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

Abstract

ObjectiveCellular 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/ResultsUsing 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. ConclusionOur 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. Summary Box* What is already known about this subject:{blacksquare} The relative capacity to use either glucose or FFA to generate acetyl CoA for mitochondrial fatty acid oxidation is a critical driver of Treg and T cell activity and proliferation. {blacksquare}ApoC-III is a known regulator of triglyceride and fatty acid metabolism in cells via LPL and LDLr endocytosis pathways {blacksquare}ApoC-III is reduced in Crohns and Colitis patients. * What are the new findings:{blacksquare} We show that Tregs express triglyceride transporters, and that LDLr expression is enriched in Tregs from the mesenteric lymph nodes. {blacksquare}We show that T cells are capable of endocytosing triglyceride from lipoproteins, and this process is inhibited by apoC-III. {blacksquare}Tregs from apoC-IIITg are metabolically unique from WT Tregs and they upregulate the genes of lipolysis, and have an increase in basal respiration. {blacksquare}The inhibition of TAG endocytosis, using 2 different models (LDLrKO and apoC-III-transgenic mice), protects mice from colitis and stimulates the accumulation of Tregs and IL-10 in the gut. {blacksquare}Intraperitoneal delivery of apoC-III on chylomicrons protects WT mice from DSS colitis. * How might it impact on clinical practice in the foreseeable future?{blacksquare} Due to the protective role apoC-III plays in these mouse models of colitis, IBD risk should be carefully considered before prescribing patient anti-apoC-III lipid-lowering therapies.