TNF alpha and Recovery from Alcoholic Liver Injury

Duke University, Durham NC

Investigators

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Abstract

Morbidity and mortality in alcohol-related liver diseases (ALD) are caused by severe alcohol-induced steatohepatitis (SAH) and cirrhosis (AC). Effective therapies are lacking because the mechanisms driving the pathogenesis and progression of SAH and AC are unclear. This research program has evaluated the general hypothesis that bad outcomes of alcohol-induced liver injury result from deregulated repair mechanisms that cause defective regeneration of mature hepatocytes. Our prior results indicate that effective liver regeneration requires reactivating fetal programs to nurture the outgrowth of liver progenitors but then silencing these programs, so the liver matures appropriately. Thus, we will continue to evaluate the hypothesis that ALD progresses because mechanisms controlling when fetal programs are switched ON and OFF in adult liver cells are dysregulated. We have evidence that liver failure in human SAH results from the over-activation of fetal programs. Conversely, our pre-clinical data suggest that cirrhosis evolves when adult programs are not suppressed sufficiently for injured livers to regenerate. RNA Binding Proteins (RBPs) dynamically control the stability, translation, and splicing of mRNAs encoded by liver genes. Thus, we propose that RBPs critically control adult-fetal “switching” in hepatocytes during ALD. To identify the repertoire of RNA binding proteins, RNA splice variants, and liver genes that change in response to alcohol-induced liver injury, we coupled high- resolution sequencing of liver RNA with single-cell transcriptomics and chromatin accessibility analyses. ESRP2 was identified as one of the most down-regulated hepatocyte RBPs in human SAH. ESRP2 regulates the splicing of ~20% of hepatocyte RNAs, generating splice variants that encode functional differences in proteins that control hepatocyte proliferation and differentiation. We have reported that ESRP2 is critically important for switching on the adult program in developing livers and that over-expressing ESRP2 blocks adult liver regeneration. Our new data show that human SAH livers are enriched with fetal splice variants of ESRP2 targets that alter the activity and cellular localization of their encoded proteins. We reported that TNF and IL1 (critical cytokines in ALD pathogenesis) regulate both ESRP2 expression and adult-to-fetal “switching” in hepatocytes. Our ongoing studies indicate that manipulating ESRP2 exacerbates liver damage in mouse models of steatohepatitis, further supporting the concept that ESRP2 misregulation is an important driver of deregulated repair mechanisms in ALD. Iterative analyses of human liver samples and mouse models of liver injury and repair will continue during the next funding cycle. Based on present data, we will prioritize studies to determine how ESRP2-regulated RNA splicing events control hepatocyte responses to alcohol-induced injury, delineate how these adapted hepatocytes reconfigure other liver cell communities to dictate ALD outcomes, and define mechanisms that regulate ESRP2 expression, thereby revealing novel therapeutic targets to improve recovery from ALD.