Title: Neutralization of Oxidized Phospholipids Restrains Nonalcoholic Steatohepatitis

Accession Number: GSE138419

Link to Dataset: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138419

Repository: Gene Expression Omnibus (GEO)

Data Type(s): Gene Expression

Experiment Type(s): Expression profiling by high throughput sequencing

Organism(s): Mus musculus

Summary: Oxidized phospholipids (OxPL) are pro-inflammatory and pro-atherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are unknown. Here, we show that OxPL accumulate in human and murine NASH. Using a transgenic mouse that expresses a functional single chain variable fragment of E06, a natural antibody that neutralizes OxPL, we demonstrate the casual role of OxPL in NASH. Targeting OxPL in hyperlipidemic Ldlr-/- mice decreased multiple aspects of NASH, including steatosis, inflammation, fibrosis, hepatocyte death and progression to hepatocellular carcinoma. Mechanistically, we found that OxPL promote ROS accumulation to induce mitochondrial dysfunction in hepatocytes. Neutralizing OxPL in AMLN diet-fed Ldlr-/- mice reduced oxidative stress, improved hepatic and adipose tissue mitochondrial function and fatty acid oxidation. Since neutralizing OxPL also protects against atherogenesis, targeting OxPL may be an effective therapeutic strategy for both NASH and atherosclerosis.

Publication(s) associated with this dataset:

• Sun X, Seidman J, Zhao P, Troutman T, Spann N, Que X, Zhou F, Liao Z, Pasillas M, Yang X, Magida J, Kisseleva T, Brenner DA, Downes M, Evans RM, Saltiel AR, Tsimikas S, Glass CK, Witztum JL. 2020. Neutralization of oxidized phospholipids ameliorates non-alcoholic steatohepatitis. Cell Metab 31(1):189-206. doi:10.1016/j.cmet.2019.10.014 PMID:31761566 PMCID:PMC7028360