Alcohol-associated liver disease (ALD) is a major cause of chronic liver diseases, leading to cirrhosis and liver cancer. The majority of patients with ALD also have moderate to severe alcohol use disorder (AUD). Our laboratory is investigating the immunological aspects and molecular pathogenesis of ALD and its associated liver cancer, and exploring novel therapeutic targets for the treatment of these maladies. We are also studying alcohol metabolism in the liver and other organs including gut, and exploring alcohol metabolism as a therapeutic target for the treatment of ALD and AUD.

Recent Stories

The liver is considered the major organ to metabolize ethanol and its metabolite acetaldehyde (AcH) by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase 2 (ALDH2), respectively; but this traditional notion has been challenged by our recent finding that deletion of the liver Aldh2 gene only partially impaired AcH clearance (Guillot et al., 2019). Our further study suggests that ALDH2 expression in multiple organs has redundant roles in metabolizing AcH, and we proposed a model below (Fu, Mackowiak et al. Nature Metabolism 2024).

Image

Laboratory of Liver Disease, NIAAA

A liver–gut axis, rather than liver alone, provides a coordinated action that drives systemic AcH clearance and voluntary alcohol drinking.

Alcohol is metabolized via ADH into AcH in hepatocytes. Approximately 70% secreted AcH from hepatocytes enters into circulation, while 30% secreted AcH is drained via the bile flow into  duodenal lumen, where AcH is detoxified and cleared by gut epithelium ALDH2, while a small portion of AcH is resorbed back to liver for further metabolism by liver ALDH2. This ‘liver–gut ALDH2 loop’ promotes systemic AcH clearance and, more importantly, controls alcohol preference and drinking behaviour. Targeting the liver–gut ALDH2 loop may represent a new therapeutic approach for AUD (created with BioRender.com).

(Fu, Mackowiak et al. Nature Metabolism 2024) 

ALD includes an array of liver disorders from steatosis to cirrhosis. Patients with underlying ALD may develop an episode of acute inflammatory liver injury, called alcohol-associated hepatitis (AH). Severe AH has high short-term mortality, and there are no FDA-approved drugs for AH. The major factor(s) that triggers severe inflammation in AH remains unknown. Our recent study suggests that self-sustaining IL-8+ neutrophil accumulation is a major factor to drive inexorable liver inflammation and failure in patients with sAH, proving a novel therapeutic target for sAH (Guan, Peiffer B, Feng, et al., JCI 2024). 

Image

Laboratory of Liver Disease, NIAAA

Targeting IL-8+ neutrophils is a promising therapeutic strategy for sAH.

Peripheral neutrophils express IL-8 at low levels. Liver neutrophils express IL-8 at high levels, which is induced by AH liver inflammatory environment that activates several signals including p38 MAPK to upregulate IL-8 in neutrophils.  Diagram was created with BioRender.com.

(Guan, Peiffer B, Feng, et al., JCI 2024) 

Recent Cover Stories

• Bile acid-activated macrophages promote biliary epithelial cell proliferation. Journal of Clinical Investigation March 2021.
• Distinct histopathological phenotypes of severe alcoholic hepatitis. Journal of Clinical Investigation July 2022.
• Monocyte-derived macrophages repair necrotic liver lesions. Journal of Clinical Investigation Aug. 2023. 

Image

Basic liver immunology and liver biology

The liver is the most important metabolic organ and is also the only mammalian organ that can fully regenerate after partial resection or injury. The liver has long been recognized to be immunologically privileged as evidenced by relative success with liver transplant. In addition, the liver has strong innate immunity that effectively and quickly defend against potentially toxic agents from the gut without launching harmful immune responses (Gao et al. 2008). Over the last two decades, our lab has been actively characterizing liver innate immune cells and cytokines produced by these cells, and exploring their functions in liver injury, regeneration, fibrosis, and cancer (He et al., 2021). Our recent studies have revealed that liver resident macrophages (Kupffer cells) regenerate after partial hepatectomy (Ahmed et al. 2021), and that macrophages play a key role in promoting necrotic liver lesion resolution (Feng et al., 2023) and promoting biliary epithelial cell regeneration after acute injury (Guillot et al. 2021).

Alcohol-associated liver disease (ALD)

The latest report from our institute shows that liver cirrhosis was the 11th leading cause of death in the USA, accounting for a total of 47,919 deaths in 2019, and 50.3% were alcohol related (https://www.niaaa.nih.gov/sites/default/files/surveillance-report118.pdf). The spectrum of ALD includes steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Patients with underlying ALD and excessive alcohol intake may develop acute alcohol-associated hepatitis (AH), a form of acute-on-chronic liver injury with the typical clinical syndrome jaundice (Mackowiak, Fu, Maccioni, Gao 2024). At present, there are no small animal models available that reproduce the full spectrum of human ALD. Thus, our laboratory has been actively using liver injury models (induced by ethanol and/or other insults) and collaborating with clinical investigators to conduct translational research on the pathogenesis and novel therapeutic targets for ALD with focusing on the following projects.

1. Inflammation in ALD: Inflammation plays a key role in ALD progression, but its role remains largely obscure (Gao et al., 2019). Our lab is characterizing liver inflammation and exploring its functions in patients with ALD by using multiplex immunofluorescence staining, bulk RNA and single-cell RNA sequencing. Our data suggest that IL-8+neutrophils are novel therapeutic targets for sAH (Ma et al., 2022; Guan et al., 2024).
2. Hepatoprotection of ALD: Currently, there are no FDA-approved drugs for ALD. We are investigating hepatoprotective factors in ALD and involving in translating these findings into new therapies for ALD. Particularly, we first discovered interleukin-22 (IL-22) as a key survival factor for hepatocytes (Radaeva et al., 2004, Pan et al., 2004), and subsequently characterized IL-22 biology in the liver (Hwang et al., 2023). These studies led to a phase IIb trial showing a promising result of IL-22 therapy in AH (Arab et al. 2019). IL-22 clinical trials are ongoing for the treatment of acute-on-chronic liver failure including AH.
3. Tumor microenvironment in alcohol-associated liver cancer: Alcohol consumption is a leading cause of liver cancer, but the underlying mechanisms remain obscure. We are studying tumor microenvironment in alcohol-associated liver cancer and exploring therapeutic targets for the treatment of this malady (Fu et al., 2023; Fu et al., 2024).

Alcohol metabolism and its role in ALD and AUD

Our data revealed that cooperative action of gut and liver, rather than liver alone, is mainly responsible for systemic AcH clearance, suggesting that targeting both liver and gut ALDH2 likely generates better therapeutic outcomes than targeting liver or gut ALDH2 alone (Fu, Mackowiak et al. 2024). We continue to explore alcohol metabolism in the organs other than the liver, and its biological significance in organ damage and AUD.

ALDH2 is a major enzyme for acetaldehyde elimination; however, approximately 30-40% east Asian populations have inactive ALDH2 due to the Glu487Lys polymorphism. Compared to individuals with normal ALDH2 activity, individuals with inactive ALDH2 generally drink lower amounts of alcohol but have higher levels of acetaldehyde and lower levels of acetate. The role of ALDH2 deficiency in pathogenesis of ALD and liver cancer remains poorly understood. We have characterized liver cancer in mice and humans with ALDH2 deficiency (Seo et al., 2019, Gao et al., 2019), and will continue to study ALD in mice and humans with inactive ALDH2, and define whether different diagnosis criteria and treatments are required for ALD patients with active or inactive ALDH2.