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Characterization of the metabolic remodeling in liver by genetic mutation of ALDH2 in muscles
Author(s) -
Hishiki Takako,
Adachi Takeshi,
Sano Motoaki,
Katayama Takaharu,
Endo Jin,
Fukuda Keiichi,
Suematsu Makoto
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1015.1
Subject(s) - aldh2 , glycolysis , biochemistry , chemistry , aldehyde dehydrogenase , beta oxidation , enzyme
Objective: Aldehyde dehydrogenases 2 (ALDH2) is the detox enzyme to catalyze aldehydes‐carboxylation, which modulates reactive oxygen species in mitochondria. We created transgenic (TG) mice expressing mutant ALDH2 in muscles, which exhibited the phenocopy of senescence. To test the mechanism of detoxification against the systemic aldehydes toxicity, we characterized the compensational metabolic remodeling in liver from TG mice. Methods: ALDH2 expression and phosphorylation of acetyl‐CoA calboxylase (P‐ACC) were assessed with immuno‐blotting. Gene chip analysis and metabolome analysis with capillary electrophoresis mass spectrometry were performed. Results: In TG mice, the mutant protein was highly expressed in heart and skeletal muscles, but not in liver. The upregulation of enzymes for fatty acid oxidation and an increase in the P‐ACC caused the elevation of citrate levels. The inhibition of phosphofructokinase by citrate caused the elevation of glucose 1‐phosphate (G1P) levels and the reduction of metabolites in glycolysis below fructose 1,6‐bisphosphate. The elevated G1P levels could increase the utilization for glucuronide conjugation to detoxify aldehydes. Conclusion: We concluded that the metabolic remodeling of fatty acid oxidation and glycolysis to augment the flux for glucuronide conjugation contributed to the detoxification in liver against the systemic aldehyde toxicity.