217 - Oxidized phospholipids regulate cellular metabolism and lipid droplet formation in hepatocytes – Implications for non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of cardio-metabolic syndrome, affects up to 30% of individuals in the United States. NAFLD is a chronic disease that initially presents as hepatic steatosis and can progress to non-alcoholic steatohepatitis, hepatic fibrosis, and liver failure. Hepatic steatosis is characterized by an increased lipid burden within hepatocytes. This has been correlated with hepatic mitochondrial dysregulation which is thought to contribute to hepatic lipid accumulation. However, the factors that cause mitochondrial dysfunction in NAFLD remain unknown. Previously, our lab has shown that oxidized phospholipids (OxPLs) regulate mitochondrial function, and here, we test the hypothesis that OxPLs that accumulate due to oxidative stress during NAFLD progression in the liver promote lipid droplet accumulation within hepatocytes by dysregulating hepatic mitochondrial function. C57Bl/6 mice were fed a high fructose, palmitate, cholesterol diet for 12 weeks to induce hepatic steatosis. Compared to mice fed a chow diet after 12 weeks, we observed a disproportionate increase in truncated oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) compared to full-length oxidation products in steatotic livers. Treatment of AML12 murine hepatocytes with truncated oxidation products of PAPC for 4-hours resulted in a significant decrease in maximum and reserve oxygen consumption rate; additionally, 48-hour treatment resulted in an increase in lipid droplet size and quantity. Incongruous with effects of truncated oxidation products, full-length oxidation products of PAPC exhibited no significant effect on oxygen consumption or lipid droplet size. These data suggest that truncated oxidation products in the hepatic milieu regulate lipid droplet size and quantity by modulating mitochondrial function which may contribute to the pathogenesis of hepatic steatosis and NAFLD.