Functions of the Human OST-alpha and OST-beta proteins

描述（由申请人提供）：本申请的目的是促进对两类主要胆固醇代谢物的处置机制的理解，即胆汁酸和类固醇偶联物，这两种化合物在许多生物过程和人类疾病中起重要作用。这个提议的背景是我们证明有机溶质转运体Ost?-Ost？在调解这些化合物的处置中起着核心作用。Ost Ost ?是一种罕见的异质转运蛋白，几乎在所有组织中表达，但在小肠、肾脏、肝脏、睾丸、肾上腺以及其他类固醇组织中表达最多。迄今为止，我们对转运蛋白的底物特异性、转运机制、组织分布、亚细胞定位、转录调控以及我们最近表征的Ost？-缺陷小鼠表明Ost?-Ost？是胆汁酸及其结构相关分子的主要基底外侧膜出口者。特别是对Ost？-缺乏的小鼠发现，这些动物的胆汁酸池大小明显减少，肠道胆汁酸吸收缺陷，肠道肥大，生长迟缓，血清胆固醇和甘油三酯水平下降。由于胆汁酸的肠肝循环对膳食脂肪和维生素的肠道吸收、胆固醇稳态、胆汁流动和胆脂分泌等过程至关重要，这些数据表明Ost?-Ost？也间接调节脂质稳态。这项提议的目标是验证两个假设：第一，Ost？既是伴侣又是功能性Ost的结构组成部分-Ost？转运体;第二，那是东岸？-东岸？胆汁酸和相关类固醇介导的转运调节脂质稳态。具体目的是：(1)鉴定Ost？对异源二聚化、贩运和/或功能活动至关重要的；(2)检查Ost？-/-小鼠对年龄相关、饮食或基因引起的肥胖有抵抗力。总的来说，这些研究将提供Ost?-Ost？在转运蛋白对脂质稳态的潜在贡献上，介导胆汁酸和类固醇处置，并将提供结构-功能信息，有助于开发针对该转运蛋白的治疗方法。

DESCRIPTION (provided by applicant): The objectives of this application are to advance understanding of mechanisms of disposition of the two major classes of cholesterol metabolites, namely bile acids and steroid conjugates, compounds that play important roles in a number of biological processes and human diseases. The background to this proposal is our demonstration that the organic solute transporter, Ost?-Ost?, plays a central role in mediating the disposition of these compounds. Ost?-Ost? is an unusual heteromeric transporter that is expressed in nearly all tissues, but is most abundant in the small intestine, kidney, liver, testis, adrenal gland, as well as other steroidogenic tissues. Our studies to date of the transporter's substrate specificity, transport mechanism, tissue distribution, subcellular localization, transcriptional regulation, as well as the phenotype of our recently characterized Ost?- deficient mice suggest that Ost?-Ost? is the major basolateral membrane exporter of bile acids and structurally related molecules. In particular, studies with Ost?-deficient mice revealed that these animals have a markedly diminished bile acid pool size, a defect in intestinal bile acid absorption, intestinal hypertrophy, growth retardation, and a decrease in serum cholesterol and triglyceride levels. Because the enterohepatic circulation of bile acids is essential for processes such as intestinal absorption of dietary fats and vitamins, cholesterol homeostasis, bile flow, and biliary lipid secretion, these data suggest that Ost?-Ost? also indirectly regulates lipid homeostasis. The goals of this proposal are to test two hypotheses: first, that Ost? is both a chaperone and a structural component of the functional Ost?-Ost? transporter; and second, that the Ost?-Ost?-mediated transport of bile acids and related steroids modulates lipid homeostasis. The specific aims are: (1) Identify specific amino acid residues of Ost? that are critical for heterodimerization, trafficking, and/or functional activity; and (2) Examine whether Ost?-/- mice are resistant to age related, dietary, or genetically induced obesity. Overall, these studies will provide important information on the mechanism by which Ost?-Ost? mediates bile acid and steroid disposition, on the potential contribution of the transporter to lipid homeostasis, and will provide structure-function information that should facilitate the development of therapeutics targeting this transporter. PUBLIC HEALTH RELEVANCE: Our recent studies have provided strong evidence that the organic solute transporter, Ost?-Ost?, plays a central role in mediating the disposition of bile acids and steroid conjugates, compounds that play important roles in a number of biological processes and human diseases, including cholestatic and fatty liver diseases, malabsorption syndrome, and cholelithiasis. The goals of this proposal are to test the hypotheses that Ost? is both a chaperone and a structural component of the functional Ost?-Ost? transporter, and that the Ost?-Ost?- mediated transport of bile acids and related molecules modulates lipid homeostasis. Overall, the proposed studies will provide important information on the mechanism by which Ost?-Ost? mediates bile acid and steroid disposition, on the potential contribution of the transporter to lipid homeostasis, and will provide structure- function information that should facilitate the development of therapeutics targeting this transporter. Such therapeutics could be of benefit in many human conditions related to imbalances in bile acid or lipid homeostasis.