Acute Phase Response-driven Hepatic Niche Remodeling Promotes Fibrosis Resolution After Alcohol Cessation
Year: 2025
Type: article
Abstract: BACKGROUND & AIMS: Abstinence is beneficial for patients with alcohol-associated liver disease (ALD), but disease resolution after alcohol cessation occurs slowly and only in a subset of patients. We aimed to study the mechanisms of ALD resolution using spatial transcriptomics. METHODS: Mice were fed Western diet with 20% alcohol in the drinking water for 20 weeks followed by chow diet with plain water for 4 weeks. Livers were analyzed by 1000-plex CosMx spatial transcriptomics assay (Nanostrings). To assess the role of serum amyloid A (SAA), mice were treated with recombinant SAA or SAA-rich high-density lipoprotein (HDL). RESULTS: hepatocytes induced matrix metalloproteinase and lysosomal enzyme (Ctsd, Psap) gene expression in liver macrophages in an SAA and FPR2-dependent way. Moreover, after alcohol cessation, SAA was enriched on circulating HDL and the SAA pro-resolving function required SR-BI-mediated HDL uptake by macrophages. In vivo recombinant SAA or SAA-enriched HDL promoted fibrosis resolution after alcohol cessation in mice. SAA expression itself was mediated by IL-22R signaling in hepatocytes regulated by KDM5B demethylase and C/EBPβ. Hepatocyte-specific Kdm5b or Cebpb knockout promoted Il22a1 expression, Saa1/2 upregulation and collagen remodeling, facilitating fibrosis resolution after alcohol cessation. CONCLUSIONS: Acute phase response activation after alcohol cessation triggers intrahepatic cell-cell communication changes for efficient fibrosis resolution.
Authors: Michael Schonfeld, Kruti Nataraj, Samson Mah, Wei Zhong, Steven A. Weinman, Irina Tikhanovich
Institution: University of Kansas Medical Center
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
Awards: Role of Arginine Methylation in Alcohol Pathogenesis, G7302615952, The role of H3K4 demethylases in alcohol-associated liver disease development and resolution, Kansas Center for Metabolism and Obesity REsearch (KC-MORE), The role of C/EBPß in sepsis associated acute-on-chronic liver failure, Role of alcohol adapted Kupffer cells in the progression and resolution of ALD
OpenAlex ID: W4416812518