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Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis.
Sun, Xiaoli; Seidman, Jason S; Zhao, Peng; Troutman, Ty D; Spann, Nathanael J; Que, Xuchu; Zhou, Fangli; Liao, Zhongji; Pasillas, Martina; Yang, Xiaohong; Magida, Jason A; Kisseleva, Tatiana; Brenner, David A; Downes, Michael; Evans, Ronald M; Saltiel, Alan R; Tsimikas, Sotirios; Glass, Christopher K; Witztum, Joseph L.
Afiliação
  • Sun X; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: x10sun@ucsd.edu.
  • Seidman JS; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Zhao P; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Troutman TD; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Spann NJ; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Que X; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Zhou F; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
  • Liao Z; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Pasillas M; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Yang X; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Magida JA; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Kisseleva T; Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
  • Brenner DA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Downes M; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Evans RM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Saltiel AR; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Tsimikas S; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Glass CK; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Witztum JL; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jwitztum@ucsd.edu.
Cell Metab ; 31(1): 189-206.e8, 2020 01 07.
Article em En | MEDLINE | ID: mdl-31761566
ABSTRACT
Oxidized phospholipids (OxPLs), which arise due to oxidative stress, are proinflammatory and proatherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are unknown. Here, we show that OxPLs accumulate in human and mouse NASH. Using a transgenic mouse that expresses a functional single-chain variable fragment of E06, a natural antibody that neutralizes OxPLs, we demonstrate the causal role of OxPLs in NASH. Targeting OxPLs in hyperlipidemic Ldlr-/- mice improved multiple aspects of NASH, including steatosis, inflammation, fibrosis, hepatocyte death, and progression to hepatocellular carcinoma. Mechanistically, we found that OxPLs promote ROS accumulation to induce mitochondrial dysfunction in hepatocytes. Neutralizing OxPLs in AMLN-diet-fed Ldlr-/- mice reduced oxidative stress, improved hepatic and adipose-tissue mitochondrial function, and fatty-acid oxidation. These results suggest targeting OxPLs may be an effective therapeutic strategy for NASH.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfolipídeos / Apoptose / Carcinoma Hepatocelular / Estresse Oxidativo / Anticorpos de Cadeia Única / Hepatopatia Gordurosa não Alcoólica / Neoplasias Hepáticas / Mitocôndrias Idioma: En Revista: Cell Metab Assunto da revista: METABOLISMO Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfolipídeos / Apoptose / Carcinoma Hepatocelular / Estresse Oxidativo / Anticorpos de Cadeia Única / Hepatopatia Gordurosa não Alcoólica / Neoplasias Hepáticas / Mitocôndrias Idioma: En Revista: Cell Metab Assunto da revista: METABOLISMO Ano de publicação: 2020 Tipo de documento: Article