title: Lipoic acid synthase (LASY): a novel role in inflammation, mitochondrial function, and insulin resistance.
abstract: 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.
  
  
  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 knockdown 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 with age- and sex-matched controls. In vitro, LASY mRNA levels were decreased by the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and high glucose. Downregulation 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 that manifested as an increase in both basal and TNF-alpha-induced expression of the proinflammatory 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.
authors.affiliation: Discovery Research, ReddyUS Therapeutics, Norcross, Georgia, USA. ipadmalayam@reddyus.com
authors.forename: Indira
authors.initials: I
authors.lastname: Padmalayam
authors.forename: Sumera
authors.initials: S
authors.lastname: Hasham
authors.forename: Uday
authors.initials: U
authors.lastname: Saxena
authors.forename: Sivaram
authors.initials: S
authors.lastname: Pillarisetti
mesh_terms: D000818:Animals; D001011:Aorta; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000201:enzymology; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology*; D007333:Insulin Resistance; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000201:enzymology; D032446:Myoblasts / Q000201:enzymology; D009765:Obesity / Q000201:enzymology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013466:Sulfurtransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D012333:RNA, Messenger; D013466:Sulfurtransferases; C116435:lipoic acid synthase