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

Author

Listed:
  • Yi-Cheng Chang

    (National Taiwan University
    National Taiwan University Hospital
    Academia Sinica)

  • Hsiao-Lin Lee

    (National Taiwan University Hospital)

  • Wenjin Yang

    (Foresee Pharmaceuticals, Co.Ltd)

  • Meng-Lun Hsieh

    (National Taiwan University
    National Taiwan University Hospital)

  • Cai-Cin Liu

    (National Taiwan University)

  • Tung-Yuan Lee

    (National Taiwan University)

  • Jing-Yong Huang

    (National Taiwan University
    National Taiwan University Hospital)

  • Jiun-Yi Nong

    (National Taiwan University
    National Taiwan University Hospital)

  • 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
    National Taiwan University
    National Taiwan University)

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.

Suggested Citation

  • 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 &, 2023. "A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41570-6
    DOI: 10.1038/s41467-023-41570-6
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    1. Cassandra N. Spracklen & Momoko Horikoshi & Young Jin Kim & Kuang Lin & Fiona Bragg & Sanghoon Moon & Ken Suzuki & Claudia H. T. Tam & Yasuharu Tabara & Soo-Heon Kwak & Fumihiko Takeuchi & Jirong Long, 2020. "Identification of type 2 diabetes loci in 433,540 East Asian individuals," Nature, Nature, vol. 582(7811), pages 240-245, June.
    2. Frédéric Langevin & Gerry P. Crossan & Ivan V. Rosado & Mark J. Arends & Ketan J. Patel, 2011. "Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice," Nature, Nature, vol. 475(7354), pages 53-58, July.
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