Hepatocyte steatosis activates macrophage inflammatory response accelerating atherosclerosis development

Area of Science:

• Metabolomics and Network Pharmacology
• Cardiovascular and Metabolic Diseases

Background:

• Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (AS) frequently coexist, sharing common risk factors and pathological pathways.
• Understanding the intricate mechanisms underlying NAFLD-AS comorbidity is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To elucidate the mechanistic links between NAFLD and AS comorbidity using metabolomics and network pharmacology.
• To identify key metabolites, molecular targets, and signaling pathways involved in the development of comorbid NAFLD and AS.

Main Methods:

• A high-fat diet-induced mouse model of NAFLD and AS comorbidity was established.
• Serum metabolomics identified differential metabolites, followed by network pharmacology analysis of core targets and pathways.
• In vitro cell models (hepatocytes and macrophages) were used to validate findings related to lipid accumulation, mitochondrial function, and inflammatory responses.

Main Results:

• Eighty-five differential metabolites were identified, with network pharmacology highlighting core targets including STAT3, EGFR, MAPK14, and PPARG.
• Key signaling pathways involved were PPAR, AGE-RAGE, TNF, and IL-17 signaling, among others.
• Experimental validation confirmed that hepatocyte steatosis leads to mitochondrial damage and dysfunction, promoting macrophage inflammation and foam cell formation, thereby exacerbating AS.

Conclusions:

• Abnormal lipid metabolism and inflammatory responses are central to NAFLD-AS comorbidity.
• Hepatocyte mitochondrial dysfunction, induced by steatosis, drives macrophage activation and accelerates atherosclerosis development.