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

人类 OST-α 和 OST-β 蛋白的功能

基本信息

批准号：
8517683
负责人：
PATRICIA M. HINKLE
金额：
$ 32.1万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517683
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

项目摘要

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.

描述（由申请人提供）：本申请的目的是提高对两种主要胆固醇代谢产物的处置机制的理解，即胆汁酸和类固醇偶联物，这些化合物在许多生物学过程和人类疾病中都起着重要作用。该提案的背景是我们的证明是有机溶质转运蛋白Ost？-ost？，在介导这些化合物的处置方面起着核心作用。 ost？-ost？是一种在几乎所有组织中表达的异性杂质转运蛋白，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最丰富。我们的研究迄今为止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的表型 - 不足的小鼠表明OST？是胆汁酸和结构相关的分子的主要基底外侧膜出口剂。特别是，对OST？缺陷小鼠的研究表明，这些动物的胆汁池尺寸明显降低，肠道胆汁酸吸收，肠道肥大，生长迟缓以及血清胆固醇和甘油三酸酯水平的降低。由于胆汁酸的肠肝循环对于诸如饮食脂肪和维生素的肠道吸收，胆固醇稳态，胆汁流量和胆汁脂质分泌的过程至关重要，因此这些数据表明OST？还间接调节脂质稳态。该提议的目标是检验两个假设：首先，那个OST？伴侣和功能性OST的结构成分是否？转运蛋白；其次，OST？-ost？介导的胆汁酸和相关类固醇的转运调节脂质稳态。具体目的是：（1）确定OST的特定氨基酸残基？对于异二聚体，贩运和/或功能活动至关重要；（2）检查OST？ - / - 小鼠是否对与年龄相关，饮食或遗传诱导的肥胖具有抵抗力。总体而言，这些研究将提供有关哪种OST？-ost？的重要信息？介导胆汁酸和类固醇处置，以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剂的发展。