PMID- 19074983
OWN - NLM
STAT- MEDLINE
DCOM- 20090324
LR  - 20211020
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 58
IP  - 3
DP  - 2009 Mar
TI  - Lipoic acid synthase (LASY): a novel role in inflammation, mitochondrial 
      function, and insulin resistance.
PG  - 600-8
LID - 10.2337/db08-0473 [doi]
AB  - 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 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.
FAU - Padmalayam, Indira
AU  - Padmalayam I
AD  - Discovery Research, ReddyUS Therapeutics, Norcross, Georgia, USA. 
      ipadmalayam@reddyus.com
FAU - Hasham, Sumera
AU  - Hasham S
FAU - Saxena, Uday
AU  - Saxena U
FAU - Pillarisetti, Sivaram
AU  - Pillarisetti S
LA  - eng
PT  - Journal Article
DEP - 20081215
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (RNA, Messenger)
RN  - EC 2.8.1.- (Sulfurtransferases)
RN  - EC 2.8.1.- (lipoic acid synthase)
SB  - IM
MH  - Animals
MH  - Aorta
MH  - Diabetes Mellitus, Type 2/*enzymology
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Endothelium, Vascular/enzymology
MH  - Gene Deletion
MH  - Humans
MH  - Inflammation/enzymology/*physiopathology
MH  - *Insulin Resistance
MH  - Mice
MH  - Mitochondria/*enzymology
MH  - Muscle, Skeletal/enzymology
MH  - Myoblasts/enzymology
MH  - Obesity/enzymology
MH  - Polymerase Chain Reaction
MH  - RNA, Messenger/genetics
MH  - Rats
MH  - Sulfurtransferases/deficiency/*genetics/metabolism
MH  - Transfection
PMC - PMC2646058
EDAT- 2008/12/17 09:00
MHDA- 2009/03/25 09:00
PMCR- 2010/03/01
CRDT- 2008/12/17 09:00
PHST- 2008/12/17 09:00 [entrez]
PHST- 2008/12/17 09:00 [pubmed]
PHST- 2009/03/25 09:00 [medline]
PHST- 2010/03/01 00:00 [pmc-release]
AID - db08-0473 [pii]
AID - 583600 [pii]
AID - 10.2337/db08-0473 [doi]
PST - ppublish
SO  - Diabetes. 2009 Mar;58(3):600-8. doi: 10.2337/db08-0473. Epub 2008 Dec 15.