title: STING-IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity.
abstract: Metabolic stress in obesity induces endothelial inflammation and activation, which initiates adipose tissue inflammation, insulin resistance, and cardiovascular diseases. However, the mechanisms underlying endothelial inflammation induction are not completely understood. Stimulator of interferon genes (STING) is an important molecule in immunity and inflammation. In the present study, we sought to determine the role of STING in palmitic acid-induced endothelial activation/inflammation.
  
  
  
  In cultured endothelial cells, palmitic acid treatment activated STING, as indicated by its perinuclear translocation and binding to interferon regulatory factor 3 (IRF3), leading to IRF3 phosphorylation and nuclear translocation. The activated IRF3 bound to the promoter of ICAM-1 (intercellular adhesion molecule 1) and induced ICAM-1 expression and monocyte-endothelial cell adhesion. When analyzing the upstream signaling, we found that palmitic acid activated STING by inducing mitochondrial damage. Palmitic acid treatment caused mitochondrial damage and leakage of mitochondrial DNA into the cytosol. Through the cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase), the mitochondrial damage and leaked cytosolic mitochondrial DNA activated the STING-IRF3 pathway and increased ICAM-1 expression. In mice with diet-induced obesity, the STING-IRF3 pathway was activated in adipose tissue. However, STING deficiency (Stinggt/gt) partially prevented diet-induced adipose tissue inflammation, obesity, insulin resistance, and glucose intolerance.
  
  
  
  The mitochondrial damage-cGAS-STING-IRF3 pathway is critically involved in metabolic stress-induced endothelial inflammation. STING may be a potential therapeutic target for preventing cardiovascular diseases and insulin resistance in obese individuals.
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Yun
authors.initials: Y
authors.lastname: Mao
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wu
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Liangshuai
authors.initials: L
authors.lastname: Yuan
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Juhee
authors.initials: J
authors.lastname: Song
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Keigi
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Abe
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Scott A
authors.initials: SA
authors.lastname: LeMaire
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston. xingliwang@sdu.edu.cn.
authors.forename: Ying H
authors.initials: YH
authors.lastname: Shen
mesh_terms: D021581:Active Transport, Cell Nucleus; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004272:DNA, Mitochondrial / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D007333:Insulin Resistance; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009713:Nucleotidyltransferases / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004272:DNA, Mitochondrial; D018799:Intercellular Adhesion Molecule-1; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D019308:Palmitic Acid; C573420:ICAM1 protein, human; C494232:IRF3 protein, human; C090509:Icam1 protein, mouse; C494233:Irf3 protein, mouse; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
keywords: DNA, mitochondrial; diet, high-fat; endothelium; palmitic acid; vascular diseases