Abstract
Aim:
To investigate the roles of acetaldehyde dehydrogenase 2 (ALDH2), the key enzyme of ethanol metabolism, in chronic low to moderate alcohol consumption-induced heart protective effects in mice.
Methods:
Twenty-one male wild-type (WT) or ALDH2-knockout (KO) mice were used in this study. In each genotype, 14 animals received alcohol (2.5%, 5% and 10% in week 1–3, respectively, and 18% in week 4–7), and 7 received water for 7 weeks. After the treatments, survival rate and general characteristics of the animals were evaluated. Serum ethanol and acetaldehyde levels and blood lipids were measured. Metabolomics was used to characterize the heart and serum metabolism profiles.
Results:
Chronic alcohol intake decreased the survival rate of KO mice by 50%, and significantly decreased their body weight, but did not affect those of WT mice. Chronic alcohol intake significantly increased the serum ethanol levels in both WT and KO mice, but KO mice had significantly higher serum acetaldehyde levels than WT mice. Chronic alcohol intake significantly increased the serum HDL cholesterol levels in WT mice, and did not change the serum HDL cholesterol levels in KO mice. After chronic alcohol intake, WT and KO mice showed differential heart and serum metabolism profiles, including the 3 main energy substrate types (lipids, glucose and amino acids) and three carboxylic acid cycles.
Conclusion:
Low to moderate alcohol consumption increases HDL cholesterol levels and improves heart energy metabolism profile in WT mice but not in ALDH2-KO mice. Thus, preserved ALDH2 function is essential for the protective effect of low to moderate alcohol on the cardiovascular system.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Au Yeung SL, Jiang C, Cheng KK, Cowling BJ, Liu B, Zhang W, et al. Moderate alcohol use and cardiovascular disease from Mendelian randomization. PloS One 2013; 8: e68054.
Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA . Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ 2011; 342: d671.
Patra J, Taylor B, Irving H, Roerecke M, Baliunas D, Mohapatra S, et al. Alcohol consumption and the risk of morbidity and mortality for different stroke types — a systematic review and meta-analysis. BMC Pub Health 2010; 10: 258.
Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J . Alcohol consumption and risk of stroke: a meta-analysis. JAMA: J Am Med Assoc 2003; 289: 579–88.
Krenz M, Korthuis RJ . Moderate ethanol ingestion and cardiovascular protection: from epidemiologic associations to cellular mechanisms. J Mol Cell Cardiol 2012; 52: 93–104.
Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, VanDenburgh M, et al. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction. New Engl J Med 1993; 329: 1829–34.
Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ . Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 1999; 319: 1523–8.
Carlsson S, Hammar N, Grill V . Alcohol consumption and type 2 diabetes Meta-analysis of epidemiological studies indicates a U-shaped relationship. Diabetologia 2005; 48: 1051–4.
Chen CH, Sun L, Mochly-Rosen D . Mitochondrial aldehyde dehydrogenase and cardiac diseases. Cardiovasc Res 2010; 88: 51–7.
Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D . Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev 2014; 94: 1–34.
Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D . Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 2008; 321: 1493–5.
Wada M, Daimon M, Emi M, Iijima H, Sato H, Koyano S, et al. Genetic association between aldehyde dehydrogenase 2 (ALDH2) variation and high-density lipoprotein cholesterol (HDL-C) among non-drinkers in two large population samples in Japan. J Atheroscler Thromb 2008; 15: 179–84.
Nakamura Y, Amamoto K, Tamaki S, Okamura T, Tsujita Y, Ueno Y, et al. Genetic variation in aldehyde dehydrogenase 2 and the effect of alcohol consumption on cholesterol levels. Atherosclerosis 2002; 164: 171–7.
Endo J, Sano M, Katayama T, Hishiki T, Shinmura K, Morizane S, et al. Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. Circ Res 2009; 105: 1118–27.
Liao J, Sun A, Xie Y, Isse T, Kawamoto T, Zou Y, et al. Aldehyde dehydrogenase-2 deficiency aggravates cardiac dysfunction elicited by endoplasmic reticulum stress induction. Mol Med 2012; 18: 785–93.
Zhou HZ, Karliner JS, Gray MO . Moderate alcohol consumption induces sustained cardiac protection by activating PKC-epsilon and Akt. Am J Physiol Heart Circ Physiol 2002; 283: H165–74.
Ou XM, Stockmeier CA, Meltzer HY, Overholser JC, Jurjus GJ, Dieter L, et al. A novel role for glyceraldehyde-3-phosphate dehydrogenase and monoamine oxidase B cascade in ethanol-induced cellular damage. Biol Psychiatr 2010; 67: 855–63.
Shi J, Zhao W, Chen Y, Guo L, Yang L . A replaceable dual-enzyme capillary microreactor using magnetic beads and its application for simultaneous detection of acetaldehyde and pyruvate. Electrophoresis 2012; 33: 2145–51.
Fan F, Sun A, Zhao H, Liu X, Zhang W, Jin X, et al. MicroRNA-34a promotes cardiomyocyte apoptosis post myocardial infarction through down-regulating aldehyde dehydrogenase 2. Curr Pharm Des 2013; 19: 4865–73.
Zhao J, Zhu H, Wang S, Ma X, Liu X, Wang C, et al. Naoxintong protects against atherosclerosis through lipid-lowering and inhibiting maturation of dendritic cells in LDL receptor knockout mice fed a high-fat diet. Curr Pharm Des 2013; 19: 5891–6.
Chen F, Xue J, Zhou L, Wu S, Chen Z . Identification of serum biomarkers of hepatocarcinoma through liquid chromatography/mass spectrometry-based metabonomic method. Analy Bioanal Chem 2011; 401: 1899–904.
Eng MY, Luczak SE, Wall TL . ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review. Alcohol Res Health 2007; 30: 22–7.
Manzo-Avalos S, Saavedra-Molina A . Cellular and mitochondrial effects of alcohol consumption. Int J Environ Res Public Health 2010; 7: 4281–304.
Gordon T, Ernst N, Fisher M, Rifkind BM . Alcohol and high-density lipoprotein cholesterol. Circulation 1981; 64 (3 Pt 2): III 63–7.
Wakabayashi I, Groschner K . Modification of the association between alcohol drinking and non-HDL cholesterol by gender. Clin Chim Acta 2009; 404: 154–9.
Doser TA, Turdi S, Thomas DP, Epstein PN, Li SY, Ren J . Transgenic overexpression of aldehyde dehydrogenase-2 rescues chronic alcohol intake-induced myocardial hypertrophy and contractile dysfunction. Circulation 2009; 119: 1941–9.
Ding X, Beier JI, Baldauf KJ, Jokinen JD, Zhong H, Arteel GE . Acute ethanol preexposure promotes liver regeneration after partial hepatectomy in mice by activating ALDH2. Am J Physiol Gastrointes Liver Physiol 2014; 306: G37–47.
Long EK, Olson DM, Bernlohr DA . High-fat diet induces changes in adipose tissue trans-4-oxo-2-nonenal and trans-4-hydroxy-2-nonenal levels in a depot-specific manner. Free Radical Biol Med 2013; 63: 390–8.
Dunner S, Sevane N, Garcia D, Leveziel H, Williams JL, Mangin B, et al. Genes involved in muscle lipid composition in 15 European Bos taurus breeds. Animal Genet 2013; 44: 493–501.
Zakhari S . Alcohol metabolism and epigenetics changes. Alcohol Res: Curr Rev 2013; 35: 6–16.
Acknowledgements
This work was supported by the National Basic Research Program of China (No 2011CB503905), National Natural Science Foundation of China (No 30971250, 81300096), and Program for New Century Excellent Talents in University (NCET).
Author information
Authors and Affiliations
Corresponding authors
Additional information
(Supplementary Tables and Figures were available at APS's website.
Rights and permissions
About this article
Cite this article
Fan, F., Cao, Q., Wang, C. et al. Impact of chronic low to moderate alcohol consumption on blood lipid and heart energy profile in acetaldehyde dehydrogenase 2-deficient mice. Acta Pharmacol Sin 35, 1015–1022 (2014). https://doi.org/10.1038/aps.2014.46
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2014.46
Keywords
This article is cited by
-
A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice
Communications Biology (2023)
-
Environmental Influences in the Etiology of Colorectal Cancer: the Premise of Metabolomics
Current Pharmacology Reports (2017)
-
ALDH2*2 Allele is a Negative Risk Factor for Cerebral Infarction in Chinese Women
Biochemical Genetics (2015)