Mechanisms of Dietary Nutrient Absorption

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

ABSTRACT Our long-term objective is to define mechanism that regulate lipid flux in cells and animals and to elucidate their impact on metabolic disease. Crosstalk with resident immune cells of the lamina propria of the gut has been shown to influence the function of the absorptive epithelium, but molecular mechanisms whereby cellular lipid levels in immune cells regulate this communication are largely undefined. We have discovered that accessible PM cholesterol abundance in gut T cells is a potent modulator of dietary lipid absorption. Our preliminary data show that inactivation of Aster-A induces changes in TH17 cell signaling, including production of the cytokine IL-22, that alter systemic metabolism and energy balance. Here we propose a complementary series of cellular, animal and pharmacological studies to define the underlying molecular mechanisms and physiological implications of this discovery. Specific Aim 1 is to understand the mechanism(s) whereby gut T cells modulate dietary lipid absorption. We will define signaling components that mediate the suppression of fatty acid uptake by IL-22, taking advantage of genetic models, chemical inhibitors and intestinal enteroids. Specific Aim 2 is to elucidate the role of IL-22/IL-22R signaling in intestinal and systemic lipid homeostasis. We will further define the importance of the IL-22/IL-22R axis for whole-body physiology and energy balance. We will utilize a novel AlpiCreER; Il22ra1F/F mouse model to dissect the function of the IL-22/IL-22R axis specifically in mature enterocytes. Specific Aim 3 is to define intrinsic and environmental cues that regulate fatty acid absorption. Diet composition has long been known to impact systemic metabolism. We hypothesize that environmental factors that perturb IL-22/IL-22R axis may serve to modulate intestinal metabolism. We will now examine the effects of dietary AHR ligands such as indole-3-acetate and tryptamine that are produced by gut microflora from ingested tryptophan. To define specific gut immune cell populations responsive to these environmental cues, we will delete IL-22 in T cells or type-3 innate lymphoid cells and characterize their function importance in intestinal metabolic responses including the response to AHR agonists.