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

人类 OST-α 和 OST-β 蛋白的功能

• 批准号: 8307406
• 负责人: PATRICIA M. HINKLE
• 金额: $ 33.27万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307406
• 关键词: Adrenal Glands; Amino Acids; Animals; Bile Acids; Bile fluid; Biliary; Biological Process; Cell membrane; Cholelithiasis; Cholesterol; Cholesterol Homeostasis; Data; Defect; Development; Diet; Dietary Fats; Drug or chemical Tissue Distribution; Dyslipidemias; Enterohepatic Circulation; Equilibrium; Fatty Liver; Fatty acid glycerol esters; Gender; Genes; Goals; Growth; Health; Heterodimerization; Homeostasis; Human; Hyperglycemic Mice; Hypertrophy; Intestinal Absorption; Intestines; Kidney; Knock-out; Leptin; Lipids; Liver; Liver diseases; Malabsorption Syndromes; Measures; Mediating; Membrane Transport Proteins; Metabolic Pathway; Modeling; Molecular Chaperones; Mus; Mutation; Na(+)-K(+)-Exchanging ATPase; Obesity; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Process; Progress Reports; Proteins; Resistance; Role; Serum; Small Intestines; Staging; Steroids; Structure; Substrate Specificity; Testing; Testis; Therapeutic; Tissues; Transcriptional Regulation; Triglycerides; Vitamins; age related; basolateral membrane; design; feeding; human disease; inhibitor/antagonist; insight; mouse model; novel; public health relevance; research study; solute; therapeutic target; trafficking

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.

描述（由申请人提供）：本申请的目的是促进对两大类胆固醇代谢物（即胆汁酸和类固醇缀合物）的处置机制的理解，这些化合物在许多生物过程和人类疾病中发挥重要作用。该提案的背景是我们证明有机溶质转运蛋白 Ost?-Ost? 在介导这些化合物的处置中发挥着核心作用。奥斯特？-奥斯特？是一种不寻常的异聚转运蛋白，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生成组织中含量最丰富。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?-缺陷小鼠的表型的研究表明，Ost?-Ost?是胆汁酸和结构相关分子的主要基底外侧膜输出者。特别是，对Ostβ缺陷小鼠的研究表明，这些动物的胆汁酸库大小明显减少，肠道胆汁酸吸收缺陷，肠道肥大，生长迟缓，以及血清胆固醇和甘油三酯水平降低。由于胆汁酸的肠肝循环对于肠道吸收膳食脂肪和维生素、胆固醇稳态、胆汁流动和胆汁脂质分泌等过程至关重要，因此这些数据表明 Ost?-Ost?还间接调节脂质稳态。该提案的目标是检验两个假设：首先，Ost？既是功能性 Ost?-Ost? 的伴侣分子又是结构成分。运输者；其次，Ost？-Ost？介导的胆汁酸和相关类固醇的运输调节脂质稳态。具体目标是：（1）鉴定Ost的特定氨基酸残基？对于异二聚化、贩运和/或功能活动至关重要； (2)检查Ost?-/-小鼠是否对年龄相关、饮食或遗传诱导的肥胖具有抵抗力。总的来说，这些研究将提供有关 Ost?-Ost? 机制的重要信息。介导胆汁酸和类固醇的处置，了解转运蛋白对脂质稳态的潜在贡献，并将提供结构功能信息，以促进针对该转运蛋白的治疗方法的开发。 公共健康相关性：我们最近的研究提供了强有力的证据，表明有机溶质转运蛋白 Ost?-Ost? 在介导胆汁酸和类固醇结合物的处置中发挥着核心作用，这些化合物在许多生物过程和人类疾病中发挥着重要作用，包括胆汁淤积性和脂肪肝疾病、吸收不良综合征和胆石症。该提案的目标是检验 Ost？既是功能性 Ost?-Ost? 的伴侣分子又是结构成分。转运蛋白，并且 Ost？-Ost？-介导胆汁酸和相关分子的转运调节脂质稳态。总体而言，拟议的研究将提供有关 Ost?-Ost? 机制的重要信息。介导胆汁酸和类固醇的处置，了解转运蛋白对脂质稳态的潜在贡献，并将提供结构-功能信息，以促进针对该转运蛋白的治疗方法的开发。这种疗法可能对许多与胆汁酸或脂质稳态失衡有关的人类疾病有益。