Intestinal angiopoietin-like protein 4: New regulatory roles in lipid transport and metabolism, lipoprotein assembly and secretion, and molecular mechanisms of action

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The intestine is an organ for the digestion and transport of nutrients, assuring growth and survival of all tissues. Recent breakthroughs have unveiled critical roles of the gastrointestinal (GI) tract such as the production of the plethora of the GI peptides. Within the digestive tract, epithelial cells coexist with large numbers of microorganisms, referred to as the microbiota. Both the microorganisms and the host cells display mutual adaptive changes required for numerous housekeeping and vital functions and safeguarding the maintenance of appropriate levels of micro-and macronutrients over the lifetime of the organism. Overall, all the systems ensure optimal nutrient transportation while maintaining intestinal barrier integrity and defending against oxidative stress (OxS) and inflammation burden. In an even more important fashion, bidirectional interactions between intestinal cells and the commensal microbiota are also central to the crosstalk with peripheral organs and integral homeostasis. Despite the significant progress, the critical signals for local and distant effects have not been established. Hense, major issues remain unsolved regarding the sites, critical protein participant identity and regulation involved in lipid translocation from the intestinal lumen into the enterocyte and blood circulation. The literature is still far from pinpointing the mechanisms of the multi-step chylomicron (CM) assembly within the enterocyte and the communication with cellular processes to warrant intestinal homeostasis by bumping off OxS and inflammation. As ANGPTL4 is a multifunctional signal protein and modulates cell differentiation, lipid and glucose metabolism, redox system, angiogenesis, we have hypothesized that ANGPTL4 is key in coordinating intestinal intracellular pathways and the crosstalk between the GI and organs. Based on our preliminary data, ANGPTL4 status may alter intestinal lipid transport and metabolism, lipoprotein assembly/processing and intra-enterocyte signaling while modifying OxS and inflammation. We suggest that ANGPTL4 is subjected to nutritional and microbiota regulation. To tackle the issues of this scientific program, cellular and animal models will be employed. Noteworthy, to quickly move the short- and long- term program forward, most of the methods have already been set up in our laboratory, which evidences the feasibility of our proposed studies. We are quite confident in establishing the role of ANGPTL4 in the gut and elucidating the molecular mechanisms behind its actions on lipid metabolism and OxS, inflammation and crosstalk with the liver and adipose tissue. We are totally convinced that our lipidomics and nutigenomics plateforms and the high level of our scientific program will efficiently serve for the excellent training of HQP.