TMET-05. LIPOPHAGY CONTROLS CHOLESTEROL HOMEOSTASIS AND BRAIN TUMOR GROWTH

Abstract

Abstract Cholesterol is an essential structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol, but with an abundant presence of cholesteryl esters (CEs) in their lipid droplets (LDs). Mechanistically, we found that SREBP-1, a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked GBM cells became quite sensitive to cholesterol deficiency with poor growth. Our study unravels a previously unrecognized SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis, while providing a potential new therapeutic avenue for GBM