Endothelial Cells as Active Lipid Gatekeepers: Vascular Control of Lipid Handling and Metabolic Homeostasis.

Endothelial cells have emerged as critical peripheral nutrient sensors that actively regulate systemic lipid metabolism rather than serving as passive conduits. Endothelial peroxisome proliferator-activated receptor γ maintains redox balance, supports nitric oxide-dependent perfusion, and preserves insulin sensitivity during high-fat feeding, while ghrelin signaling through endothelial GHS-R promotes triglyceride clearance and lipid uptake into white adipose tissue through an endothelial peroxisome proliferator-activated receptor γ-dependent program. These pathways reveal that the endothelium integrates hormonal and metabolic cues to tune lipid trafficking, vectorial fatty acid delivery, and depot-specific energy storage. The concept that the endothelial phenotype, rather than circulating lipid levels alone, determines organ-level lipid exposure reframes endothelial lipid sensing as a key regulator of whole-body metabolic homeostasis. Understanding how endocrine and transcriptional pathways shape endothelial lipid handling may reveal new therapeutic targets for the treatment of obesity, dyslipidemia, and related metabolic diseases.