Nrf2-mediated antioxidant defense and peroxiredoxin 6 are linked to biosynthesis of palmitic acid ester of 9-hydroxystearic acid


  • O. Kuda
  • M. Brezinova
  • J. Silhavy
  • V. Landa
  • V. Zidek
  • C. Dodia
  • F. Kreuchwig
  • M. Vrbacky
  • L. Balas
  • T. Durand
  • N. Hübner
  • A.B. Fisher
  • J. Kopecky
  • M. Pravenec


  • Diabetes


  • Diabetes 67 (6): 1190-1199


  • Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising anti-diabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) vialipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, QTL mapping and correlation analyses in rat BXH/HXB recombinant inbred strains, and response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs.Comprehensive analysis of WAT samples identified ∼160 regioisomers documenting the complexity of this lipid class. The linkage analysis highlighted several members of Nuclear factor, erythroid 2-like 2 ()-mediated antioxidant defense system (), lipid-handling proteins () and family of Flavin Containing Monooxygenase () as the positional candidate genes. Transgenic expression ofand deletion ofgenes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically.Our results indicate that the synthesis of FAHFAscarbohydrate-responsive element-binding protein (ChREBP)-drivenlipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues.