title: MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Homozygosity for a common non-coding rs4374383 G>A polymorphism in MERTK (myeloid-epithelial-reproductive tyrosine kinase) has been associated with the protection against fibrosis progression in chronic hepatitis C. The main study objective was to assess whether MERTK AA genotype influences liver fibrosis, and secondarily MERTK expression in patients with non-alcoholic fatty liver disease (NAFLD). We also investigated whether MERTK is expressed in human hepatic stellate cells (HSC) and in murine models of fibrogenesis.
  
  
  METHODS
  We considered 533 consecutive patients who underwent liver biopsy for suspected non-alcoholic steatohepatitis (NASH) without severe obesity from two Italian cohorts. As controls, we evaluated 158 patients with normal liver enzymes and without metabolic disturbances. MERTK rs4374383 genotype was assessed by 5'-nuclease assays. MERTK expression was analysed in mouse models of fibrosis, and the effect of the MERTK ligand GAS6 were investigated in human HSC.
  
  
  RESULTS
  Clinically significant fibrosis (stage F2-F4) was observed in 19% of patients with MERTK AA compared to 30% in those with MERTK GG/GA (OR 0.43, CI 0.21-0.88, p=0.02; adjusted for centre, and genetic, clinical-metabolic and histological variables). The protective rs4374383 AA genotype was associated with lower MERTK hepatic expression. MERTK was overexpressed in the liver of NAFLD patients with F2-F4 fibrosis and in in vivo models of fibrogenesis. Furthermore, exposure of cultured human HSC to the MERTK ligand GAS6, increased cell migration and induced procollagen expression. These effects were counteracted by inhibition of MERTK activity, which also resulted in apoptotic death of HSC.
  
  
  CONCLUSIONS
  The rs4374383 AA genotype, associated with lower intrahepatic expression of MERTK, is protective against F2-F4 fibrosis in patients with NAFLD. The mechanism may involve modulation of HSC activation.
authors.affiliation: Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy. Electronic address: petsa@inwind.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Petta
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marra
authors.affiliation: Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Grimaudo
authors.affiliation: Cattedra di Anatomia Patologica, University of Palermo, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.affiliation: Division of Gastro-Hepatology, Department of Medical Sciences, San Giovanni Battista Hospital, University of Torino, Torino, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
authors.affiliation: Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy.
authors.forename: Calogero
authors.initials: C
authors.lastname: Cammà
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappon
authors.affiliation: Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Di Marco
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Maira
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.affiliation: Cattedra di Anatomia Patologica, University of Palermo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mozzi
authors.affiliation: Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Orlando
authors.affiliation: Pathology, Fondazione IRCCS Ca' Granda Policlinico, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.affiliation: Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy.
authors.forename: Rosaria Maria
authors.initials: RM
authors.lastname: Pipitone
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi, Internal Medicine, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.affiliation: Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Craxì
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics*; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D000076202:c-Mer Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
keywords: Fibrosis; MERTK; NASH