Function of ileal lipid binding proteins

脂肪酸结合蛋白（FABPs）是一种丰富的小分子量可溶性蛋白，存在于各种组织中。迄今为止，FABP家族有9个成员可以结合小的疏水化合物。每个FABP具有独特的配体特异性，并与某些组织相关。fabp具有相似的三维结构，尽管初级结构存在显著差异，这可能有助于其特征配体偏好。功能丧失突变为了解FABP在各种代谢过程中的功能提供了重要的见解，但FABP的精确分子功能仍未得到很好的理解。这些蛋白可以作为细胞的储存库、各自配体的细胞内转运体，并作为细胞内转运体（内化配体的膜结合转运体）和与基因启动子结合的同源核受体之间的穿梭体。******Fabp6首先在小肠远端被发现。这种类型的FABP结合胆汁酸和脂肪酸，但表现出胆汁酸的偏好。胆汁酸由肝脏从胆固醇合成，是脂质和脂溶性营养物质吸收所必需的。这些化合物作为核受体法内甾体x受体和g蛋白偶联受体TGR5的调节配体，已成为基因表达的重要调节剂。最近，我们发现Fabp6是回肠肠细胞转运结合胆汁酸所必需的。缺乏Fabp6的小鼠胆汁酸排泄增强，使大肠暴露于高于正常浓度的胆汁酸中。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的胆汁酸中可能会重塑肠道微生物群。此外，不同种类的胆汁酸对FABP6的不同结合亲和力可能对释放到大肠中的胆汁酸类型有很大影响。Fabp6 mRNA已在其他组织（如卵巢）中被检测到，这提高了这种蛋白质可能具有生物学功能的可能性，而不仅仅是在小肠胆汁酸代谢中所记载的作用。******拟建的研究项目有3个主题：***在主题一中，我们将研究不同种类Fabp6的配体偏好，以及Fabp6在调节不同种类胆汁酸调控潜力中的影响。在主题二中，我们将分析Fabp6在非肠细胞中的生物学重要性。在主题三中，我们将研究回肠Fabp6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。******该项目将对Fabp6生物学、Fabp6在代谢中的重要性产生新的见解，并推进我们对FABP功能的一般理解。* * * * *

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.*** **