The role of Acute Phase Response signaling in Alcohol-associated liver disease resolution

About This Grant

PROJECT SUMMARY Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. The specific mechanisms responsible for ALD development and progression are not fully understood, and there is limited therapy for any stage of ALD. Alcohol cessation is the most beneficial intervention for patients with ALD. But abstinence benefits fewer people than expected; improvement is generally slow, and many patients do not improve. Our preliminary data show that following alcohol cessation, a subset of hepatocytes directs a resolution program where they produce signals that alter the phenotype of liver macrophages and other non-parenchymal cells (NPC) to modulate inflammatory responses and stimulate collagen degradation. Preliminary spatial transcriptomics analysis in mice and human ALD identified different subsets of hepatocytes within distinct liver niches that are involved in promoting either a pro-fibrogenic or a pro-fibrolytic microenvironment in the liver. We found that one of the main signaling programs present in the fibrolytic niche was the Acute Phase Response (APR) in hepatocytes. Our data further suggest that APR induction and consequent fibrosis resolution are impeded in ALD because of persistent alcohol-induced epigenetic changes in hepatocytes mediated by CCAAT enhancer binding protein beta (C/EBPβ). We found that hepatocyte specific Cebpb knockout at the time of alcohol cessation induced acute phase proteins such as Serum amyloid A (SAA) and promoted fibrosis resolution. Moreover, we found that SAA or SAA-enriched acute phase HDL had potent pro- resolving properties in vitro and in vivo. Taken together our data suggest that APR signaling can stimulate fibrosis resolution. We hypothesize that after alcohol cessation hepatocytes produce APR proteins, such as SAA, either alone or in association with HDL particles, that alter the phenotype of non-parenchymal cells and stimulate pro-resolving changes required for collagen degradation and fibrosis resolution. Persistent alcohol- induced activation of C/EBPβ reduces the ability of hepatocytes to promote the resolution program by blunting APR response at the gene expression level. We propose to study this hypothesis with following specific aims: Aim 1 To define how APR signaling remodels the fibrolytic liver niche Aim 2 To determine the mechanism of C/EBPβ-dependent APR gene expression Aim 3 To assess the role of HDL in APR-induced niche remodeling Results of the proposed project will provide novel insights into the nature of resolution of alcohol-associated liver disease after alcohol cessation. They will provide the mechanistic underpinning to exploit the therapeutic potential of APR and acute phase HDL for enhancing fibrosis resolution after alcohol cessation.