Neutralization of Oxidized Phospholipids Restrains Nonalcoholic Steatohepatitis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA575823 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10230541.fastq.gz | Fastqsanger.gz | |||
| SRR10230542.fastq.gz | Fastqsanger.gz | |||
| SRR10230543.fastq.gz | Fastqsanger.gz | |||
| SRR10230544.fastq.gz | Fastqsanger.gz | |||
| SRR10230545.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description: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.
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