Abstract 20520: A New Lysosome-Mediated Degradation Mechanism for Hepatic Lipid Droplets Turnover

Dietary supplementation with fish oil, rich in n-3 fatty acids such as EPA (20:5n-3), has been shown in many studies to exert a hypotriglyceridemic effect by reducing both plasma triglycerides (in the form of VLDL) and intrahepatic triglycerides (presented in cytoplasm as lipid droplets). To date, no cellular or molecular mechanisms have been defined to explain the hypotriglyceridemic action of n-3 fatty acids. Intrahepatocellular triglycerides are an important contributor to plasma fatty acids and lipoproteins level. We have discovered a direct interaction between lysosome and lipid droplets, in a Kiss-and-run fashion, as the principal mechanism for the lipid droplets turnover upon EPA treatment. Inactivating lysosome function or disrupting lysosome movement resulted in accumulation of lipid droplets under EPA treatment conditions, whereas inactivating the known lipolysis enzymes ATGL or HSL was unable to attenuate droplets turnover. Lipophagy has been reported as a selective autophagic mechanism for degradation of lipid droplets under starvation conditions. However, knockdown of autophagy proteins did not prevent droplets turnover induced by EPA. On the other hand, silencing lysosome-associated GTPase Rab7 or the Rab7 effectors, such as FYCO1 and RILP, entirely blocked EPA-induced droplets turnover. Overexpression of the lysosome-associated Arf-like GTPase Arl8b markedly accelerated the EPA-induced droplets turnover. The current study thus unveiled a new lysosome-mediated lipid degradation mechanism that is responsible for the hypotriglyceridemia action of n-3 fatty acids. The therapeutic potential for the treatment of non-alcoholic hepatosteatosis will be discussed.