Abstract
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.
Highlights
Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear
We have previously shown that palmitoylation of CD36 by DHHC4 and DHHC5 is required for its plasma membrane localization and FA uptake activity[20]
As CD36 is primarily localized in the caveolae structures[8], we have examined the dynamic localization of Caveolin[1] (CAV1), a scaffold protein of caveolae, and found that CAV1 co-migrated with CD36 (Fig. 1a and Supplementary Movies 1–6)
Summary
Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Unlike glucose and amino acids, FAs are hydrophobic and have extremely low aqueous solubility at physiological pH7.4, and they are usually bound with serum albumins and cytoplasmic FA binding proteins[2] The hydrophobicity makes it difficult to track the movement of FAs. It was proposed that passive diffusion might be the predominant way to absorb FAs3, but accumulating evidences support that protein-facilitated FA uptake is the key pathway in metabolic tissues including liver, adipose tissue, and muscle[4,5]. CD36 has an FA binding pocket[14], and it was proposed to be a transporter[6]; a study using HEK293 cells shows that CD36 increases intracellular esterification but not translocation of FAs15 It still remains unknown about how exactly CD36 transports FAs across the plasma membrane. It is unknown about whether and how the palmitoylation of CD36 is dynamically regulated
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