studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 687A
Disclosures:
The following authors have nothing to disclose: Fengxia Ge, Jose L. Walewski,
Paul D. Berk
973
Role of the receptor tyrosine kinase Mer in the development
of fibrosis in NAFLD
Giovanni Di Maira 1 , Salvatore Petta 2 , Andrea Cappon 1 , Elisa
Vivoli 1 , Luca Valenti 3 , Paola Dongiovanni 3 , Elisabetta Bugianesi 4 ,
Vito Di Marco 2 , Fabio Marra 1 ; 1 University of Florence, Florence,
Italy; 2 University of Palermo, Palermo, Italy; 3 University of Milan,
Milan, Italy; 4 University of Turin, Turin, Italy
Background/aims: Non-alcoholic fatty liver disease (NAFLD)
describes a spectrum of conditions ranging from steatosis to
non-alcoholic steatohepatitis (NASH), which may progress
to fibrosis, cirrhosis and hepatocellular carcinoma. Several
genetic factors involved in NAFLD severity and progression
have been identified through genome-wide association studies
(GWAS) but their biologic significance and sites of action is
still unclear. Mer (MerTK) is a receptor tyrosine kinase with
oncogenic properties, over-expressed or activated in various
malignancies. In a recent GWAS, a SNP of the non-coding
region of MerTK (rs4374383 G>A) has been associated with
fibrosis severity in patients with chronic hepatitis C, but currently
there is no evidence of the involvement of this factor
in the progression of NAFLD. Aim of this study was to assess
the possible role of MerTK in the fibrogenic progression of
NAFLD. Methods: Genetic analyses were performed on specimens
from patients who underwent liver biopsy for suspected
NASH without severe obesity. For murine models of fibrogenesis,
C57BL6/J mice were treated with CCl4 for 6 weeks, and
Balb/C mice were fed with a methionine and choline deficient
(MCD) diet for 8 weeks. Biopsy samples from patients with
NAFLD and different stages of fibrosis were also analyzed.
Intrahepatic gene expression was measured by qPCR. Human
HSC were isolated from normal liver tissue and cultured on
plastic. UNC569 was used to inhibit MerTK activity. Results:
The MerTK rs4374383 AA polymorphism, which is linked with
a decreased expression of MerTK, was associated with a lower
prevalence of clinically significant fibrosis in patients with
NAFLD. In murine models of hepatic fibrogenesis, an increased
hepatic expression of MerTK was observed. In human hepatic
stellate cells (HSC) Mertk was found to be highly expressed
at the gene and protein levels. Stimulation of MerTK with the
cognate ligand, GAS6, resulted in time-dependent activation of
ERK1/2 and in stimulation of cell migration. Moreover, pharmacological
inhibition of MerTK with UNC569 reduced HSC
survival activating apoptotic pathways. Finally, patients with
NAFLD and severe fibrosis had significantly higher intrahepatic
expression of MerTK than those with mild or no fibrosis.
Conclusion: These data indicate the novel role of MerTK as a
modulator of fibrogenesis in NAFLD and identify HSC as a
cellular target of this kinase.
Disclosures:
Fabio Marra - Advisory Committees or Review Panels: Abbvie; Consulting: Bayer
Healthcare; Grant/Research Support: ViiV
The following authors have nothing to disclose: Giovanni Di Maira, Salvatore
Petta, Andrea Cappon, Elisa Vivoli, Luca Valenti, Paola Dongiovanni, Elisabetta
Bugianesi, Vito Di Marco
974
GFT505 (ELAFIBRANOR) prevents nonalcoholic steatohepatitis
(NASH), hepatic fibrosis and hepatocarcinoma
in a new disease model
Benoit Noel 1 , Geraldine Rigou 1 , Nathalie Degallaix 1 , Valérie
Daix 1 , Linda Cambula 1 , Alice Roudot 1 , Rémy Hanf 1 , Dean W.
Hum 1 , Bart Staels 2 , Robert Walczak 1 ; 1 Genfit SA, Loos, France;
2 INSERM UMR1011, Institut Pasteur, Lille, France
Background: NAFLD is present in 20-30% of the adult population
in developed countries. NASH, cirrhosis and hepatocellular
carcinoma will develop in a substantial proportion of
people with NAFLD. Recently, the phase 2B GOLDEN-505 trial
has demonstrated the efficacy of GFT505 in reversing NASH
in patients with advanced disease. In the present study we
have assessed the efficacy of GFT505 in preventing NASH,
liver fibrosis and hepatocarcinoma development in a new rat
model. Methods: Steatohepatitis, NASH and hepatocarcinoma
were induced by feeding Wistar rats with a choline-deficient
L-amino-acid-defined-diet (CDAA) that was supplemented with
1% cholesterol. In the intervention group, animals also received
GFT505 (10mg/kg/day PO) for the entire study period.
NASH, fibrosis and hepatocarcinoma development were evaluated
by histology. Additional biochemical and molecular
analyses were also performed on different relevant biomarkers.
Results: CDAA diet administration in Wistar rats causes
liver transaminase elevation and fibrosing steatohepatitis that is
similar to human NASH pathology. In this study the supplementation
of the CDAA diet with 1% cholesterol led to increased
NASH incidence (92% vs 58%) and to fibrosis aggravation as
evidenced by higher prevalence of cirrhotic animals (42% vs.
8%). NASH development was significantly attenuated in rats on
CDAA diet that were also administered GFT505. Consistently,
hepatic inflammation, hepatocyte ballooning, oxidative stress
and plasma transaminase levels were decreased, whereas
plasma levels of FGF-21 and β-hydroxybutyrate, as well as
the expression of fatty acid oxidation genes in the liver were
increased in rats that received GFT505. Hepatic collagen was
lower, fibrosis and cirrhosis development were all significantly
prevented by GFT505 administration on CDAA diet. Finally,
GFT505 administration completely prevented pre-neoplastic
lesion development in rats exposed to CDAA diets as revealed
by the GST-P staining. Conclusion: GFT505 prevented NASH,
fibrosis, cirrhosis and pre-neoplastic lesion development in this
novel NASH model. Since the effect of GFT505 on hepatic
steatosis was rather modest in this particular model, this study
demonstrates that the antifibrotic activity of GFT505 can be
dissociated from its hypolipidemic efficacy.
Disclosures:
Benoit Noel - Employment: Genfit SA
Nathalie Degallaix - Employment: GENFIT SA
Linda Cambula - Employment: GENFIT SA
Alice Roudot - Employment: GENFIT
Rémy Hanf - Management Position: GENFIT
Dean W. Hum - Management Position: Genfit
Bart Staels - Advisory Committees or Review Panels: MSD; Consulting: Genfit
Robert Walczak - Management Position: Genfit SA
The following authors have nothing to disclose: Geraldine Rigou, Valérie Daix