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

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 Pipitone, Silvia Fargion, Antonio Craxì

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background & Aim 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.

Original languageEnglish
Pages (from-to)682-690
Number of pages9
JournalJournal of Hepatology
Volume64
Issue number3
DOIs
Publication statusPublished - Mar 1 2016

Fingerprint

Protein-Tyrosine Kinases
Fibrosis
Hepatic Stellate Cells
Genotype
Liver
Non-alcoholic Fatty Liver Disease
Ligands
Procollagen
Morbid Obesity
Chronic Hepatitis C
Fatty Liver
Liver Cirrhosis
Cell Movement
Biopsy

Keywords

  • Fibrosis
  • MERTK
  • NASH

ASJC Scopus subject areas

  • Hepatology

Cite this

MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. / Petta, Salvatore; Valenti, Luca; Marra, Fabio; Grimaudo, Stefania; Tripodo, Claudio; Bugianesi, Elisabetta; Cammà, Calogero; Cappon, Andrea; Di Marco, Vito; Di Maira, Giovanni; Dongiovanni, Paola; Rametta, Raffaela; Gulino, Alessandro; Mozzi, Enrico; Orlando, Emanuele; Maggioni, Marco; Pipitone, Rosaria Maria; Fargion, Silvia; Craxì, Antonio.

In: Journal of Hepatology, Vol. 64, No. 3, 01.03.2016, p. 682-690.

Research output: Contribution to journalArticle

Petta, S, Valenti, L, Marra, F, Grimaudo, S, Tripodo, C, Bugianesi, E, Cammà, C, Cappon, A, Di Marco, V, Di Maira, G, Dongiovanni, P, Rametta, R, Gulino, A, Mozzi, E, Orlando, E, Maggioni, M, Pipitone, RM, Fargion, S & Craxì, A 2016, 'MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease', Journal of Hepatology, vol. 64, no. 3, pp. 682-690. https://doi.org/10.1016/j.jhep.2015.10.016
Petta, Salvatore ; Valenti, Luca ; Marra, Fabio ; Grimaudo, Stefania ; Tripodo, Claudio ; Bugianesi, Elisabetta ; Cammà, Calogero ; Cappon, Andrea ; Di Marco, Vito ; Di Maira, Giovanni ; Dongiovanni, Paola ; Rametta, Raffaela ; Gulino, Alessandro ; Mozzi, Enrico ; Orlando, Emanuele ; Maggioni, Marco ; Pipitone, Rosaria Maria ; Fargion, Silvia ; Craxì, Antonio. / MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. In: Journal of Hepatology. 2016 ; Vol. 64, No. 3. pp. 682-690.
@article{282d79b2038c4c1b99a882933a36cf5a,
title = "MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease",
abstract = "Background & Aim 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.",
keywords = "Fibrosis, MERTK, NASH",
author = "Salvatore Petta and Luca Valenti and Fabio Marra and Stefania Grimaudo and Claudio Tripodo and Elisabetta Bugianesi and Calogero Camm{\`a} and Andrea Cappon and {Di Marco}, Vito and {Di Maira}, Giovanni and Paola Dongiovanni and Raffaela Rametta and Alessandro Gulino and Enrico Mozzi and Emanuele Orlando and Marco Maggioni and Pipitone, {Rosaria Maria} and Silvia Fargion and Antonio Crax{\`i}",
year = "2016",
month = "3",
day = "1",
doi = "10.1016/j.jhep.2015.10.016",
language = "English",
volume = "64",
pages = "682--690",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier B.V.",
number = "3",

}

TY - JOUR

T1 - MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease

AU - Petta, Salvatore

AU - Valenti, Luca

AU - Marra, Fabio

AU - Grimaudo, Stefania

AU - Tripodo, Claudio

AU - Bugianesi, Elisabetta

AU - Cammà, Calogero

AU - Cappon, Andrea

AU - Di Marco, Vito

AU - Di Maira, Giovanni

AU - Dongiovanni, Paola

AU - Rametta, Raffaela

AU - Gulino, Alessandro

AU - Mozzi, Enrico

AU - Orlando, Emanuele

AU - Maggioni, Marco

AU - Pipitone, Rosaria Maria

AU - Fargion, Silvia

AU - Craxì, Antonio

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Background & Aim 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.

AB - Background & Aim 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.

KW - Fibrosis

KW - MERTK

KW - NASH

UR - http://www.scopus.com/inward/record.url?scp=84958880042&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958880042&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2015.10.016

DO - 10.1016/j.jhep.2015.10.016

M3 - Article

VL - 64

SP - 682

EP - 690

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 3

ER -