Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans

Authors

  • Montserrat Moreno,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Javier F. Chaves,

    1. Genotyping and Genetic Diagnosis Unit, Research Foundation, Hospital Clínico Universitario de Valencia, Valencia, Spain
    Search for more papers by this author
  • Pau Sancho-Bru,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Fernando Ramalho,

    1. Experimental Hepatic Ischemia-Reperfusion Unit, Centro Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques de Barcelona, Barcelona, Catalonia, Spain
    Search for more papers by this author
  • Leandra N. Ramalho,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Maria L. Mansego,

    1. Genotyping and Genetic Diagnosis Unit, Research Foundation, Hospital Clínico Universitario de Valencia, Valencia, Spain
    Search for more papers by this author
  • Carmen Ivorra,

    1. Genotyping and Genetic Diagnosis Unit, Research Foundation, Hospital Clínico Universitario de Valencia, Valencia, Spain
    Search for more papers by this author
  • Marlene Dominguez,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Laura Conde,

    1. Genomics Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Cristina Millán,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Montserrat Marí,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Jordi Colmenero,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Juan J. Lozano,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Pedro Jares,

    1. Genomics Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Josep Vidal,

    1. Endocrinology Unit, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Xavier Forns,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Vicente Arroyo,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Juan Caballería,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Pere Ginès,

    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Search for more papers by this author
  • Ramón Bataller

    Corresponding author
    1. Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    • Liver Unit, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain
    Search for more papers by this author
    • fax: (34)-93-451-55-22.


  • Potential conflict of interest: Dr. Forns received grants from Roche and Schering-Plough.

Abstract

There are no effective antifibrotic therapies for patients with liver diseases. We performed an experimental and translational study to investigate whether ghrelin, an orexigenic hormone with pleiotropic properties, modulates liver fibrogenesis. Recombinant ghrelin was administered to rats with chronic (bile duct ligation) and acute (carbon tetrachloride) liver injury. Hepatic gene expression was analyzed by way of microarray analysis and quantitative polymerase chain reaction. The hepatic response to chronic injury was also evaluated in wild-type and ghrelin-deficient mice. Primary human hepatic stellate cells were used to study the effects of ghrelin in vitro. Ghrelin hepatic gene expression and serum levels were assessed in patients with chronic liver diseases. Ghrelin gene polymorphisms were analyzed in patients with chronic hepatitis C. Recombinant ghrelin treatment reduced the fibrogenic response, decreased liver injury and myofibroblast accumulation, and attenuated the altered gene expression profile in bile duct–ligated rats. Moreover, ghrelin reduced the fibrogenic properties of hepatic stellate cells. Ghrelin also protected rats from acute liver injury and reduced the extent of oxidative stress and inflammation. Ghrelin-deficient mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis, and ghrelin gene hepatic expression correlated with expression of fibrogenic genes. In patients with chronic hepatitis C, polymorphisms of the ghrelin gene (−994CT and −604GA) influenced the progression of liver fibrosis. Conclusion: Ghrelin exerts antifibrotic effects in the liver and may represent a novel antifibrotic therapy. (HEPATOLOGY 2010;51:974–985.)

Ancillary