Function of ileal lipid binding proteins

回肠脂质结合蛋白的功能

• 批准号: RGPIN-2015-04390
• 负责人: Agellon, Luis
• 金额: $ 2.19万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=643536
• 关键词: Function; ileal; lipid; binding; proteins

Fatty acid binding proteins (FABPs) are abundant, small molecular weight soluble proteins found in various tissues. To date, the FABP family has 9 members that bind small hydrophobic compounds. Each FABP has a distinct ligand specificity and is associated with certain tissues. FABPs have similar three dimensional structures despite significant dissimilarity in primary structures which likely contributes to their characteristic ligand preferences. Loss-of-function mutations gave important insights into FABP function in a variety of metabolic processes, but the precise molecular functions of FABPs are still not well understood. These proteins may act as cellular storage depots, intracellular transporters for their respective ligands, and serve as intracellular shuttles between the membrane-bound transporter that internalize their ligands and the cognate nuclear receptors bound to gene promoters.******Fabp6 was first identified in the distal portion of the small intestine. This FABP type binds both bile acids and fatty acids, but shows a preference for bile acids. Bile acids are synthesized by the liver from cholesterol, and are needed for absorption of lipids and lipid-soluble nutrients. These compounds have emerged as important regulators of gene expression by serving as modulating ligands for the nuclear receptor farnesoid x receptor and the G-protein coupled receptor TGR5.  Recently, we showed that Fabp6 is needed for transport of conjugated bile acid in ileal enterocytes. Mice lacking Fabp6 show enhanced bile acid excretion, exposing the large intestine to higher than normal concentrations of bile acids. Given the bacteriostatic/bactericidal activity of bile acids, it is likely that exposure of gut bacteria in the large intestine to excess bile acids remodels the gut microbiome. As well, the differing binding affinities of various bile acids species to FABP6 may have a large influence on the type of bile acids released into the large intestine. Fabp6 mRNA has been detected in other tissues (such as ovaries), raising the possibility that this protein may have biological functions beyond its documented roles in the metabolism of bile acids in the small intestine.******The proposed research program has 3 themes: ***In Theme I, we will investigate the ligand preferences of different Fabp6 species, and the impact of Fabp6 in modulating the regulatory potential of different bile acid species. In Theme II, we will analyze the biological importance of Fabp6 in non-intestinal cells. In Theme III, we will study the consequences of the loss of ileal Fabp6 function on the gut microbiota and nutrition, and the capacity of the microbiota to metabolize bile acids.  ******This program will yield new insights on Fabp6 biology, the importance of Fabp6 in metabolism, as well as advance our general understanding of FABP function.*** **

脂肪酸结合蛋白（Fatty Acid Binding Proteins，FABPs）是一种存在于多种组织中的小分子量可溶性蛋白质。迄今为止，FABP家族有9个成员结合小的疏水化合物。每个FABP具有不同的配体特异性，并与某些组织相关。FABPs具有相似的三维结构，尽管一级结构显著不同，这可能有助于其特征性配体偏好。功能丧失突变对FABP在各种代谢过程中的功能提供了重要的见解，但FABP的精确分子功能仍然没有得到很好的理解。这些蛋白质可以作为细胞储存库，其各自配体的细胞内转运蛋白，并作为内化其配体的膜结合转运蛋白和与基因启动子结合的同源核受体之间的细胞内穿梭。Fabp 6首先在小肠的远端部分被鉴定。这种FABP类型结合胆汁酸和脂肪酸，但显示出对胆汁酸的偏好。胆汁酸由肝脏从胆固醇合成，并且是吸收脂质和脂溶性营养素所必需的。这些化合物通过作为核受体法尼醇X受体和G蛋白偶联受体TGR 5的调节配体而成为基因表达的重要调节剂。最近，我们发现Fabp 6是回肠肠细胞转运结合胆汁酸所必需的。缺乏Fabp 6的小鼠显示出增强的胆汁酸排泄，使大肠暴露于高于正常浓度的胆汁酸。鉴于胆汁酸的抑菌/杀菌活性，大肠中的肠道细菌暴露于过量胆汁酸可能会重塑肠道微生物组。同样，各种胆汁酸物质与FABP 6的不同结合亲和力可能对释放到大肠中的胆汁酸的类型具有很大影响。Fabp 6 mRNA已在其他组织（如卵巢）中检测到，这增加了这种蛋白质可能具有超出其在小肠中胆汁酸代谢中的记录作用的生物学功能的可能性。拟议的研究计划有3个主题：* 在主题I中，我们将研究不同Fabp 6物种的配体偏好，以及Fabp 6在调节不同胆汁酸物种的调节潜力中的影响。在主题II中，我们将分析Fabp 6在非肠道细胞中的生物学重要性。在主题III中，我们将研究回肠Fabp 6功能丧失对肠道微生物群和营养的影响，以及微生物群代谢胆汁酸的能力。** 该计划将产生关于Fabp 6生物学的新见解，Fabp 6在代谢中的重要性，以及推进我们对FABP功能的一般理解。 **