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Tadi, Surendar,Kim, Soung Jung,Ryu, Min Jeong,Park, Taeseong,Jeong, Ji-Seon,Kim, Young Hwan,Kweon, Gi Ryang,Shong, Minho,Yim, Yong-Hyeon Korean Chemical Society 2013 Bulletin of the Korean Chemical Society Vol.34 No.1
Metabolic analysis of CR6 interacting factor 1 (Crif1) deficient mouse embryonic fibroblasts with impaired oxidative phosphorylation has been carried out using LC-MS/MS and GC-MS methods. Metabolic profiles of the Crif1 deficient cells were comprehensively obtained for the first time. Loss of oxidative phosphorylation functions in mitochondria resulted in cancer-like metabolic reprogramming with consumption of majority of glucose carbon from up-regulated glycolysis to produce lactate, suppressed utilization of glucose carbon in the TCA cycle, increased amounts of amino acids. The changes in metabolic profile of the Crif1 deficient cells are most probably a consequence of metabolic reprogramming to meet the needs of energy balance and anabolic precursors in compensation for the loss of major oxidative phosphorylation functions.
Surendar Tadi,김성정,류민정,박태성,정지선,김영환,권기량,송민호,임용현 대한화학회 2013 Bulletin of the Korean Chemical Society Vol.34 No.1
Metabolic analysis of CR6 interacting factor 1 (Crif1) deficient mouse embryonic fibroblasts with impaired oxidative phosphorylation has been carried out using LC-MS/MS and GC-MS methods. Metabolic profiles of the Crif1 deficient cells were comprehensively obtained for the first time. Loss of oxidative phosphorylation functions in mitochondria resulted in cancer-like metabolic reprogramming with consumption of majority of glucose carbon from up-regulated glycolysis to produce lactate, suppressed utilization of glucose carbon in the TCA cycle, increased amounts of amino acids. The changes in metabolic profile of the Crif1 deficient cells are most probably a consequence of metabolic reprogramming to meet the needs of energy balance and anabolic precursors in compensation for the loss of major oxidative phosphorylation functions.
Kim, Yong Deuk,Kim, Yong-Hoon,Tadi, Surendar,Yu, Ji Hoon,Yim, Yong-Hyeon,Jeoung, Nam Ho,Shong, Minho,Hennighausen, Lothar,Harris, Robert A.,Lee, In-Kyu,Lee, Chul-Ho,Choi, Hueng-Sik American Diabetes Association 2012 Diabetes Vol.61 No.10
<P><B/></P><P>Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the <I>PDK4</I> gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP–dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.</P>
Ahn, Seung Won,Gang, Gil-Tae,Tadi, Surendar,Nedumaran, Balachandar,Kim, Yong Deuk,Park, Ji Hoon,Kweon, Gi Ryang,Koo, Seung-Hoi,Lee, Keesook,Ahn, Ryun-Sup,Yim, Yong-Hyeon,Lee, Chul-Ho,Harris, Robert A. American Society for Biochemistry and Molecular Bi 2012 The Journal of biological chemistry Vol.287 No.50
Ryu, Min Jeong,Kim, Soung Jung,Kim, Yong Kyung,Choi, Min Jeong,Tadi, Surendar,Lee, Min Hee,Lee, Seong Eun,Chung, Hyo Kyun,Jung, Saet Byel,Kim, Hyun-Jin,Jo, Young Suk,Kim, Koon Soon,Lee, Sang-Hee,Kim, Public Library of Science 2013 PLoS genetics Vol.9 No.3
<▼1><P>Impaired mitochondrial oxidative phosphorylation (OXPHOS) has been proposed as an etiological mechanism underlying insulin resistance. However, the initiating organ of OXPHOS dysfunction during the development of systemic insulin resistance has yet to be identified. To determine whether adipose OXPHOS deficiency plays an etiological role in systemic insulin resistance, the metabolic phenotype of mice with OXPHOS–deficient adipose tissue was examined. Crif1 is a protein required for the intramitochondrial production of mtDNA–encoded OXPHOS subunits; therefore, <I>Crif1</I> haploinsufficient deficiency in mice results in a mild, but specific, failure of OXPHOS capacity <I>in vivo</I>. Although adipose-specific <I>Crif1</I>-haploinsufficient mice showed normal growth and development, they became insulin-resistant. <I>Crif1</I>-silenced adipocytes showed higher expression of chemokines, the expression of which is dependent upon stress kinases and antioxidant. Accordingly, examination of adipose tissue from <I>Crif1</I>-haploinsufficient mice revealed increased secretion of MCP1 and TNFα, as well as marked infiltration by macrophages. These findings indicate that the OXPHOS status of adipose tissue determines its metabolic and inflammatory responses, and may cause systemic inflammation and insulin resistance.</P></▼1><▼2><P><B>Author Summary</B></P><P>Type 2 diabetes is one of the most challenging health problems in the 21<SUP>st</SUP> century. Although insulin resistance is regarded as a fundamental defect that precedes the development of type 2 diabetes, the nature and cause of insulin resistance remain unknown. Adipose tissue is an important organ that determines whole-body energy metabolism, and its dysfunction is a critical element in the development of systemic insulin resistance. Adipose mitochondrial function is suppressed in the insulin-resistant state, and increased adipose mitochondrial biogenesis is associated with the reversal of insulin resistance by a PPARγ agonist. However, despite these important observations, little is known about how mitochondrial respiratory dysfunction in white adipose tissue (WAT) causes insulin resistance. To determine whether adipose deficiency of mitochondrial respiratory capacity plays an etiological role in systemic insulin resistance, the metabolic phenotype of mice with mitochondrial OXPHOS (oxidative phosphorylation)–deficient adipose tissue was examined. Crif1 is a protein required for the translation of mtDNA–encoded OXPHOS subunits. Interestingly, mice haploinsufficient for <I>Crif1</I> in adipose tissue showed reduced OXPHOS capacity and developed marked insulin resistance.</P></▼2>
Kim, Sun-Yee,Jeoung, Nam Ho,Oh, Chang Joo,Choi, Young-Keun,Lee, Hyo-Jeong,Kim, Han-Jong,Kim, Joon-Young,Hwang, Jung Hwan,Tadi, Surendar,Yim, Yong-Hyeon,Lee, Ki-Up,Park, Keun-Gyu,Huh, Seung,Min, Ki-Nam Ovid Technologies Wolters Kluwer -American Heart A 2009 Circulation research Vol.104 No.7
<P>Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are important pathogenic mechanisms in atherosclerosis and restenosis after vascular injury. In this study, we investigated the effects of beta-lapachone (betaL) (3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione), which is a potent antitumor agent that stimulates NAD(P)H:quinone oxidoreductase (NQO)1 activity, on neointimal formation in animals given vascular injury and on the proliferation of VSMCs cultured in vitro. betaL significantly reduced the neointimal formation induced by balloon injury. betaL also dose-dependently inhibited the FCS- or platelet-derived growth factor-induced proliferation of VSMCs by inhibiting G(1)/S phase transition. betaL increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase 1 in rat and human VSMCs. Chemical inhibitors of AMPK or dominant-negative AMPK blocked the betaL-induced suppression of cell proliferation and the G(1) cell cycle arrest, in vitro and in vivo. The activation of AMPK in VSMCs by betaL is mediated by LKB1 in the presence of NQO1. Taken together, these results show that betaL inhibits VSMCs proliferation via the NQO1 and LKB1-dependent activation of AMPK. These observations provide the molecular basis that pharmacological stimulation of NQO1 activity is a new therapy for the treatment of vascular restenosis and/or atherosclerosis which are caused by proliferation of VSMCs.</P>