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，确保所有组织的生长和存活。最近的突破已经揭示了胃肠道（GI）的关键作用，如产生过多的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，这些变化是许多管家和重要功能所需的，并确保在生物体的一生中维持适当水平的微量营养素和常量营养素。总的来说，所有系统都能确保最佳的营养运输，同时保持肠道屏障的完整性，并抵御氧化应激（OxS）和炎症负担。更重要的是，肠道细胞和肠道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相互作用的核心。 尽管取得了重大进展，但局部和远程影响的关键信号尚未确定。因此，主要的问题仍然没有解决的网站，关键蛋白质参与者的身份和监管参与脂质易位从肠腔到肠上皮细胞和血液循环。文献仍然远未查明肠上皮细胞内的多步乳糜微粒（CM）组装的机制以及与细胞过程的通信，以通过阻止OxS和炎症来保证肠内稳态。 由于ANGPTL 4是一种多功能信号蛋白，并调节细胞分化、脂质和葡萄糖代谢、氧化还原系统、血管生成，因此我们假设ANGPTL 4在协调肠细胞内途径以及GI和器官之间的串扰中发挥关键作用。根据我们的初步数据，ANGPTL 4状态可能会改变肠道脂质转运和代谢，脂蛋白组装/加工和肠细胞内信号传导，同时改变OxS和炎症。我们认为ANGPTL 4受到营养和微生物群的调节。 为了解决这个科学计划的问题，将采用细胞和动物模型。值得注意的是，为了快速推进短期和长期计划，大多数方法已经在我们的实验室建立，这证明了我们提出的研究的可行性。我们非常有信心建立ANGPTL 4在肠道中的作用，并阐明其对脂质代谢和OxS，炎症以及与肝脏和脂肪组织的串扰的作用背后的分子机制。我们完全相信，我们的脂质组学和营养基因组学平台以及我们高水平的科学计划将有效地为HQP的优秀培训服务。