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

肠血管生成素样蛋白4：脂质转运和代谢、脂蛋白组装和分泌以及分子作用机制中的新调节作用

• 批准号: RGPIN-2016-04761
• 负责人: Levy, Emile
• 金额: $ 2.77万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709457
• 关键词: Intestinal; angiopoietin; like; protein; New

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.

肠道是消化和运输营养物质的器官，保证所有组织的生长和存活。最近的突破揭示了胃肠道（GI）的关键作用，如生产过剩的GI肽。在消化道内，上皮细胞与大量微生物共存，称为微生物群。微生物和宿主细胞都表现出相互适应的变化，这些变化是许多家务和重要功能所必需的，并在生物体的一生中维持适当水平的微量和大量营养物质。总的来说，所有的系统确保最佳的营养运输，同时保持肠道屏障的完整性和防御氧化应激（OxS）和炎症负担。更重要的是，肠道细胞和共生微生物群之间的双向相互作用也是与外周器官和整体稳态的串扰的核心。