Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis

Xiaoli Sun, Jason S. Seidman, Peng Zhao, Ty D. Troutman, Nathanael J. Spann, Xuchu Que, Fangli Zhou, Zhongji Liao, Martina Pasillas, Xiaohong Yang, Jason A. Magida, Tatiana Kisseleva, David A. Brenner, Michael Downes, Ronald M. Evans, Alan R. Saltiel, Sotirios Tsimikas, Christopher K. Glass, Joseph L. Witztum

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

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. Oxidized phospholipids (OxPLs) accumulate in murine and human NASH, promoting oxidative stress, mitochondrial damage, and fibrosis. Antibody-mediated neutralization of OxPLs ameliorates murine NASH and the progression to hepatocellular carcinoma (HCC), suggesting this avenue as a potential therapeutic target for NASH.

Original languageEnglish (US)
Pages (from-to)189-206.e8
JournalCell Metabolism
Volume31
Issue number1
DOIs
StatePublished - Jan 7 2020
Externally publishedYes

Keywords

  • MnSOD
  • atherosclerosis
  • fibrosis
  • inflammation
  • mitochondria
  • natural antibody
  • nonalcoholic steatohepatitis
  • oxidative stress
  • oxidized phospholipids
  • steatosis

ASJC Scopus subject areas

  • Molecular Biology
  • Physiology
  • Cell Biology

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