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Principal Investigator: STEVEN A WEINMAN
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2024
Award: $602,586
Funding agency: National Institute on Alcohol Abuse and Alcoholism
PROJECT SUMMARY
Alcohol-associated liver disease (ALD) is a major world-wide health problem that accounts for
approximately 40,000 deaths per year in the US. A major cause of death in ALD is the onset of an acute
liver failure event called alcohol-associated hepatitis (AH). The mechanisms that cause the onset of AH
in patients with ALD are unknown. The most important treatment for ALD is alcohol abstinence.
Unfortunately, some people with ALD who stop drinking fail to adequately improve in terms of liver
function or fibrosis. Again, the mechanisms leading to incomplete disease resolution after abstinence
are unknown. Liver macrophages, including Kupffer cells and infiltrating macrophages, play a central
role in regulating liver function during ALD but how they contribute to the onset of AH and what role
they play in the outcome of liver disease following alcohol abstinence is unknown. We recently
developed a new western diet alcohol (WDA) model of ALD that reproduces features of human alcohol-
associated steatohepatitis in mice. Using single cell RNA sequencing, we have identified alcohol
specific Kupffer cell subsets and assessed the function of these by selectively ablating them using
diphtheria toxin receptor techniques. During alcohol exposure, KC ablation resulted in liver failure with
hepatocytes de-differentiating into a progenitor-like phenotype very similar to the situation in human
AH. This result demonstrates that KCs play a previously unrecognized role in maintaining differentiated
hepatocyte function during chronic alcohol exposure. The overall hypothesis of this proposal is that
during alcohol exposure, KCs produce signals, such as exosomal Let-7, that help to maintain
hepatocytes in their differentiated state. Loss of KCs or KC function can trigger an AH-like loss of liver
function. Upon alcohol cessation, KCs are also required for resumption of liver homeostasis and fibrosis
resolution. Loss of KC subsets can delay recovery and suppress resolution of ALD fibrosis. In the
current proposal we will determine how specific KC and IM subsets regulate hepatocyte function during
alcohol exposure, how they change and function upon cessation of alcohol consumption, and how this
information can be used to improve liver function and enhance recovery from ALD. We will achieve
these goals with the following specific aims. (1) To determine the functions of KC and IM subsets in a
mouse model of ALD, (2) to determine how Kupffer cell loss promotes hepatocyte transition to a
progenitor-like state, and (3) to assess the role of MΦ subsets in fibrosis development and resolution
after alcohol cessation. Understanding the factors that regulate the presence and function of alcohol-
specific KC subsets would provide the opportunity to develop macrophage-based therapies to reverse
liver failure in patients with AH and accelerate recovery in patients with ALD who cease alcohol
consumption.
Terms: <Ablation><Abstinence><Acceleration><Acute><Acute Hepatic Failure><Acute Liver Failure><Alcohol Chemical Class><Alcohol Drinking><Alcohol associated hepatitis><Alcohol consumption><Alcohol hepatitis><Alcohol induced hepatitis><Alcohol related hepatitis><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcohols><Appearance><Autoregulation><Biochemical><Body Tissues><CITE sequencing><CITE-seq><CITEseq><Cause of Death><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Count><Cell Function><Cell Interaction><Cell Number><Cell Physiology><Cell Process><Cell Signaling><Cell secretion><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Indexing of Transcriptomes and Epitopes by Sequencing><Cellular Physiology><Cellular Process><Cellular Secretion><Cessation of life><Chronic><Collagen><DTR Protein><Death><Development><Diphtheria Toxin Sensitivity><Disease><Disorder><EtOH drinking><EtOH use><Ethanol-induced hepatitis><Event><Family><Family member><Fibrosis><Fulminant Liver Failure><Fulminating Hepatic Failure><Fulminating Liver Failure><Gene Expression><Gene Transcription><Genetic Transcription><Goals><Grant><Growth Agents><Growth Factor><Growth Substances><HB-EGF precursor><Health><Hepatic Cells><Hepatic Disorder><Hepatic Failure><Hepatic Parenchymal Cell><Hepatic Transplantation><Hepatitis><Hepatocyte><Histologic><Histologically><Homeostasis><Human><IGF1><IGF1 gene><IGFI><Immune infiltrates><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><In Vitro><Infiltration><Inflammation><Intracellular Communication and Signaling><Kupffer Cells><Liver><Liver Cells><Liver Failure><Liver Fibrosis><Liver Grafting><Liver Regeneration><Liver Transplant><Liver diseases><Liver necrosis><MMPs><Macrophage><Matrix Metalloproteinases><Metabolic><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Modern Man><Murine><Mus><Mφ><Necrosis hepatocellular><Outcome><Pathogenicity><Patients><Persons><Phenotype><Physiological Homeostasis><Play><Population><Process><Progenitor Cells><Proliferating><Property><Proteins Growth Factors><Protocol><Protocols documentation><RNA Expression><RNA-Binding Proteins><Recovery><Resolution><Role><Signal Transduction><Signal Transduction Systems><Signaling><Sorting><Steatohepatitis><Stellate Sinusoidal Macrophage><Stem Cell like><Subcellular Process><Techniques><Technology><Testing><Therapeutic Intervention><Time><Tissues><Transcription><Work><abstaining from alcohol><abstaining from ethanol><abstinence from alcohol><abstinence from ethanol><alcohol abstinence><alcohol exposed><alcohol exposure><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol product use><alcohol related liver disease><alcohol use><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><biological signal transduction><cellular indexing of transcriptomes and epitopes by single cell sequencing><develop therapy><developmental><diphtheria toxin receptor><diptheria toxin receptor><disease phenotype><drinking><effective therapy><effective treatment><ethanol abstinence><ethanol consumption><ethanol drinking><ethanol exposed><ethanol exposure><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol liver disease><ethanol product use><ethanol use><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><exosome><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><extracellular><extracellular vesicles><fatty liver disease><feeding><fibrotic liver><fulminant hepatic failure><hepatic body system><hepatic disease><hepatic fibrosis><hepatic necrosis><hepatic organ system><hepatopathy><immune cell infiltrate><improved><in vivo><intervention development><intervention therapy><liver disorder><liver function><liver macrophage><liver transplantation><member><miRNA><miRNAs><mortality><mouse model><murine model><nanocarrier><nanovessel><progenitor><resolutions><restoration><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem cell characteristics><stem cells><stemness><therapy development><treatment development><western diet><western-style diet><western-type diet>