Identification of a common ketohexokinase-dependent link driving alcohol intake and alcohol-associated liver disease in mice.

ABSTRACT: Alcohol and sugar share reinforcing properties and both contribute to liver disease progression, ultimately leading to cirrhosis. Emerging evidence suggests that ethanol activates the aldose reductase pathway, resulting in endogenous fructose production. Here we investigated whether alcohol preference and alcohol-associated liver disease (ALD) are mediated through fructose metabolism by ketohexokinase (KHK)-A/C. Using global, conditional and tissue-specific KHK-A/C knockout mice, we assessed ethanol intake, reinforcement behaviours and liver injury. Ethanol consumption increased portal vein osmolality and activated the polyol pathway in the liver and intestine, leading to fructose production metabolized by KHK-A/C. Mice lacking KHK-A/C showed reduced ethanol preference across multiple para

SUBMITTER: Andres-Hernando A 

PROVIDER: S-EPMC12638252 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature