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An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Adipose tissue-derived MFG-E8 promotes hepatic inflammation and fibrosis through macrophage activation in a mouse
Masashi Kuroda1, Kazuhiro Nomura1,2, Azumi Wada1
1Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Tokushima, Japan.
Abstract:
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatocellular injury, macrophage activation, and severe fibrosis, and often progresses to liver cirrhosis and hepatocellular carcinoma. Excessive accumulation of visceral fat exacerbates hepatic inflammation and fibrosis independently of fatty liver, but the underlying molecular mechanisms have remained unclear. We here identify MFG-E8 (milk fat globule-EGF8) as a secreted protein that is overexpressed in adipose tissue of obese mice and contributes to such exacerbation. MFG-E8 deficiency in MASH model (STAM-MASH) mice was associated with reduced hepatic expression of inflammation- and fibrosis-related genes without attenuation of steatosis. Conversely, MFG-E8 supplementation in MFG-E8 knockout mice intensified hepatic inflammation and promoted the formation of hepatic crownlike structures. Coculture of macrophages with apoptotic hepatocytes induced expression of inflammatory cytokine genes, and this effect was enhanced by the presence of exogenous MFG-E8 in the culture medium. Our findings suggest that adipose tissue-derived MFG-E8 infiltrates the liver and promotes macrophage-hepatocyte interaction, thereby contributing to hepatic inflammation and fibrosis in MASH.
Insights
Milk fat globule-EGF8 (MFG-E8), overexpressed in obesity, drives liver inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) by promoting macrophage-hepatocyte interactions. MFG-E8 deficiency reduces liver inflammation without affecting steatosis.
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) involves liver injury, inflammation, and fibrosis, potentially progressing to cirrhosis and cancer.
- Visceral fat accumulation worsens MASH-related liver inflammation and fibrosis, but the molecular drivers are not fully understood.
Purpose of the Study:
- To identify molecular mechanisms by which adipose tissue contributes to MASH progression.
- To investigate the role of milk fat globule-EGF8 (MFG-E8) in MASH pathogenesis.
Main Methods:
- Utilized STAM-MASH mouse models with MFG-E8 deficiency or supplementation.
- Employed coculture systems of macrophages and apoptotic hepatocytes.
- Analyzed gene expression related to inflammation and fibrosis in liver tissues.
Main Results:
- MFG-E8 deficiency in MASH mice reduced hepatic inflammation and fibrosis markers without altering steatosis.
- MFG-E8 supplementation exacerbated liver inflammation and promoted hepatic crownlike structures.
- Exogenous MFG-E8 enhanced inflammatory cytokine gene expression in macrophage-hepatocyte cocultures.
Conclusions:
- Adipose tissue-derived MFG-E8 infiltrates the liver in MASH.
- MFG-E8 promotes macrophage-hepatocyte interactions, contributing to hepatic inflammation and fibrosis.
- MFG-E8 is a key mediator linking obesity-associated adipose tissue dysfunction to MASH progression.
