Objective: Cellular metabolism is a key regulator of CD4+Foxp3+ regulatory T cell (Treg) homeostasis, but the foundational studies in this area use free fatty acid treatment as a proxy for plasma triglycerides. In vivo, plasma triglyceride is the main source of fatty acids for cells, not free fatty acids. Design/Results: Using apolipoprotein C-III transgenic and LDLr-/- mice, we report that the loss of lipoprotein triglycerides transport in these models results in protection from DSS-colitis and accumulation of intestinal Tregs and plasma IL-10. Total loss of apoC-III increases colitis severity. Tregs exposed to apoC-III increase lipolysis and fatty acid oxidation and apoC-III inhibits Bodipy- triglyceride uptake. Therapeutic treatment of WT mice with apoC-III-containing lipoproteins protects mice from colitis. Conclusion: Our data suggest that therapies that reduce apoC-III could have negative effects in patients who are at risk of IBD, and conversely, that apoC-III could be a new therapeutic target to stimulate intestinal Tregs and IL-10 for the management of IBD. These data identify apoC-III and lipoprotein metabolism as a novel regulator of tolerance in the intestine.

ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs