Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty 
liver disease (NAFLD) which sets the stage for further liver damage. The 
mechanism for the progression of NASH involves multiple parallel hits including 
oxidative stress, mitochondrial dysfunction, inflammation and others. 
Manipulation of any of these pathways may be an approach to prevent NASH 
development and progression. Aramchol (arachidyl-amido cholanoic acid) is 
presently in a phase IIb NASH study. The aim of this study was to investigate 
Aramchol's mechanism of action and its effect on fibrosis using the methionine- 
and choline-deficient (MCD) diet model of NASH. We collected liver and serum 
from mice fed a MCD diet containing 0.1% methionine (0.1MCD) for four weeks, 
which developed steatohepatitis and fibrosis, as well as mice receiving a 
control diet; the metabolomes and proteomes were determined. 0.1MCD fed mice 
were given Aramchol (5mg/kg/day for the last 2 weeks); liver samples were 
analyzed histologically. Aramchol administration reduced features of 
steatohepatitis and fibrosis in 0.1MCD fed mice. Aramchol downregulated 
stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in triglyceride 
biosynthesis whose loss enhances fatty acid β-oxidation. Aramchol increased the 
flux through the transsulfuration pathway, leading to a rise in glutathione 
(GSH) and GSH/GSSG ratio, the main cellular antioxidant that maintains 
intracellular redox status. Comparison of serum metabolomic pattern between 
0.1MCD fed mice and NAFLD patients showed a substantial overlap.
CONCLUSIONS: Aramchol treatment improved steatohepatitis and fibrosis by 1) 
decreasing SCD1, and 2) increasing the flux through the transsulfuration pathway 
maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD 
model resembles the metabolic phenotype observed in about 50% of NAFLD patients, 
which supports the potential use of Aramchol in NASH treatment.