1. Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis
- Author
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Joseph L. Witztum, Nathanael J. Spann, Ronald M. Evans, Sotirios Tsimikas, Alan R. Saltiel, Xuchu Que, Michael Downes, Zhongji Liao, Tatiana Kisseleva, Fangli Zhou, Christopher K. Glass, David A. Brenner, Ty D. Troutman, Jason A. Magida, Peng Zhao, Xiaohong Yang, Xiaoli Sun, Jason S. Seidman, and Martina P. Pasillas
- Subjects
0301 basic medicine ,Liver Cirrhosis ,Male ,Physiology ,Apoptosis ,Mitochondrion ,medicine.disease_cause ,Mice ,0302 clinical medicine ,Fibrosis ,Non-alcoholic Fatty Liver Disease ,RNA-Seq ,Phospholipids ,Chemistry ,Liver Neoplasms ,Mitochondria ,medicine.symptom ,Oxidation-Reduction ,Genetically modified mouse ,Carcinoma, Hepatocellular ,Inflammation ,Mice, Transgenic ,Diet, High-Fat ,digestive system ,Article ,Proinflammatory cytokine ,03 medical and health sciences ,Microscopy, Electron, Transmission ,medicine ,Animals ,Humans ,Obesity ,Molecular Biology ,nutritional and metabolic diseases ,Cell Biology ,medicine.disease ,digestive system diseases ,Fatty Liver ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Gene Ontology ,Cancer research ,Hepatocytes ,Steatosis ,Steatohepatitis ,Reactive Oxygen Species ,030217 neurology & neurosurgery ,Oxidative stress ,Single-Chain Antibodies - Abstract
Oxidized phospholipids (OxPLs), which arise due to oxidative stress, are pro-inflammatory and pro-atherogenic, 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 casual 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.
- Published
- 2019