title: Myeloperoxidase-Hepatocyte-Stellate Cell Cross Talk Promotes Hepatocyte Injury and Fibrosis in Experimental Nonalcoholic Steatohepatitis.
abstract: OBJECTIVE
  Myeloperoxidase (MPO), a highly oxidative enzyme secreted by leukocytes has been implicated in human and experimental nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unknown. In this study, we investigated how MPO contributes to progression from steatosis to NASH.
  
  
  RESULTS
  In C57Bl/6J mice fed a diet deficient in methionine and choline to induce NASH, neutrophils and to a lesser extent inflammatory monocytes are markedly increased compared with sham mice and secrete abundant amounts of MPO. Through generation of HOCl, MPO directly causes hepatocyte death in vivo. In vitro experiments demonstrate mitochondrial permeability transition pore induction via activation of SAPK/JNK and PARP. MPO also contributes to activation of hepatic stellate cells (HSCs), the most important source of collagen in the liver. In vitro MPO-activated HSCs have an activation signature (MAPK and PI3K-AKT phosphorylation) and upregulate COL1A1, α-SMA, and CXCL1. MPO-derived oxidative stress also activates transforming growth factor β (TGF-β) in vitro, and TGF-β signaling inhibition with SB-431542 decreased steatosis and fibrosis in vivo. Conversely, congenital absence of MPO results in reduced hepatocyte injury, decreased levels of TGF-β, fewer activated HSCs, and less severe fibrosis in vivo.
  
  
  CONCLUSIONS
  Cumulatively, these findings demonstrate important cross talk between inflammatory myeloid cells, hepatocytes, and HSCs via MPO and establish MPO as part of a proapoptotic and profibrotic pathway of progression in NASH, as well as a potential therapeutic target to ameliorate this disease.
authors.affiliation: 1 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.|2 Department of Radiology, Massachusetts General Hospital , Boston, Massachusetts.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pulli
authors.affiliation: 1 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: 1 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: 1 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
authors.forename: Matthias W G
authors.initials: MW
authors.lastname: Zeller
authors.affiliation: 1 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schob
authors.affiliation: 1 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Linnoila
authors.affiliation: 1 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.|2 Department of Radiology, Massachusetts General Hospital , Boston, Massachusetts.
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002450:Cell Communication; D002463:Cell Membrane Permeability; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007425:Intracellular Membranes / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D008954:Models, Biological; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016207:Cytokines; D016212:Transforming Growth Factor beta; D009195:Peroxidase