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

ABSTRACT: 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- (Aldh2 ^-/-) and tissue-specific Aldh2-deficient mice, and to examine whether liver-specific ALDH2 inhibition can prevent alcohol-seeking behavior. Aldh2 ^-/- mice showed markedly higher acetaldehyde concentrations than wild-type (WT) mice after acute ethanol gavage. Acetaldehyde levels in hepatocyte-specific Aldh2 knockout (Aldh2 ^Hep-/-) mice were significantly higher than those in WT mice post gavage, but did not reach the levels observed in Aldh2 ^-/- mice. Energy expenditure and motility were dramatically dampened in Aldh2 ^-/- mice, but moderately decreased in Aldh2 ^Hep-/- mice compared to controls. In the 2-bottle paradigm and the drinking-in-the-dark model, Aldh2 ^-/- mice drank negligible volumes from ethanol-containing bottles, whereas Aldh2 ^Hep-/- mice showed reduced alcohol preference at high but not low alcohol concentrations. Glial cell- or neuron-specific Aldh2 deficiency did not affect voluntary alcohol consumption. Finally, specific liver Aldh2 knockdown via injection of shAldh2 markedly 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 hepatic ALDH2 targeting/editing for the treatment of AUD.

SUBMITTER: Guillot A

PROVIDER: S-EPMC6926021 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Guillot Adrien A Ren Tianyi T Jourdan Tony T Pawlosky Robert J RJ Han Elaine E Kim Seung-Jin SJ Zhang Li L Koob George F GF Gao Bin B

Proceedings of the National Academy of Sciences of the United States of America 20191202 51

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- (<i>Aldh2</i><sup>-/-</sup>) and tissue-s ...[more]

PMID: 31792171

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Project description:BackgroundBehavioral economic theory predicts that low access to environmental reward is a risk factor for alcohol use disorder (AUD). The Substance-Free Activity Session (SFAS) is a behavioral economic supplement to standard brief alcohol interventions that attempts to increase environmental reward and may therefore have beneficial effects, particularly for individuals with low levels of environmental reward.MethodsParticipants were 393 college students who reported at least 2 heavy-drinking episodes in the past month. Participants were randomly assigned to 1 of 3 conditions following a baseline assessment: a standard alcohol-focused brief motivational intervention plus relaxation training session (BMI + RT), BMI plus Substance-Free Activity Session (BMI + SFAS), or an assessment-only control condition (AO). In a secondary analysis of the data from this study, we used person-centered statistical techniques to describe trajectories of alcohol severity and environmental reward over a 16-month follow-up and examined whether environmental reward levels moderated the effectiveness of the interventions.ResultsPiecewise growth mixture modeling identified 2 trajectories of reward availability: low increasing (LR; n = 120) and high stable (HR; n = 273). Depressive symptoms, cannabis use, sensation seeking, and low life satisfaction were associated with a greater probability of classification in the LR trajectory. Alcohol severity was greater in the LR trajectory than the HR trajectory. For students in the LR trajectory, at 1, 6, and 12 months, BMI + SFAS led to greater increases in reward availability and reduced levels of alcohol severity compared with the BMI + RT and AO conditions and at 16 months compared with AO.ConclusionsYoung adults with low levels of environmental reward are at heightened risk for greater alcohol severity and may show greater benefit from brief alcohol interventions that focus on increasing substance-free reward than individuals who are not deficient in reward availability.

Project description:BackgroundMost physiological studies interested in alcohol-dependence examined ethanol as a pharmacological agent rather than a nutrient. We conducted two studies, which assessed the metabolic and endocrine factors involved in the regulation of alcohol and nutrient intake in alcohol-dependent (AD) subjects. We also examined the potential role of a disruption in energy balance in alcohol-dependence.Methods and resultsIn Study-1, quantitative dietetic interviews of eating and drinking habits were conducted with 97 AD subjects. The population was split around a median alcohol intake value of 12.5 kcal/kg/day. The results showed that the "low alcohol" drinking AD subjects had high Body Mass Index (BMI) and Fat Mass (FM) and alcohol intake was compensated for by a decrease in non-alcoholic intakes. "High alcohol" drinking AD subjects, on the other hand, had low BMI and FM and the total caloric intakes were largely above norms. In Study-2, 24 AD inpatients were submitted to dietetic interviews, calorimetry and blood samplings for the measurement of biomarkers of the regulation of metabolism and satiety, on day 2, 5 and 16 of abstinence. These patients were compared with 20 controls matched for age and gender. We observed in AD patients an increase in cortisol, leptin and PYY plasma levels and a decrease in ghrelin, which might explain the observed decrease in non-alcoholic intakes. However, alcoholic and non-alcoholic intakes correlated positively with basal metabolism and negatively with leptin and leptin/BMI.ConclusionFor individuals consuming below 12.5 kcal/kg/day of alcohol, alcohol intake is compensated for by a decrease in non-alcoholic nutrient intakes, probably due to changes in metabolic and satiety factors. For individuals consuming above 12.5 kcal/kg/day of alcohol, alcohol accelerates metabolism and decreases fat mass and leptin levels, and the total caloric intake largely exceeds norms. A dual model for regulation of energy intake in AD subjects is proposed.

Dataset Information

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

Publications

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

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