The intestinal lymphatic system is essential for lipid absorption, yet its regulatory mechanisms remain poorly understood. Here, we identify DHHC5, an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferase,...The intestinal lymphatic system is essential for lipid absorption, yet its regulatory mechanisms remain poorly understood. Here, we identify DHHC5, an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferase, as a critical regulator of intestinal lymphatic integrity and lipid uptake. Whole-body inducible Dhhc5 knockout (Dhhc5-IKO) mice were resistant to diet-induced obesity and exhibited impaired intestinal lipid absorption due to lymphatic dysfunction. Similar defects were observed upon specific knockout of DHHC5 in lymphatic endothelial cells (LECs), underscoring its cell-autonomous role. Mechanistically, DHHC5 facilitates vascular endothelial growth factor receptor 2 (VEGFR2) signaling by promoting its lipid raft localization in LECs. We further identified CRYBG1, an actin-binding protein, as the substrate of DHHC5. CRYBG1 interacts with VEGFR2, and its palmitoylation is required for the lipid raft localization of VEGFR2. These findings reveal a DHHC5–CRYBG1–VEGFR2 axis that governs intestinal lymphatic function and lipid absorption, providing new insights into the regulation of dietary lipid metabolism.展开更多
基金supported by the National Natural Science Foundation of China(32125022,32230053,92157301,and 32401059)the National Key R&D Program of China(2024YFA1306101 and 2020YFA0803601)the Shanghai Basic Research Field Project“Science and Technology Innovation Action Plan”(21JC1400400).
文摘The intestinal lymphatic system is essential for lipid absorption, yet its regulatory mechanisms remain poorly understood. Here, we identify DHHC5, an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferase, as a critical regulator of intestinal lymphatic integrity and lipid uptake. Whole-body inducible Dhhc5 knockout (Dhhc5-IKO) mice were resistant to diet-induced obesity and exhibited impaired intestinal lipid absorption due to lymphatic dysfunction. Similar defects were observed upon specific knockout of DHHC5 in lymphatic endothelial cells (LECs), underscoring its cell-autonomous role. Mechanistically, DHHC5 facilitates vascular endothelial growth factor receptor 2 (VEGFR2) signaling by promoting its lipid raft localization in LECs. We further identified CRYBG1, an actin-binding protein, as the substrate of DHHC5. CRYBG1 interacts with VEGFR2, and its palmitoylation is required for the lipid raft localization of VEGFR2. These findings reveal a DHHC5–CRYBG1–VEGFR2 axis that governs intestinal lymphatic function and lipid absorption, providing new insights into the regulation of dietary lipid metabolism.
