Characterization of the roles for the Hepatocyte Nuclear Factor 4 and lipid metabolism in intestinal inflammation
Developmental Biology
Final Report Abstract
This project addressed a fundamental aspect of metabolism that remains largely unknown, despite its impact on all aspects of physiology – how the absorption, storage and export of lipids are coordinated in the gut to maintain systemic homeostasis. It is now widely accepted that the gut, in addition to exporting lipids to peripheral tissues, can also actively store these nutrients. How this switch in lipid utilization is controlled remains a mystery, although it may have dramatic implications for metabolic health. Researchers have used a powerful genetic system, the fruit fly Drosophila, to study this question. They show that (1) specialized enterocytes are responsible for absorbing dietary lipids, (2) a gut-liver axis controls a lipid storage and export in these cells, and (3) perturbation of this switch triggers hallmarks of inflammatory bowel disease. During the course of this project, researchers have shown that a defined population of enterocytes is responsible for the uptake and export of dietary lipids in the Drosophila intestine. These cells communicate with distant oenocytes, the functional equivalent of hepatocytes in fruit flies, to regulate intestinal fat storage and export. Researchers discovered that Hepatocyte nuclear factor 4 (HNF4), a fat-sensing transcription factor that is conserved between insects and humans, acts in fly enterocytes and oenocytes to control this gut-liver axis. In enterocytes, HNF4 activates a lipolytic program that limit the incorporation of dietary fats into cytoplasmic droplets, thereby favoring their export. In oenocytes, HNF4 induces the expression of an insulin inhibitor to activate Foxo signaling in the intestine, thereby suppressing lipid storage in this organ. This gut-liver axis may fine-tune intestinal function to meet the changing nutritional needs of the organism, but intestinal lipid retention comes at a cost: it induces local inflammation and several other hallmarks of inflammatory bowel disease. As variants in HNF4A have been associated with Crohn’s disease in several patient cohorts, this work provides a new level of understanding of how this regulatory link is established. From a broader perspective, this work sheds new light on the mechanisms that control a crucial metabolic decision in the gut: whether to store or to export dietary lipids. These pathways may have important implications for our understanding of metabolic disorders such as obesity and type 2 diabetes.
Publications
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Transcriptomic analysis of control intestines and intestines with dHNF4 suppression in enterocytes. GEO: GSE271746.
Storelli, Gilles
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Drosophila HNF4 acts in distinct tissues to direct a switch between lipid storage and export in the gut. Cell Reports, 43(9), 114693.
Vonolfen, Maximilian C.; Meyer, zu Altenschildesche Fenja L.; Nam, Hyuck-Jin; Brodesser, Susanne; Gyenis, Akos; Buellesbach, Jan; Lam, Geanette; Thummel, Carl S. & Storelli, Gilles
