Hepatic Aquaporin 8 Promotes Alcohol Consumption and Ameliorates Alcohol-Induced Liver Injury by Facilitating Acetaldehyde Excretion

Sep 30, 2026

Acetaldehyde, the first metabolite of ethanol, modulates alcohol consumption and liver injury, with liver ALDH2 long considered its primary clearing route. This study identifies hepatic aquaporin 8 (AQP8) as a key channel for acetaldehyde excretion into bile, enhancing efflux from hepatocytes with or without changes in bile flow. Acute ethanol increases AQP8-mediated bile flow and promotes acetaldehyde clearance, while chronic exposure downregulates Aqp8; restoring AQP8 alleviates lipid metabolism disruption and inflammation in alcohol-associated liver disease, supporting therapeutic targeting.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Introduction

Acetaldehyde metabolism and ALDH2

Gut-liver ALDH2 axis and bile transport

AQP8 localization and transport roles

Study design and main findings

Ivyspring International Publisher InternationalJournal of Biological Sciences 2026; 22(2): 566-581. doi: 10.7150/ijbs.122713 Research Paper Hepatic Aquaporin 8 Promotes Alcohol Consumption and Ameliorates Alcohol-Induced Liver Injury by Facilitating Acetaldehyde Excretion Cheng Chen1,2, Yu-Hong Lin1, Dechun Feng1, Yukun Guan1, Yaojie Fu1, Yang Wang1, Luca Maccioni1,2, Deniz Seyhan1, Tiantian Yao1, Shoupeng Wei3, Li Zhang3, George Kunos2, Bryan Mackowiak1􀀍, Bin Gao1,4􀀍 1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. 2. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. 3. Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. 4. Lead contact. 􀀍 Corresponding authors: [bryan.mackowiak@nih.gov](bryan.mackowiak@nih.gov) (B.M.), [bgao@mail.nih.gov](bgao@mail.nih.gov) (B.G.) . © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.07.30; Accepted: 2025.10.28; Published: 2026.01.01 Abstract Acetaldehyde (AcH), the first metabolite of ethanol, is an aversive and bioactive compound that plays a key role in modulating alcohol consumption and liver injury. The traditional notion is that AcH is primarily metabolized in the liver by aldehyde dehydrogenase 2 (ALDH2). However, our recent study suggests that the gut-liver ALDH2 axis, rather than the liver alone, plays a key role in metabolizing and clearing AcH partially via bile secretion. Aquaporin 8 (AQP8) is a membrane channel that localizes at the canalicular membrane of hepatocytes and is known to increase bile flow. Here, we identify hepatic AQP8 as an important channel of AcH excretion, mediating its efflux from hepatocytes into bile both with and without altering bile flow. We demonstrated that acute alcohol exposure enhanced AQP8-mediated bile flow and AQP8 promoted hepatic AcH clearance and increased alcohol consumption in both male and female mice. Furthermore, chronic alcohol exposure downregulated hepatic Aqp8 expression, whereas overexpression of hepatic Aqp8 alleviated dysregulated lipid metabolism and liver inflammation in a murine model of alcohol-associated liver disease (ALD). Collectively, our study uncovers a novel role for AQP8 in AcH secretion, demonstrating how this pathway influences both alcohol consumption and liver injury. These findings provide a foundation for exploring AcH excretion as a therapeutic target in alcohol use disorder and ALD. Introduction Acetaldehyde (AcH), the primary product of ethanol (EtOH) metabolism, is a known carcinogen whose broad physiological effects are largely dependent on tissue type and concentration [1] . Aldehyde dehydrogenase 2 (ALDH2) metabolizes AcH to acetate, and the inactive ALDH2 polymorphism (Aldh2*2), which is prevalent in the Eastern Asian population, causes the accumulation of AcH following alcohol consumption [2] . Individuals carrying the Aldh2*2 allele are protected from alcohol use disorder (AUD) due to the aversive effects of AcH accumulation. However, they have higher rates of head & neck and esophageal cancers, likely due to the high level of AcH in the mouth and throat after alcohol consumption [3-5] . Our recent studies have shown that liver and gut ALDH2 work synergistically to clear systemic AcH, with AcH excretion in bile serving as a critical pathway for its clearance via enterohepatic circulation [6, 7] . Notably, while ethanol distributes uniformly [https://www.ijbs.com](https://www.ijbs.com) across tissues according to water content [1], AcH

FAQs

What role does acetaldehyde (AcH) play in alcohol consumption and liver injury?

AcH is an aversive and bioactive metabolite of ethanol that modulates alcohol consumption and contributes to liver injury, with its effects depending on tissue type and concentration.

How does AQP8 influence acetaldehyde clearance in the liver?

Hepatic AQP8 facilitates acetaldehyde efflux from hepatocytes into bile, mediating clearance both with and without altering bile flow.

What are the effects of acute versus chronic alcohol exposure on Aqp8 and liver outcomes?

Acute exposure enhances AQP8-mediated bile flow and acetaldehyde clearance, whereas chronic exposure suppresses hepatic Aqp8 expression; restoring AQP8 levels improves lipid metabolism dysregulation and liver inflammation in alcohol-associated liver disease.

Sep 30, 2026

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