An mTORC1-Plin3 pathway is essential to activate lipophagy and protects against hepatosteatosis.

Abstract

BACKGROUND & AIMS\nNon-alcoholic fatty liver disease (NAFLD) is the most common hepatic pathology in western countries and no treatment is currently available. NAFLD is characterized by the aberrant hepatocellular accumulation of fatty acids in the form of lipid droplets (LD). Recently, it was shown that liver LD degradation occurs via a process termed lipophagy; a novel form of autophagy. However, the molecular mechanisms governing liver lipophagy are elusive. Here, we aimed to ascertain the key molecular players that regulate hepatic lipophagy and their importance in NAFLD.\n\n\nAPPROACH & RESULTS\nWe analyzed the formation and degradation of LD in vitro (fibroblasts and primary mouse hepatocytes), in vivo and ex vivo (mouse and human liver slices) and focused on the role of the autophagy master regulator mammalian Target Of Rapamycin Complex 1 (mTORC1) and the LD coating protein Plin3 in these processes. We show that the autophagy machinery is recruited to the LD upon hepatic overload of oleic acid in all experimental settings. This led to activation of lipophagy, a process that was abolished by Plin3 knockdown using RNA interference. Furthermore, Plin3 directly interacted with the autophagy proteins Fip200 and Atg16L, suggesting that Plin3 functions as a docking protein or is involved in autophagosome formation to activate lipophagy. Finally, we show that mTORC1 phosphorylated Plin3 to promote LD degradation.\n\n\nCONCLUSIONS\nThese results reveal that mTORC1 regulates liver lipophagy through a mechanism dependent on Plin3 phosphorylation. We propose that stimulating this pathway can enhance lipophagy in hepatocytes to help protect the liver from lipid-mediated toxicity, thus offering a new therapeutic strategy in NAFLD.