Tuesday, January 21, 2025
1/21/2025
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.
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