MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease

• DOI: 10.1016/j.jhep.2015.10.016
• Publication Date: 2015-10-26T11:58:07Z
• Authors: Salvatore Petta; Luca Valenti; Fabio Marra; Stefania Grimaudo; Claudio Tripodo; Elisabetta Bugianesi; Calogero Cammà; Andrea Cappon; Vito Di Marco; Giovanni Di Maira; Paola Dongiovanni; Raffaela Rametta; Alessandro Gulino; Enrico Mozzi; Emanuele Orlando; Marco Maggioni; Rosaria Maria Pip...; Silvia Fargion; Antonio Craxì
• Keywords: Adult; Liver Cirrhosis; Male; Mice, Inbred BALB C; 0303 health sciences; Polymorphism, Genetic; c-Mer Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; nafld, fibrosis, mertk; Middle Aged; 3. Good health; 03 medical and health sciences; Fibrosis; MERTK; NASH; Hepatology; Non-alcoholic Fatty Liver Disease; Proto-Oncogene Proteins; Animals; Humans; Fibrosis; MERTK; NASH; Adult; Animals; Cells, Cultured; Female; Humans; Liver Cirrhosis; Male; Mice, Inbred BALB C; Middle Aged; Non-alcoholic Fatty Liver Disease; Proto-Oncogene Proteins; RNA, Messenger; Receptor Protein-Tyrosine Kinases; Polymorphism, Genetic; Medicine (all); Hepatology; Female; RNA, Messenger; Cells, Cultured

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.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.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.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.