Acute Phase Response-driven Hepatic Niche Remodeling Promotes Fibrosis Resolution After Alcohol Cessation

Area of Science:

• Hepatology
• Molecular Biology
• Immunology

Background:

• Alcohol-associated liver disease (ALD) resolution is slow and incomplete after alcohol cessation.
• Understanding the mechanisms of ALD fibrosis resolution is critical for therapeutic development.

Purpose of the Study:

• To investigate the molecular mechanisms driving liver fibrosis resolution in alcohol-associated liver disease (ALD) after alcohol cessation.
• To identify key cellular players and signaling pathways involved in ALD resolution using spatial transcriptomics.

Main Methods:

• Utilized a mouse model of ALD followed by alcohol cessation.
• Performed 1000-plex CosMx spatial transcriptomics on liver tissues.
• Assessed the role of serum amyloid A (SAA) by in vitro and in vivo manipulation.

Main Results:

• Identified distinct fibrogenic and fibrolytic niches in the liver post-cessation.
• Discovered SAA-expressing hepatocytes within fibrolytic niches, correlating with fibrosis resolution genes.
• Demonstrated that SAA, enriched on HDL, promotes fibrosis resolution via macrophage activation and requires SR-BI mediated uptake.

Conclusions:

• Activation of the acute phase response, particularly SAA signaling, is a key driver of fibrosis resolution in ALD.
• Spatial transcriptomics revealed crucial intrahepatic cell-cell communication networks mediating liver repair after alcohol cessation.