# Mechanisms of Hepatic Alcohol Tolerance

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $260,403

## Abstract

PROJECT DESCRIPTION/SUMMARY
Acute alcoholic hepatitis (AH) is a severe inflammatory liver disease triggered by both chronic and binge drinking.
The disease has a 30-day mortality of approximately 20%. One of the most striking features of AH is that it affects
only a small minority of heavy drinkers suggesting that most individuals are protected from developing alcoholic
liver inflammation by unknown mechanisms. We have shown that alcohol causes changes in mouse liver
macrophage (MΦ) populations with a rapid loss of up to 50% of Kupffer cells and entry of infiltrating MΦs. By 10
days Kupffer cell numbers are restored but they have become more anti-inflammatory. In mice lacking the initial
burst of MΦ apoptosis, the shift to an anti-inflammatory phenotype at 10 days does not occur. The MΦ population
changes correlate with changes in the sensitivity of the liver to a challenge with LPS and preliminary studies in
both MΦ-MΦ and MΦ-hepatocyte co-cultures demonstrate that 10-day liver MΦs can suppress LPS-induced
inflammatory responses. We hypothesize that exposure to alcohol causes dynamic and adaptive changes in
both Kupffer cells and non-Kupffer cell infiltrating MΦs and when this adaptation is successful it leads to an
adaptive state in which liver inflammation is minimal. Adaptation requires Kupffer cell-derived apoptotic bodies
and Th2 cytokines such as IL4 and IL13. The balance of pro-and anti-inflammatory MΦs and the sensitivity of
hepatocytes to pro-inflammatory cytokines change over time so that with prolonged alcohol exposure, adaptation
can be lost and liver inflammation can occur. Better understanding of the identity and function of adaptive MΦs
will allow us to identify similar cells in humans. Understanding the factors that lead to their formation and
maintenance would provide new approaches for the therapy of alcoholic liver disease. We will explore this
hypothesis with the following specific aims: Aim 1: To examine alcohol-induced adaptive changes in mouse
liver MΦ populations and use this information to identify similar MΦ populations in humans. We will use
single cell RNA-seq and lineage tracing approaches to define the changing MΦ populations that follow alcohol
exposure, characterize the different MΦ populations phenotypically, and identify MΦs associated with alcohol
adaptation in human liver tissue. Aim 2: To define the signals responsible for production and maintenance
of anti-inflammatory, alcohol adaptive MΦ populations in mice. We will examine the role of apoptotic body
receptors and hepatocyte derived factors including Th2 cytokines. Aim 3: To examine the hepatocyte-MΦ
interactions responsible for tolerance and injury. We will use micro-patterned hepatocyte-MΦ co-cultures to
examine defined mixtures of hepatocytes and MΦs to evaluate the different roles of MΦ subsets and hepatocytes
in inflammatory sensitivity. These studies will enhance our knowledge of how MΦ phenotype changes protect
the liver from alcohol and will provid...

## Key facts

- **NIH application ID:** 10002155
- **Project number:** 5R01AA012863-18
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** STEVEN A WEINMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $260,403
- **Award type:** 5
- **Project period:** 2000-09-27 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002155

## Citation

> US National Institutes of Health, RePORTER application 10002155, Mechanisms of Hepatic Alcohol Tolerance (5R01AA012863-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10002155. Licensed CC0.

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