Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis.

Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis. Cell Metab. 2019 Nov 14;: Authors: Sun X, Seidman JS, Zhao P, Troutman TD, Spann NJ, Que X, Zhou F, Liao Z, Pasillas M, Yang X, Magida JA, Kisseleva T, Brenner DA, Downes M, Evans RM, Saltiel AR, Tsimikas S, Glass CK, Witztum JL 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. PMID: 31761566 [PubMed - as supplied by publisher]
Source: Cell Metabolism - Category: Cytology Authors: Tags: Cell Metab Source Type: research