCA and NorUDCA. The impact of these treatments on the progression of NASH was evaluated.

Results We show that high expression of DR5 in livers from NEMOΔhepa mice is accompanied by an abundant presence of bile acids (BAs), misregulation of BA transporters and significant alteration of lipid metabolism-related genes. Additionally, mice lacking NEMO in hepatocytes spontaneously showed ductular response at young age. Unexpectedly, feeding of NEMOΔhepa mice with low-fat diet failed to improve chronic liver injury. Conversely, anti-cholestatic treatment with nor-ursodeoxycholic acid (NorUDCA), but not with ursodeoxycholic acid (UDCA), led to a significant attenuation of liver damage in NEMOΔhepa mice. The strong therapeutic effect of NorUDCA relied on a significant downregulation of LXR-dependent lipogenesis and the normalisation of BA metabolism through mechanisms involving cross-talk between Cyp7a1 and SHP. This was associated with the significant improvement of liver histology, NEMOΔhepa/NorUDCA-treated mice showed lower apoptosis and reduced CyclinD1 expression, indicating attenuation of the compensatory proliferative response to hepatocellular damage. Finally, fibrosis and ductular reaction markers were significantly reduced in NorUDCA-treated NEMOΔhepa mice.

Conclusions Overall, our work demonstrates the contribution of bile acids metabolism to the progression of NASH in the absence of hepatocyte-NF-kB through mechanisms involving DR5-apoptosis, inflammation and fibrosis. Our work suggests a potential therapeutic effect of NorUDCA in attenuating the progression of NASH.

  • Bile acid
  • nonalcoholic steatohepatitis
  • nuclear factor kappa

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Footnotes

  • Funding This work was supported by the SFB TRR57 grant and by the “Kompetenznetz Adipositas (Competence Network of Obesity)”, group “Obesity and GI tract” funded by the Federal Ministry of Education and Research (FKZ: 01GI0843). NB is funded by Program Ramón y Cajal (Ministry of Science and Innovation, Spain) and by Instituto de Salud Carlos III (FIS, PS09/02010; Ministry of Health, Spain).

  • Competing interests The Medical University of Vienna has filed a patent on the medical use of NorUDCA and Michael Trauner is listed as co-inventor. The other authors have no competing interests to declare.

  • Ethics approval The animals were treated according to the guidelines by the National Academy of Sciences (NIH publication 86-23, revised 1985). Animal husbandry and procedures were approved by the authority for environment conservation and consumer protection of the state North Rhine–Westphalia (LANUV) and guidelines of the University Hospital Aachen Animal Care Facility.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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