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

Significance It is generally accepted that ethanol and its metabolite acetaldehyde are primarily metabolized in the liver via the alcohol dehydrogenase and the aldehyde dehydrogenase-2 (ALDH2), respectively. However, by using tissue-specific Aldh2 knockout mice, we demonstrated that the liver ALDH2 is only responsible for approximately half of circulating acetaldehyde clearance after acute alcohol intake. Thus, cumulative ALDH2 activity from multiple organs may contribute to circulating acetaldehyde clearance. The present study shows that, although the liver ALDH2 only partially contributes to acetaldehyde clearance, genetic deletion or knockdown of the liver Aldh2 decreases excessive but not light to moderate alcohol drinking. Our results suggest that liver-specific ALDH2 inhibition may be an effective strategy for the treatment of alcohol user disorder with excessive drinking.