Christoph Tschuor1, Ekaterina Kachaylo1, Përparim Limani1, Dimitri A Raptis1, Michael Linecker1, Yinghua Tian1, Uli Herrmann2, Kamile Grabliauskaite1, Achim Weber3, Amedeo Columbano4, Rolf Graf1, Bostjan Humar5, Pierre-Alain Clavien6. 1. Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland. 2. Department of Neuropathology, University Hopital Zürich, Switzerland. 3. Institute of Surgical Pathology, University Hopital Zürich, Switzerland. 4. Department of Biomedical Sciences, University of Cagliari, Italy. 5. Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland. Electronic address: bostjan.humar@usz.ch. 6. Laboratory of the Swiss HPB and Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland. Electronic address: clavien@access.uzh.ch.
Abstract
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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.
BACKGROUND & AIMS: 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. METHODS: Activators of Car, various hepatectomies, Car(-/-) mice, humanized CARmice, 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. RESULTS: 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 humanCAR mitigates SFSS in humanized CARmice and improves the culture of human liver slices. CONCLUSIONS: 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. LAY SUMMARY: 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: Bharat Bhushan; John W Stoops; Wendy M Mars; Anne Orr; William C Bowen; Shirish Paranjpe; George K Michalopoulos Journal: Hepatology Date: 2018-12-31 Impact factor: 17.425
Authors: Rowan F van Golen; Pim B Olthof; Daniël A Lionarons; Megan J Reiniers; Lindy K Alles; Zehra Uz; Lianne de Haan; Bulent Ergin; Dirk R de Waart; Adrie Maas; Joanne Verheij; Peter L Jansen; Steven W Olde Damink; Frank G Schaap; Thomas M van Gulik; Michal Heger Journal: Sci Rep Date: 2018-11-08 Impact factor: 4.379