Lipoic Acid Synthase (LASY): A Novel Role in Inflammation, Mitochondrial Function and Insulin Resistance

Objective: Lipoic acid synthase (LASY) is the enzyme that is involved in the endogenous synthesis of lipoic acid, a potent mitochondrial antioxidant. The aim of this study was to study the role of LASY in type 2 diabetes. Research Design and Methods: We studied expression of LASY in animal models of type 2 diabetes. We also looked at regulation of LASY in vitro under conditions that exist in diabetes. Additionally, we looked at effects of LASY knock down on cellular antioxidant status, inflammation, mitochondrial function and insulin stimulated glucose uptake. Results: LASY expression is significantly reduced in tissues from animal models of diabetes and obesity compared to age and sex-matched controls. In vitro, LASY mRNA levels were decreased by the pro-inflammatory cytokine TNFα and high glucose. Down-regulation of the LASY gene by RNA interference (RNAi) reduced endogenous levels of lipoic acid, and the activities of critical components of the antioxidant defense network, increasing oxidative stress. Treatment with exogenous lipoic acid compensated for some of these defects. RNAi mediated downregulation of LASY induced a significant loss of mitochondrial membrane potential, and decreased insulin-stimulated glucose uptake in skeletal muscle cells. In endothelial cells, downregulation of LASY aggravated the inflammatory response which manifested as increase in both basal and TNF-α induced expression of the pro-inflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1). Overexpression of the LASY gene ameliorated the inflammatory response. Conclusions: Deficiency of LASY results in an overall disturbance in the antioxidant defense network, leading to increased inflammation, insulin resistance and mitochondrial dysfunction.