Insulin regulation of lymphatic vessel integrity

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PROJECT SUMMARY/ABSTRACT Integrity of lymphatic vessels enables maintenance of organ function and protective immunity. The role of lipid metabolism in lymphatic development and maintenance is now emerging, but less is known about how the lipid milieu regulates lymphatic vessel integrity. Lipid and insulin signaling are associated with abnormal endothelial function but targets of lipid and insulin signaling in the lymphatics are understudied. Lipids affect endothelial cellular homeostasis through protein modifications such as lipidation. Emerging studies show that insulin regulates endothelial lipidation of proteins relevant to vascular integrity and remodeling. Whether this regulation applies to endothelial cells of lymphatic origin remain unexplored. Lymphatic endothelial cells have higher sensitivity to insulin than blood endothelial cells but physiological relevance remains unclear. Lymphatic endothelial insulin resistance could impair LEC homeostasis and function, however in vivo verification is necessary in the prospect of clinical translation. Our studies showed an unexpected higher expression of the lipid translocase CD36 in collecting lymphatic vessels. Loss of CD36 in lymphatic endothelial cells compromises vessel integrity and causes multi-organ inflammation typical of endothelial dysfunction. Insulin and CD36 are mutually regulated in many cell types. We hypothesize that insulin-mediated regulation of CD36 post-translational modifications and turnover regulates lymphatic vessel integrity. Toward this goal, we aim to examine the novel regulation of lymphatic vessel integrity and the contribution of impaired insulin signaling to dysfunctional lymphatic vessels. We will identify new targets of insulin-mediated lipidation in lymphatic vessels and address whether loss of CD36 skews phenotypic and functional heterogeneity of LEC subsets in the mesenteric collecting vessels promoting an inflammatory, profibrotic, and metabolically abnormal phenotype. Our study will uncover the cross-talk between lymphatic vascular function and commensal microbiota, and reveal organ-specific and systemic effects of dysfunctional lymphatics. We will then evaluate whether transient ablation of the microbiota, or dietary intervention improves lymphatic integrity and could ameliorate metabolic outcomes and inflammation.