title: Na(+) /H(+) exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury.
abstract: The intercellular adhesion molecule 1 (ICAM-1) is induced in mouse liver after bile duct ligation (BDL) and plays a key role in neutrophil-mediated liver injury in BDL mice. ICAM-1 has been shown to interact with cytoskeletal ezrin-radixin-moesin (ERM) proteins that also interact with the PDZ protein, Na(+) /H(+) exchanger regulatory factor 1 (NHERF-1/EBP50). In NHERF-1(-/-) mice, ERM proteins are significantly reduced in brush-border membranes from kidney and small intestine. ERM knockdown reduces ICAM-1 expression in response to tumor necrosis factor alpha. Here we show that NHERF-1 assembles ERM proteins, ICAM-1 and F-actin into a macromolecule complex that is increased in mouse liver after BDL. Compared to wild-type (WT) mice, both sham-operated and BDL NHERF-1(-/-) mice have lower levels of activated ERM and ICAM-1 protein in the liver accompanied by significantly reduced hepatic neutrophil accumulation, serum alanine aminotransferase, and attenuated liver injury after BDL. However, total bile acid concentrations in serum and liver of sham and BDL NHERF-1(-/-) mice were not significantly different from WT controls, although hepatic tetrahydroxylated bile acids and Cyp3a11 messenger RNA levels were higher in NHERF-1(-/-) BDL mice.
  
  
  CONCLUSIONS
  NHERF-1 participates in the inflammatory response that is associated with BDL-induced liver injury. Deletion of NHERF-1 in mice leads to disruption of the formation of ICAM-1/ERM/NHERF-1 complex and reduction of hepatic ERM proteins and ICAM-1, molecules that are up-regulated and are essential for neutrophil-mediated liver injury in cholestasis. Further study of the role of NHERF-1 in the inflammatory response in cholestasis and other forms of liver injury should lead to discovery of new therapeutic targets in hepatic inflammatory diseases.
authors.affiliation: Yale Liver Center, Yale University School of Medicine, New Haven, CT.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Yale Liver Center, Yale University School of Medicine, New Haven, CT.
authors.forename: Albert
authors.initials: A
authors.lastname: Mennone
authors.affiliation: Yale Liver Center, Yale University School of Medicine, New Haven, CT.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Soroka
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA.
authors.forename: Lee R
authors.initials: LR
authors.lastname: Hagey
authors.affiliation: Yale Liver Center, Yale University School of Medicine, New Haven, CT.
authors.forename: Xinshou
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Weinman
authors.affiliation: Yale Liver Center, Yale University School of Medicine, New Haven, CT.
authors.forename: James L
authors.initials: JL
authors.lastname: Boyer
mesh_terms: D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000209:etiology*; D006505:Hepatitis / Q000209:etiology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D008107:Liver Diseases / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D025581:Neurofibromin 2 / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000502:physiology*
chemical_list: D025581:Neurofibromin 2; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D018799:Intercellular Adhesion Molecule-1