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Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis.

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机构: [1]Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA [2]Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA [3]Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China [4]Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA [5]Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA [6]Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
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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. Copyright © 2019 Elsevier Inc. All rights reserved.

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大类 | 1 区 生物学
小类 | 1 区 细胞生物学 1 区 内分泌学与代谢
最新[2023]版:
大类 | 1 区 生物学
小类 | 1 区 细胞生物学 1 区 内分泌学与代谢
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第一作者机构: [1]Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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