Mice with heterozygous deficiency of lipoic acid synthase have an increased
sensitivity to lipopolysaccharide-induced tissue injury.
Authors Yi X, Kim K, Yuan W, Xu L, Kim HS, Homeister JW, Key NS, Maeda N
Submitted By Nobuyo Maeda on 2/8/2009
Status Published
Journal Journal of leukocyte biology
Year 2009
Date Published 1/1/2009
Volume : Pages 85(1) : 146 - 153
PubMed Reference 18845616
Abstract 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

Investigators with authorship
Nobuyo MaedaUniversity of North Carolina
Haitao YuanBeth Israel Deaconess Medical


Liaslipoic acid synthetase
Nfkb1nuclear factor of kappa light chain gene enhancer in B-cells 1, p105
Seleselectin, endothelial cell
Tnftumor necrosis factor
Vcam1vascular cell adhesion molecule 1