Protocatechuic Acid Reduces Liver Fatty Acid Uptake in HFD‐Fed Mice Associated With the Inhibition of DHHC5‐Mediated CD36 Palmitoylation

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) is highly prevalent and has emerged as a pressing issue for human health. A highly palmitoylated cluster of differentiation 36 (CD36) promotes free fatty acid (FFA) uptake, which contributes to the development of MASLD. Protocatechuic acid (PCA), the main metabolite of anthocyanins, was reported to inhibit MASLD by regulating the expression of CD36. However, the impact of PCA on CD36 palmitoylation has not been extensively studied. In the present study, we found that PCA could significantly reduce lipid uptake and accumulation in hepatocytes by decreasing CD36 palmitoylation. Inhibitors were used to prove that PCA suppressed CD36 palmitoylation by lowering zinc finger DHHC‐type palmitoyltransferase 5 (DHHC5) palmitoylation, but not in an acyl protein thioesterase 1 (APT1)‐dependent manner. Further experiments showed that PCA‐mediated inhibition of DHHC5 palmitoylation and acyltransferase activity was closely related to the reduction of the CD36/Fyn/Lyn complex. PCA diminished the palmitoylation of CD36 and DHHC5 and ultimately lessened lipid uptake and accumulation in hepatocytes.