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: 8005351
• 负责人: NAZZARENO BALLATORI
• 金额: $ 38.28万
• 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/8005351
• 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; 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，在许多生物过程和人类疾病中起重要作用的化合物）的处置机制的理解。这一建议的背景是我们证明，有机溶质转运蛋白，奥斯特？-奥斯特？，在调节这些化合物的处置中起着核心作用。奥斯特？奥斯特？是一种罕见的异聚体转运蛋白，几乎在所有组织中表达，但在小肠、肾、肝、睾丸、肾上腺以及其他类固醇生成组织中最丰富。我们的研究到目前为止的转运蛋白的底物特异性，运输机制，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？奥斯特？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，研究与奥斯特？缺陷小鼠显示这些动物具有显著减少的胆汁酸池大小、肠胆汁酸吸收缺陷、肠肥大、生长迟缓和血清胆固醇和甘油三酯水平降低。因为胆汁酸的肝肠循环对于诸如膳食脂肪和维生素的肠吸收、胆固醇稳态、胆汁流动和胆汁脂质分泌等过程是必不可少的，这些数据表明Ost？奥斯特？还间接调节脂质体内平衡。这项建议的目标是测试两个假设：第一，奥斯特？是一个伴侣和结构组成部分的功能Ost？奥斯特？第二，这是一个“东？奥斯特？胆汁酸和相关类固醇的介导转运调节脂质体内平衡。具体目的是：（1）鉴定Ost？对异源二聚化、运输和/或功能活性至关重要的蛋白质;和（2）检查Ost？-/-小鼠对年龄相关的、饮食或遗传诱导的肥胖具有抗性。总体而言，这些研究将提供重要的信息的机制，其中奥斯特？-奥斯特？介导胆汁酸和类固醇的处置，对转运蛋白的脂质稳态的潜在贡献，并将提供结构-功能信息，应促进针对该转运蛋白的治疗剂的发展。 公共卫生相关性：我们最近的研究提供了强有力的证据，有机溶质转运蛋白，Ost？-奥斯特？，在介导胆汁酸和类固醇缀合物的处置中起核心作用，所述胆汁酸和类固醇缀合物是在许多生物过程和人类疾病（包括胆汁淤积性和脂肪肝疾病、吸收不良综合征和胆石症）中起重要作用的化合物。这项建议的目标是测试的假设，奥斯特？是一个伴侣和结构组成部分的功能Ost？奥斯特？运输机，那是奥斯特号？奥斯特？胆汁酸和相关分子的介导转运调节脂质体内平衡。总的来说，拟议的研究将提供重要的信息机制，其中奥斯特？-奥斯特？介导胆汁酸和类固醇的处置，对转运蛋白的脂质稳态的潜在贡献，并将提供结构-功能信息，应促进开发针对这种转运蛋白的治疗。这种治疗方法在许多与胆汁酸或脂质稳态失衡相关的人类疾病中可能是有益的。