Lipoic Acid Synthase (LASY)

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.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 ageand sex-matched controls. In vitro, LASY mRNA levels were decreased by the proinflammatory cytokine tumor necrosis factor (TNF)-␣ 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 insulinstimulated 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-␣-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. Diabetes 58:600-608, 2009 T ype 2 diabetes is the most prevalent chronic metabolic disease in the world. In the past decade, considerable evidence has accumulated implicating oxidative stress as a key factor that accelerates the onset and progression of type 2 diabetes. Chronic oxidative stress causes inflammation and mitochondrial dysfunction and culminates in insulin resistance, which ultimately progresses to diabetes. Oxidative stress also promotes cellular dysfunction and damage, leading to the development of secondary complications of diabetes. The underlying cause of redox imbalance is a deficiency in the endogenous antioxidant network. This deficiency would result in an inability to combat excessive amounts of reactive oxygen species (ROS) and tip the balance in favor of oxidative stress.Redox balance is maintained by an antioxidant defense network within mitochondria, consisting of stress-responsive enzymes such as superoxide dismutase (SOD), catalase and reduced glutathione (GSH), and antioxidants. The antioxidant defense network is activated in response to excessive production of ROS in the mitochondria, thereby neutralizing the ROS before they inflict damage on cellular molecules. Lipoic acid is a potent mitochondrial antioxidant that plays a central role in...

4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic Acid (C75), an Inhibitor of Fatty-acid Synthase, Suppresses the Mitochondrial Fatty Acid Synthesis Pathway and Impairs Mitochondrial Function

“…As a redox regulator, R-LA is a well known powerful mitochondrial antioxidant (37,38). In addition, we found that R-LA could activate HsmtKAS expression, suggesting that additional lipoic acid stimulated its own production, which is consistent with previous studies that exogenously administered lipoic acid increases lipoic acid synthase expression (39). Likewise, the effect of C75 treatment on HsmtKAS expression might due to decreased R-LA content.…”

Role of food-derived antioxidant agents against acetaminophen-induced hepatotoxicity

“…ALA can be also synthesized through enzymatic reactions in plants and animals' mitochondria from octanoic acid and cysteine (as a sulphur donor) (Padmalayam et al 2009;Szeląg et al 2012).…”

Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes

“…A recent study has demonstrated that down-regulation of lipoic acid synthase (LASY), the enzyme involved in the endogenous synthesis of LA, reduced endogenous levels of LA as well as critical components of the antioxidant defence network, increasing oxidative stress. Moreover, this down-regulation of LASY induced a significant loss of mitochondrial membrane potential and decreased insulin-stimulated glucose uptake in skeletal muscle cells along with an increased inflammatory response which, in turn, leads to increased insulin resistance, mitochondrial dysfunction and inflammation [11]. Thus, LA can be considered as a promising therapeutic approach for chronic inflammatory diseases such as diabetes and obesity [12,13].…”