Dynamic Oxidized Phospholipid Composition within the Liver Plays a Role in Non-alcoholic Fatty Liver Disease Progression

摘要

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of cardio-metabolic syndrome, affects up to 25% of individuals within the USA. NAFLD is a progressive pathology initiating with accumulation of fat within the liver (hepatic steatosis) followed by inflammation (steatohepatitis) and liver fibrosis. Currently, drivers of NAFLD progression are poorly understood. Recently, it was shown that fatty acid-induced metabolic dysregulation of hepatocytes results in succinate release. Hepatic stellate cells, the primary instigators of liver fibrosis, have been shown to be activated by succinate, via GPR91, a putative succinate receptor. Here we show that products of phospholipid oxidation increase succinate levels within bone marrow-derived macrophages. Furthermore, using immunohistochemistry with E06, an antibody that recognizes oxidized phospholipids (OxPL), we found increased E06 staining of carbon tetrachloride treated livers, a model of liver damage, compared to control. To determine the composition of OxPL present within steatotic liver, we developed a liquid chromatography-mass spectrometry method to quantify 14 products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (PAPC) oxidation in whole liver tissue. Using this method, we find a change in OxPL composition between high fat diet-fed livers compared to healthy controls. Furthermore, we see a change in OxPL composition in murine whole blood from animals on high fat diet compared to chow. Taken together, OxPL in steatotic liver may play a role in stellate cell activation and subsequent fibrosis.