Physiologically, triglyceride-rich lipoproteins (chylomicron and VLDL) are the largest source of lipids during both fasting and feeding. Plasma fatty acids average ~550μM during fasting (when they are at their highest), the fatty acids available in plasma TRLs are at least ~5,100μM. Traditionally, chylomicrons have been difficult to study, and are therefore a potentially under-appreciated target for treating metabolic diseases.
PROJECT 1: Do chylomicrons deliver triglyceride fuel to intestinal Tregs?
Energy metabolism is a key driver of immune cell function. CD4+CD25+Foxp3+ Regulatory T cell (Tregs) are critical tolerogenic immune cells at mucosal surfaces. Tregs use fatty acids to fuel oxidative phosphorylation (OXPHOS), in contrast with CD4+ effector T cells (Th1, Th2, and Th17) which prefer aerobic glycolysis. This fuel preference is a key driver of Treg function and proliferation. A challenge in the field is determining how to manipulate these metabolic preferences of Tregs in vivo to control Treg differentiation in inflammatory disease.
In vivo, the largest pool of extracellular fatty acid substrates comes from the two types of triglyceride-rich lipoproteins (TRLs): chylomicrons, which carry dietary lipids, and from very-low density lipoproteins (VLDLs), which carry endogenous hepatic-derived lipids. Physiologically, TRLs are the largest source of acyl substrates during both fasting and feeding. Whereas plasma FFAs average ~550μM during fasting (when they are at their highest), the fatty acids available in plasma TRLs are at least ~5,100μM. We currently do not know whether Tregs acquire fatty acid substrates from circulating TRLs, or how this acquisition influences their cellular metabolism and proliferation.
PROJECT 2: Enterocyte fuel choice and its impact on chylomicron secretion
Determining the influence of plasma lipoproteins, particularly triglyceride-rich lipoproteins with apoC-III, on intestinal lipid metabolism. Key questions include: How do plasma lipoproteins regulate enterocyte metabolism? Does this impact dietary lipid absorption? How does this influence inflammatory disease?
“The inability to form normal chylomicrons, due to changes in enterocyte lipid metabolism or dietary fat malabsorption, is under-appreciated in the etiology of inflammatory bowel disease and cystic fibrosis symptoms. ”
PROJECT 3: Using intestinal organoids for discovery science.
Chylomicrons are difficult to isolate, and the intestine is notoriously finicky to study. We use primary intestinal organoids to get around these issues and discover new metabolic processes that are chylomicron driven.
The Kohan Lab has been using primary intestinal organoids to study chylomicron secretion mechanisms and how these may go awry in different diseases.
“Not all chylomicrons are created equal: they are secreted from the intestine with a variety of antigens, lipids, and protein cargos and can go on to exacerbate many diseases, including inflammatory bowel disease (IBD) and cardiovascular disease (CVD). ”
