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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase, Mitochondrial / genetics
  • Aldehyde Dehydrogenase, Mitochondrial / metabolism
  • Animals
  • Diabetes Mellitus, Type 2* / genetics
  • Fatty Acids
  • Fatty Liver*
  • Humans
  • Male
  • Mice
  • Mutation
  • Obesity / genetics
  • Proteomics

Substances

  • 4-hydroxy-2-nonenal
  • Aldehyde Dehydrogenase, Mitochondrial
  • Fatty Acids
  • Aldehyde Dehydrogenase
  • ALDH2 protein, human
  • ALDH2 protein, mouse