Acute Phase Response-driven Hepatic Niche Remodeling Promotes Fibrosis Resolution After Alcohol Cessation
Michael Schonfeld, Kruti Nataraj, Samson Mah, Wei Zhong, Steven A. Weinman, Irina Tikhanovich
TL;DR
After stopping alcohol, the liver activates a healing process involving specific cells and proteins that help reduce liver scarring.
Contribution
The study reveals a novel mechanism involving SAA and HDL in promoting fibrosis resolution after alcohol cessation.
Findings
SAA-expressing hepatocytes correlate with fibrolytic genes in mice and humans after alcohol cessation.
SAA and SAA-enriched HDL promote fibrosis resolution in mice via macrophage activation.
IL-22R signaling and KDM5B/C/EBPβ regulate SAA expression in hepatocytes.
Abstract
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. 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). Using a mouse model of ALD after alcohol cessation we performed spatial transcriptomics and identified a discrete multicellular fibrogenic and fibrolytic niches. Fibrolytic niches contained a unique subpopulation of hepatocytes that express SAA. SAA expression correlated with fibrolytic genes…
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Taxonomy
TopicsLiver physiology and pathology · Organ Transplantation Techniques and Outcomes · Genetic and Kidney Cyst Diseases