title: New Insight Into Metformin Action: Regulation of ChREBP and FOXO1 Activities in Endothelial Cells.
abstract: Metformin has been considered a potential adjunctive therapy in treating poorly controlled type 1 diabetes with obesity and insulin resistance, owing to its potent effects on improving insulin sensitivity. However, the underlying mechanism of metformin's vascular protective effects remains obscure. Thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox state induced by high-glucose concentration, decreases thioredoxin reductase activity and mediates apoptosis induced by oxidative stress. Here we report that high glucose-induced endothelial dysfunction is associated with induction of TXNIP expression in primary human aortic endothelial cells exposed to high-glucose conditions, whereas the metformin treatment suppresses high-glucose-induced TXNIP expression at mRNA and protein levels. We further show that metformin decreases the high-glucose-stimulated nuclear entry rate of two transcription factors, carbohydrate response element-binding protein (ChREBP) and forkhead box O1 (FOXO1), as well as their recruitment on the TXNIP promoter. An AMP-activated protein kinase inhibitor partially compromised these metformin effects. Our data suggest that endothelial dysfunction resulting from high-glucose concentrations is associated with TXNIP expression. Metformin down-regulates high-glucose-induced TXNIP transcription by inactivating ChREBP and FOXO1 in endothelial cells, partially through AMP-activated protein kinase activation.
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Kover
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Heruth
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Dara J
authors.initials: DJ
authors.lastname: Watkins
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Wayne V
authors.initials: WV
authors.lastname: Moore
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Kathyrin
authors.initials: K
authors.lastname: Jackson
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Mengwei
authors.initials: M
authors.lastname: Zang
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Clements
authors.affiliation: Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yan
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D042783:Endothelial Cells / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; C442825:Mlxipl protein, rat; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; C486715:TXNIP protein, human; C493796:TXNIP protein, rat; D014157:Transcription Factors; C445672:Txnip protein, mouse; C074639:Foxo1 protein, rat; D013879:Thioredoxins; D008687:Metformin; D000263:Adenylate Kinase