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

Yi-Cheng Chang, Hsiao-Lin Lee, Wenjin Yang, Meng-Lun Hsieh, Cai-Cin Liu, Tung-Yuan Lee, Jing-Yong Huang, Jiun-Yi Nong, Fu-An Li, Hsiao-Li Chuang, Zhi-Zhong Ding, Wei-Lun Su, Li-Yun Chueh, Yi-Ting Tsai, Che-Hong Chen, Daria Mochly-Rosen () and Lee-Ming Chuang ()
Additional contact information
Yi-Cheng Chang: National Taiwan University
Hsiao-Lin Lee: National Taiwan University Hospital
Wenjin Yang: Foresee Pharmaceuticals, Co.Ltd
Meng-Lun Hsieh: National Taiwan University
Cai-Cin Liu: National Taiwan University
Tung-Yuan Lee: National Taiwan University
Jing-Yong Huang: National Taiwan University
Jiun-Yi Nong: National Taiwan University
Fu-An Li: Academia Sinica
Hsiao-Li Chuang: National Laboratory Animal Center
Zhi-Zhong Ding: National Taiwan University
Wei-Lun Su: National Taiwan University
Li-Yun Chueh: National Taiwan University
Yi-Ting Tsai: National Taiwan University
Che-Hong Chen: Stanford University School of Medicine
Daria Mochly-Rosen: Stanford University School of Medicine
Lee-Ming Chuang: National Taiwan University Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41570-6

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