A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators

• Published in: Nature communications Vol. 14; no. 1; pp. 5971 - 16
• Main Authors: Chang, Yi-Cheng, Lee, Hsiao-Lin, Yang, Wenjin, Hsieh, Meng-Lun, Liu, Cai-Cin, Lee, Tung-Yuan, Huang, Jing-Yong, Nong, Jiun-Yi, Li, Fu-An, Chuang, Hsiao-Li, Ding, Zhi-Zhong, Su, Wei-Lun, Chueh, Li-Yun, Tsai, Yi-Ting, Chen, Che-Hong, Mochly-Rosen, Daria, Chuang, Lee-Ming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.09.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 14/63; 4-Hydroxynonenal; 631/154/436/108; 631/208/727/2000; 64/110; 64/60; 692/163/2743/393; 82/16; 82/29; 82/58; 82/80; Acetaldehyde; Acetaldehyde dehydrogenase; Adipose tissue; Adipose tissue (brown); Aldehyde dehydrogenase; Aldehyde dehydrogenase (NAD); Aldehydes; Body fat; Diabetes mellitus (non-insulin dependent); Diet; Electron transport; Electron transport chain; Energy expenditure; Enzymatic activity; Enzymes; Fatty acids; Fatty liver; Glucose; Glucose tolerance; Homeostasis; Humanities and Social Sciences; Insulin resistance; Liver; Males; Metabolic disorders; Mitochondria; multidisciplinary; Mutation; Obesity; Oxidation; Oxidation rate; Proteomics; Science; Science (multidisciplinary); Thermogenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41570-6

Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases. A common East Asian-specific defect of an alcohol metabolizing enzyme (ALDH2) causes glucose abnormality, obesity, and fatty liver. Here, the authors show an ALDH2 activator can treat these metabolic disorders in mice.