title: Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss.
abstract: Liver can recover following resection. If tissue loss is too excessive, however, liver failure will develop as is known from the small-for-size-syndrome (SFSS). The molecular processes underlying liver failure are ill-understood. Here, we explored the role and the clinical potential of Nr1i3 (constitutive androstane receptor, Car) in liver failure following hepatectomy.
  
  
  
  Activators of Car, various hepatectomies, Car(-/-) mice, humanized CAR mice, human tissue and ex vivo liver slice cultures were used to study Car in the SFSS. Pathways downstream of Car were investigated by in vivo siRNA knockdown.
  
  
  
  Excessive tissue loss causing liver failure is associated with deficient induction of Car. Reactivation of Car by an agonist normalizes all features associated with experimental SFSS. The beneficial effects of Car activation are relayed through Foxm1, an essential promoter of the hepatocyte cell cycle. Deficiency in the CAR-FOXM1 axis likewise is evident in human SFSS. Activation of human CAR mitigates SFSS in humanized CAR mice and improves the culture of human liver slices.
  
  
  
  Impaired hepatic Car-Foxm1 signaling provides a first molecular characterization of liver that fails to recover after tissue loss. Our findings place deficient regeneration as a principal cause behind the SFSS and suggest CAR agonists may bear clinical potential against liver failure.
  
  
  
  The unique regenerative capacity of liver has its natural limits. Following tissue loss that is too excessive, such as through extended resection in the clinic, liver failure may develop. This is known as small-for-size-syndrome (SFSS) and represents the most frequent cause of death due to liver surgery. Here we show that deficient induction of the protein Car, a central regulator of liver function and growth, is a cause of liver failure following extended resection; reactivation of Car through pharmacological means is sufficient to prevent or rescue the SFSS.
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Tschuor
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kachaylo
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Përparim
authors.initials: P
authors.lastname: Limani
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Dimitri A
authors.initials: DA
authors.lastname: Raptis
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Linecker
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Neuropathology, University Hopital Zürich, Switzerland.
authors.forename: Uli
authors.initials: U
authors.lastname: Herrmann
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Kamile
authors.initials: K
authors.lastname: Grabliauskaite
authors.affiliation: Institute of Surgical Pathology, University Hopital Zürich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland. Electronic address: bostjan.humar@usz.ch.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.affiliation: Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland. Electronic address: clavien@access.uzh.ch.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D000090702:Constitutive Androstane Receptor; D006498:Hepatectomy; D006801:Humans; D008099:Liver; D017093:Liver Failure; D008115:Liver Regeneration; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear
chemical_list: D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear
keywords: CITCO; Hepatomegaly; Small-for-size syndrome; TCPOBOP