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

  • Nat Commun. 2023 Sep 25;14(1):5971. doi: 10.1038/s41467-023-41570-6.
Yi-Cheng Chang  #  1  2  3 ,  Hsiao-Lin Lee  #  2 ,  Wenjin Yang  4 ,  Meng-Lun Hsieh  1  2 ,  Cai-Cin Liu  1 ,  Tung-Yuan Lee  1 ,  Jing-Yong Huang  1  2 ,  Jiun-Yi Nong  1  2 ,  Fu-An Li  3 ,  Hsiao-Li Chuang  5 ,  Zhi-Zhong Ding  1 ,  Wei-Lun Su  1 ,  Li-Yun Chueh  1 ,  Yi-Ting Tsai  6 ,  Che-Hong Chen  7 ,  Daria Mochly-Rosen  8 ,  Lee-Ming Chuang  9  10  11
Affiliations
  • 1. Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, Taiwan.
  • 2. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • 3. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • 4. Foresee Pharmaceuticals, Co.Ltd, Taipei, Taiwan.
  • 5. National Laboratory Animal Center, Taipei, Taiwan.
  • 6. Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 7. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 8. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 9. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. [email protected].
  • 10. Graduate Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan. [email protected].
  • 11. Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan. [email protected].
  • # Contributed equally.
PMID: 37749090 DOI: 10.1038/s41467-023-41570-6
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.

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