title: Nod2 deficiency protects mice from cholestatic liver disease by increasing renal excretion of bile acids.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Lirui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Phillipp
authors.initials: P
authors.lastname: Hartmann
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Haimerl
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Sai P
authors.initials: SP
authors.lastname: Bathena
authors.affiliation: Rheumatology/AIR, Department of Clinical and Experimental Medicine, Linköping University, Sweden.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sjöwall
authors.affiliation: Karolinska Institute, Department of Medicine, Solna, and Karolinska University Hospital, GastroCentrum, Stockholm, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Almer
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Yazen
authors.initials: Y
authors.lastname: Alnouti
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Hofmann
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address: beschnabl@ucsd.edu.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schnabl
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D041781:Jaundice, Obstructive / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018345:Mice, Knockout; D064307:Microbiota / Q000502:physiology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000276:immunology
chemical_list: D001647:Bile Acids and Salts; D053583:Interleukin-1beta; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D053473:Nod2 Signaling Adaptor Protein; C489540:Abcc4 protein, mouse; C495945:Nod2 protein, mouse
keywords: Bacterial translocation; Bile acids transporter; Chronic liver disease; IL-1β; Microbiome; Renal tubular epithelial cells