A common East Asian-specific ALDH2 mutation causes obesity and insulin resistance: therapeutic effect of reducing toxic aldehydes by ALDH2 activation

ABSTRACT: Obesity and type 2 diabetes have reached pandemic proportion. In particular, the population with diabetes is expected to rise rapidly in East and South Asia. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal (4-HNE). A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We found that Aldh2 knock-in (KI) mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver compared with controls due to reduced adaptive thermogenesis and energy expenditure. We found elevated 4-HNE levels and increased 4-HNE adducted proteins due to reduced activity of ALDH2 of the brown adipose tissue (BAT) from the Aldh2 homozygous KI mice. Proteomic analyses of the BAT from the Aldh2 KI mice identified increased 4-HNE-adducted proteins involved in mitochondrial fatty acid oxidation (FAO) and electron transport chain (ETC), leading to markedly decreased FAO and mitochondrial respiration of BAT, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble prodrug of a potent and highly selective ALDH2 activator AD-5591. In vitro, AD-5591 enhanced both WT and mutant ALDH2 enzymatic activities. AD-9308 allosterically activates ALDH2 mainly by partially blocking the substrate exit tunnel, thereby accelerating the substrate-enzyme collision.4-HNE-adducted proteins, especially those involved in mitochondrial fatty acid beta-oxidation and electron transfer chain of the brown adipose tissue from the Aldh2 knock-in mice, leading to impaired mitochondrial dysfunction brown adipose tissue. In vivo, AD-9308 treatment reduced serum 4-HNE levels, ameliorated diet-induced obesity and fatty liver, and improved glucose homeostasis in both Aldh2 WT and KI mice dose-dependently. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for treating metabolic diseases.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Sp. (ncbitaxon:10095)

SUBMITTER: Yi-Cheng Chang  

PROVIDER: MSV000091724 | MassIVE | Sun Apr 16 23:19:00 BST 2023

REPOSITORIES: MassIVE