Nod2 deficiency protects mice from cholestatic liver disease by increasing renal excretion of bile acids

Lirui Wang, Phillipp Hartmann, Michael Haimerl, Sai P. Bathena, Christopher Sjöwall, Sven Almer, Yazen Alnouti, Alan F. Hofmann, Bernd Schnabl

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Background & Aims Chronic liver disease is characterized by fibrosis that may progress to cirrhosis. Nucleotide oligomerization domain 2 (Nod2), a member of the Nod-like receptor (NLR) family of intracellular immune receptors, plays an important role in the defense against bacterial infection through binding to the ligand muramyl dipeptide (MDP). Here, we investigated the role of Nod2 in the development of liver fibrosis. Methods We studied experimental cholestatic liver disease induced by bile duct ligation or toxic liver disease induced by carbon tetrachloride in wild type and Nod2-/- mice. Results Nod2 deficiency protected mice from cholestatic but not toxin-induced liver injury and fibrosis. Most notably, the hepatic bile acid concentration was lower in Nod2-/- mice than wild type mice following bile duct ligation for 3 weeks. In contrast to wild type mice, Nod2-/- mice had increased urinary excretion of bile acids, including sulfated bile acids, and an upregulation of the bile acid efflux transporters MRP2 and MRP4 in tubular epithelial cells of the kidney. MRP2 and MRP4 were downregulated by IL-1β in a Nod2 dependent fashion. Conclusions Our findings indicate that Nod2 deficiency protects mice from cholestatic liver injury and fibrosis through enhancing renal excretion of bile acids that in turn contributes to decreased concentration of bile acids in the hepatocyte.

Original languageEnglish (US)
Pages (from-to)1259-1267
Number of pages9
JournalJournal of Hepatology
Volume60
Issue number6
DOIs
StatePublished - Jun 2014

Keywords

  • Bacterial translocation
  • Bile acids transporter
  • Chronic liver disease
  • IL-1β
  • Microbiome
  • Renal tubular epithelial cells

ASJC Scopus subject areas

  • Hepatology

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    Wang, L., Hartmann, P., Haimerl, M., Bathena, S. P., Sjöwall, C., Almer, S., Alnouti, Y., Hofmann, A. F., & Schnabl, B. (2014). Nod2 deficiency protects mice from cholestatic liver disease by increasing renal excretion of bile acids. Journal of Hepatology, 60(6), 1259-1267. https://doi.org/10.1016/j.jhep.2014.02.012