Insulin regulates lymphatic endothelial integrity via palmitoylation

Area of Science:

• Cell Biology
• Metabolism
• Immunology

Background:

• Lipid metabolism is vital for lymphatic endothelial cell (LEC) function and lymphatic vessel integrity.
• Dysregulated lipid metabolism contributes to lymphatic dysfunction, impacting organ function, immunity, and metabolic health.
• Protein palmitoylation, a lipid modification, regulates protein function, but its role in LECs, especially under insulin influence, is unknown.

Purpose of the Study:

• To investigate the role of protein palmitoylation in human LEC function.
• To characterize the impact of insulin on protein palmitoylation in LECs.
• To explore the function of CD36 in regulating palmitoylation in LECs.

Main Methods:

• Generated the first palmitoylation proteomics profile in human LECs.
• Validated insulin-regulated palmitoylation targets.
• Assessed the role of palmitoylation in LEC barrier function.
• Investigated the effect of CD36 silencing on protein palmitoylation.

Main Results:

• Palmitoylation in unstimulated LECs primarily targeted proteins involved in trafficking and translation.
• Insulin treatment increased palmitoylation of junctional proteins (e.g., claudin 5), small GTPases, and ubiquitination enzymes, enhancing LEC integrity.
• CD36 silencing in LECs led to a twofold increase in palmitoylation of proteins related to inflammation and immune activation.

Conclusions:

• Insulin-driven protein palmitoylation is critical for maintaining lymphatic endothelial cell integrity and function.
• Lipid modification, particularly palmitoylation, plays a significant role in LEC biology.
• Findings suggest potential therapeutic targets for lymphatic dysfunction by modulating insulin signaling and palmitoylation pathways.