Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury

J Leukoc Biol. 2009 Jan;85(1):146-53. doi: 10.1189/jlb.0308161. Epub 2008 Oct 9.


Alpha-lipoic acid (1, 2-dithiolane-3-pentanoic acid; LA), synthesized in mitochondria by LA synthase (Lias), is a potent antioxidant and a cofactor for metabolic enzyme complexes. In this study, we examined the effect of genetic reduction of LA synthesis on its antioxidant and anti-inflammatory properties using a model of LPS-induced inflammation in Lias+/- mice. The increase of plasma proinflammatory cytokine, TNF-alpha, and NF-kappaB at an early phase following LPS injection was greater in Lias+/- mice compared with Lias+/+ mice. The circulating blood white blood cell (WBC) and platelet counts dropped continuously during the initial 4 h. The counts subsequently recovered partially in Lias+/+ mice, but the recovery was impaired totally in Lias+/- mice. Administration of exogenous LA normalized the recovery of WBC counts in Lias+/- mice but not platelets. Enhanced neutrophil sequestration in the livers of Lias+/- mice was associated with increased hepatocyte injury and increased gene expression of growth-related oncogene, E-selectin, and VCAM-1 in the liver and/or lung. Lias gene expression in tissues was 50% of normal expression in Lias+/- mice and reduced further by LPS treatment. Decreased Lias expression was associated with diminished hepatic LA and tissue oxidative stress. Finally, Lias+/- mice displayed enhanced mortality when exposed to LPS-induced sepsis. These data demonstrate the importance of endogenously produced LA for preventing leukocyte accumulation and tissue injury that result from LPS-induced inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytokines / blood
  • E-Selectin / metabolism
  • Energy Metabolism
  • Heterozygote
  • Lipopolysaccharides / pharmacology*
  • Liver / drug effects
  • Liver / pathology
  • Lung / drug effects
  • Lung / pathology
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Oxidative Stress
  • Sepsis / metabolism
  • Sepsis / mortality
  • Sepsis / pathology*
  • Sulfurtransferases / genetics
  • Sulfurtransferases / physiology*
  • Thioctic Acid / metabolism*
  • Thioctic Acid / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Cytokines
  • E-Selectin
  • Lipopolysaccharides
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Thioctic Acid
  • Sulfurtransferases
  • lipoic acid synthase