CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis

Nat Commun. 2020 Sep 21;11(1):4765. doi: 10.1038/s41467-020-18565-8.


Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Acyltransferases / metabolism
  • Adipocytes / metabolism
  • Animals
  • CD36 Antigens / deficiency
  • CD36 Antigens / genetics
  • CD36 Antigens / metabolism*
  • Caveolae / metabolism
  • Cells, Cultured
  • Diet, High-Fat / adverse effects
  • Endocytosis / physiology*
  • Fatty Acids / metabolism*
  • Humans
  • Lipid Droplets / metabolism
  • Lipoylation*
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Obesity / drug therapy
  • Phosphorylation
  • Signal Transduction
  • Syk Kinase / antagonists & inhibitors
  • Syk Kinase / metabolism
  • Weight Gain / drug effects
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism


  • CD36 Antigens
  • Cd36 protein, mouse
  • Fatty Acids
  • Membrane Proteins
  • Acyltransferases
  • DHHC5 protein, mouse
  • Syk Kinase
  • Syk protein, mouse
  • lyn protein-tyrosine kinase
  • src-Family Kinases