ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis
Shengfang JinJiang ChenLizao ChenGavin HistenZhi‐Zhong LinStefan GrößJeffrey HixonYue ChenCharles KungYiwei ChenYufei FuYuxuan LuHui LinXiujun CaiHua YangRob A. CairnsMarion DorschShinsan M. SuScott A. BillerTak W. MakYong Cang
83
Citation
47
Reference
10
Related Paper
Citation Trend
Abstract:
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2*2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2*2 allele-alcohol interaction may be an even greater human public health hazard than previously appreciated.Keywords:
ALDH2
Ethanol metabolism
Significance About 560 million East Asians have an impaired ability to eliminate acetaldehyde because of a point mutation in an enzyme called aldehyde dehydrogenase 2 (ALDH2). Humans with this mutation have ∼20-fold higher blood acetaldehyde levels than those with normal enzyme activity after consuming one to two units of alcoholic beverages. Because acetaldehyde is a potent carcinogen and causes behavioral impairment, its accumulation is a health risk. We identified a pharmacologic agent that recruits ALDH3A1, a closely related enzyme, to compensate for a loss of ability of ALDH2 to metabolize acetaldehyde. Pharmacologic agents that alter substrate specificity of an enzyme have not yet been described and may have wide clinical application in treating patients with impaired ability to detoxify toxic substances.
ALDH2
Ethanol metabolism
Cite
Citations (55)
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 (Aldh2Hep-/-) 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 Aldh2Hep-/- 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 Aldh2Hep-/- 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.
ALDH2
Ethanol metabolism
Alcohol tolerance
Cite
Citations (52)