Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking

Dec 4, 2019Proceedings of the National Academy of Sciences of the United States of America

Blocking a liver enzyme reduces heavy but not moderate alcohol drinking

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Abstract

Mice with liver-specific ALDH2 inhibition exhibited reduced alcohol preference, suggesting the liver's crucial role in acetaldehyde metabolism.

Global and liver-specific ALDH2-deficient mice showed significantly higher acetaldehyde concentrations after ethanol intake compared to wild-type mice.
Energy expenditure and activity levels were notably lower in global ALDH2-deficient mice than in controls.
In a two-bottle test, global ALDH2-deficient mice consumed negligible amounts of ethanol, while liver-specific inhibition reduced preference for high alcohol concentrations.
Deficiency in glial or neuronal ALDH2 did not influence voluntary alcohol consumption.
The findings indicate that while the liver is the primary organ for acetaldehyde metabolism, contributions from other organs may also play a role.

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Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for detoxification the ethanol metabolite acetaldehyde, is recognized as a promising therapeutic target to treat alcohol use disorders (AUDs). Disulfiram, a potent ALDH2 inhibitor, is an approved drug for the treatment of AUD but has clinical limitations due to its side effects. This study aims to elucidate the relative contribution of different organs in acetaldehyde clearance through ALDH2 by using global- () and tissue-specific-deficient mice, and to examine whether liver-specific ALDH2 inhibition can prevent alcohol-seeking behavior.mice showed markedly higher acetaldehyde concentrations than wild-type (WT) mice after acute ethanol gavage. Acetaldehyde levels in hepatocyte-specificknockout () mice were significantly higher than those in WT mice post gavage, but did not reach the levels observed inmice. Energy expenditure and motility were dramatically dampened inmice, but moderately decreased inmice compared to controls. In the 2-bottle paradigm and the drinking-in-the-dark model,mice drank negligible volumes from ethanol-containing bottles, whereasmice showed reduced alcohol preference at high but not low alcohol concentrations. Glial cell- or neuron-specificdeficiency did not affect voluntary alcohol consumption. Finally, specific liverknockdown via injection ofmarkedly decreased alcohol preference. In conclusion, although the liver is the major organ responsible for acetaldehyde metabolism, a cumulative effect of ALDH2 from other organs likely also contributes to systemic acetaldehyde clearance. Liver-targeted ALDH2 inhibition can decrease heavy drinking without affecting moderate drinking, providing molecular basis for hepatictargeting/editing for the treatment of AUD. Aldh2Aldh2Aldh2Aldh2Aldh2Aldh2Aldh2Aldh2Aldh2Aldh2Aldh2Aldh2shAldh2ALDH2 -/--/-Hep-/--/--/-Hep-/--/-Hep-/-

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Targeting liver aldehyde dehydrogenase-2 prevents heavy but not moderate alcohol drinking

Abstract

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