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.

脂肪酸 (FAs) 是必需的营养素，但它们如何运输到细胞中仍不清楚。在这里，我们展示了 FAs 触发了小窝依赖的 CD36 内化，进而将 FAs 传递到脂肪细胞中。在此过程中，FAs 与 CD36 的结合激活了其下游激酶 LYN，后者在 Tyr91 处磷酸化 DHHC5（CD36 的棕榈酰酰基转移酶）并使其失活。然后 CD36 被 APT1 去棕榈酰化并招募另一种酪氨酸激酶 SYK 来磷酸化 JNK 和 VAV，以启动 FA 的内吞摄取。通过抑制 APT1、LYN 或 SYK 来阻断 CD36 内化可消除 CD36 依赖的 FA 摄取。在棕榈酰化或去棕榈酰化状态下限制 CD36 会消除其 FA 吸收活性，表明 CD36 的动态棕榈酰化的重要作用。此外，通过靶向 LYN 或 SYK 阻断内吞作用可抑制脂肪细胞中 CD36 依赖性脂滴的生长和高脂肪饮食诱导的小鼠体重增加。我们的研究发现了一种动态棕榈酰化调节的内吞途径来摄取 FA。