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

## 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.

## Key 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 in mice after alcohol cessation and in human liver samples. In vitro analysis confirmed that Saa1/2high 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.

Acute phase response activation after alcohol cessation triggers intrahepatic cell-cell communication changes for efficient fibrosis resolution.