Dynamic Palmitoylation-Regulated Endocytosis Is Essential For CD36-Mediated Fatty Acid Uptake

Fatty acids are hydrophobic molecules and were thought to enter cells through passive diffusion.Accumulating evidences suggest that fatty acid uptake can be facilitated by proteins,but the underlying mechanism remains unclear.In adipocytes,fatty acid uptake is mainly through CD36.In previous reports,palmitoylation of CD36 affects localization and fatty acid uptake,but the underlying mechanism remains unclear.Here,we report that adipocytes actively take up fatty acids via caveolar endocytosis,which is critical for the lipid storage function and adipocytes homeostasis.Binding of fatty acids with CD36 on the cell surface triggers a cascade of intracellular signaling,including activation of LYN,phosphorylation and inactivation of DHHC5,depalmitoylation of CD36 by APT1,recruitment of SYK,and phosphorylation of JNK and VAV.These events eventually lead to caveolar endocytosis,which delivers fatty acids to lipid droplet-associated endoplasmic reticulum for esterification and lipid storge.Blocking the endocytosis abolishes CD3 6-dependent fatty acid uptake and protects WT,but not Cd36-/-mice from high-fat-diet induced obesity.Our findings have thus uncovered a physiological pathway to transport fatty acids into cells and provided potential strategies for treating obesity.