Editors' ChoiceMetabolic Disease

Targeting NASH with OxPL neutralization

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Science Translational Medicine  18 Dec 2019:
Vol. 11, Issue 523, eaaz9770
DOI: 10.1126/scitranslmed.aaz9770

Abstract

Accumulation of oxidized phospholipids (OxPLs) contribute to NASH development.

Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, fibrosis, and hepatocellular injury. Currently, NASH is the leading cause of chronic liver disease, and it increases the risk for cirrhosis and hepatocellular carcinoma (HCC). Despite its increased prevalence worldwide, there are no U.S. Food and Drug Administration (FDA)-approved drugs for NASH treatment, in part due to our lack of understanding of its pathogenesis. Proinflammatory oxidized phospholipids (OxPLs) are generated by nonenzymatic oxidation of lipids and play an important role in the development of many inflammatory diseases, including atherosclerosis. In a recent study, Sun et al. found that OxPLs also contribute to NASH development.

The authors first reported that the concentrations of hepatic and plasma OxPLs were elevated in different mouse NASH models and human subjects with NASH. To understand whether OxPL accumulation contributes to NASH development, they used transgenic mice expressing a single chain variant of E06, a natural monoclonal antibody targeted to OxPLs (E06-scFV). Using a mouse model that mimics human NASH, they showed that these mice exhibited a decrease in hepatic steatosis, inflammation, fibrosis, hepatocyte death, and were protected from HCC development. Remarkably, neutralization of OxPLs in mice resulted in increased energy expenditure and prevention of diet-induced obesity, without a change in food intake or insulin sensitivity. Studies in isolated hepatocytes and mouse NASH-liver samples revealed that OxPLs induced reactive oxygen species (ROS) accumulation and mitochondrial dysfunction through binding and inhibiting the activity of mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD). Further mechanistic work showed that OxPL-neutralization improved systemic inflammation and attenuated hepatic fibrosis even in the severe carbon tetrachloride-induced liver damage model that does not induce hepatic steatosis. These results provide new insight into the pathophysiology of NASH; however, it remains to be investigated whether OxPL neutralization reverses the features of established NASH. In view of the fact that OxPLs also contribute to atherosclerosis development, future therapies that inactivate OxPLs may be beneficial for reducing inflammation in metabolic diseases, including NASH and atherosclerosis.

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