2026/04/01 by Cheng Chen, Bryan Mackowiak, Dechun Feng +7 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Alcohol Consumption and Health Effects #Ion Transport and Channel Regulation #Liver Disease and Transplantation
paper · doi:10.1111/acer.70272
openalex publication_date 2026/04/01 · openalex created_date 2026/04/07 · openalex updated_date 2026/07/28
BACKGROUND: Acetaldehyde (AcH), a highly reactive metabolite of ethanol, plays a pivotal role in the pathogenesis of alcohol-associated liver disease (ALD) and alcohol use disorder (AUD). Post alcohol consumption, AcH generated in hepatocytes is further metabolized into acetate by aldehyde dehydrogenase 2 (ALDH2) or excreted into circulation and bile via the basolateral and apical membranes, respectively. Our previous studies have demonstrated that aquaporin 8 (AQP8), which is a water channel and mainly expressed on the apical membrane, facilitates AcH excretion into bile. AQP9 is predominantly expressed on the basolateral membrane of hepatocytes; however, the roles of AQP9 in AcH relocation and pathogenesis of ALD and AUD remain unknown. METHODS: AQP9 expression was examined in human ALD liver samples. The role of AQP9 was investigated by using the NIAAA mouse model of ALD, voluntary and binge-drinking behavior paradigms, global Aqp9 knockout (KO) mice, in situ liver perfusion, and primary hepatocyte culture assays. RESULTS: Our data demonstrated that hepatic AQP9 expression was markedly downregulated in ALD patients and correlated with liver injury markers and metabolic gene expression. In mice, Aqp9 KO ameliorated early-stage ALD by reducing hepatic lipogenesis, lipid peroxidation, and inflammation. In vivo and in vitro experiments revealed that AQP9 promotes AcH influx into hepatocytes. By using drinking in the dark experiments, we found that Aqp9 KO mice had reduced binge-like alcohol consumption compared with wild-type mice, while two-bottle choice experiments revealed that Aqp9 KO mice had slightly higher alcohol preference compared with wild-type mice. CONCLUSIONS: Our findings suggest that AQP9 promotes hepatocytes to take up AcH, thereby exacerbating ALD progression and regulating alcohol-drinking behavior.