Ron Receptor Signaling Ameliorates Hepatic Fibrosis in a Diet-Induced Nonalcoholic Steatohepatitis Mouse Model

Area of Science:

• Hepatology
• Immunology
• Metabolomics

Background:

• Nonalcoholic steatohepatitis (NASH) is a leading cause of liver fibrosis with limited treatment options.
• The macrophage-scavenger receptor 1 (MSR1)/Ron receptor axis exhibits anti-inflammatory properties.
• Understanding Ron receptor's role in NASH-associated liver fibrosis is crucial for developing new therapies.

Purpose of the Study:

• To investigate the role of the Ron receptor in NASH-induced hepatic fibrosis.
• To evaluate the impact of Ron receptor deficiency on steatohepatitis progression and liver fibrosis.
• To identify metabolic and molecular changes associated with Ron receptor dysfunction in NASH.

Main Methods:

• Utilized Ron ligand domain knockout (DKO) mice on an apolipoprotein E knockout background, fed a high-fat, high-cholesterol diet for 18 weeks.
• Employed 1H nuclear magnetic resonance (NMR)-based metabolomics to analyze serum metabolite profiles.
• Conducted gene expression profiling and histological analysis of liver tissues to assess inflammation, steatosis, and fibrosis.

Main Results:

• Loss of Ron activation in DKO mice led to exacerbated NASH, including increased steatosis, hepatocellular injury, inflammation, and fibrosis.
• Metabolomic analysis revealed altered serum lipid profiles, elevated VLDL/LDL and pyruvate, and reduced glycine in DKO mice.
• DKO mice showed increased collagen deposition, immune cell infiltration, myofibroblast accumulation, and elevated expression of pro-fibrogenic genes in the liver.

Conclusions:

• Ron receptor activation confers protection against NASH-induced hepatic fibrosis.
• Ron receptor deficiency promotes NASH progression and liver fibrosis through inflammatory and fibrogenic pathways.
• Targeting the MSP/Ron receptor axis may represent a novel therapeutic strategy for NASH-associated liver fibrosis.