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

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 <i>Aqp8</i> expression, whereas overexpression of hepatic <i>Aqp8</i> 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.