Bile Acid Activated Cell Signaling in the Liver and Nutrition

胆汁酸激活肝脏和营养中的细胞信号传导

基本信息

批准号：
7629638
负责人：
PHILLIP B HYLEMON
金额：
$ 28.64万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-21 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7629638
关键词：
ADP ribosylation AKT Signaling Pathway Apoptosis Bile Acids Bile fluid CYP7A1 gene CYP8B1 gene Cell physiology Ceramides Cholestasis Cholesterol Chronic D Cells Data EGFR gene Endosomes Epithelial Cells Excision Fat-Soluble Vitamin Fistula G Protein-Coupled Receptor Genes G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gallbladder Genes Genus Cola Grant Hepatocyte In Vitro Insulin Insulin Receptor Intestines Intravenous infusion procedures Lipids Lipoproteins Liver MAPK8 gene Messenger RNA Modeling Molecular Necrosis Nuclear Receptors Pathway interactions Pertussis Toxin Phospholipids Process Protein Kinase C Proteins Proto-Oncogene Proteins c-akt Publications Rattus Receptor Cell Reporting Research Personnel Rodent Signal Pathway Signal Transduction Signaling Molecule Small Intestines Solutions Specificity Sphingosine Steroids Stream Vitamin D acidic sphingomyelinase bile salts carcinogenesis ceramide 1-phosphate cholangiocyte cholesterol absorption cholesterol control colon carcinogenesis gastrointestinal system glucose metabolism in vivo inhibitor/antagonist insight lipoprotein cholesterol liver metabolism mouse model nutrition programs promoter receptor sphingosine 1-phosphate

项目摘要

DESCRIPTION (provided by applicant): Bile acids are steroid molecules that are synthesized from cholesterol in the liver hepatocytes. Their synthesis represents a major excretory pathway for removal of cholesterol from the body. Recent studies show that bile acids also function as powerful regulatory molecules helping to coordinately control cholesterol, lipoprotein, and glucose metabolism in the liver. Bile acids are able to regulate the expression of numerous genes and activities of proteins through 2 distinct, yet highly coordinated cellular mechanisms. They can activate specific nuclear receptors (i.e. FXR, PXR, Vitamin D) and cell signaling pathways (i.e. JNK1/2, ERK1/2, AKT, protein kinase C). Each bile acid appears to show some degree of specificity as to which nuclear receptor and cell signaling pathway that it activates, suggesting that the bile acid pool composition may be an important regulator of liver metabolism. The specific aims of the current grant renewal application are: 1) Determine the identity of the G protein coupled receptor(s) (GPCR), which transduces conjugated bile acid signaling in primary hepatocytes via ERBB1 and the insulin receptor, to ERK1/2 and AKT pathways. Determine the molecular mechanism(s) by which the pertussis toxin sensitive GPCR signal causes activation of ERBB1 and the insulin receptor in primary hepatocytes. 2) Determine the mechanism(s) of activation of the JNK1/2 pathway by bile acids in primary rodent hepatocytes and in vivo. Determine how different bile acids activate acidic sphingomyelinase (ASM) in vitro. 3). Characterize the activation of the JNK1/2, ERK1/2 and AKT signaling pathways by different bile acids in the chronic bile fistula rat and mouse models. Determine the effects of different bile acid infusion (IV and ID) on the activation of cell signaling pathways, levels of selected lipid signaling molecules, and mRNA levels of key genes involved in cholesterol and glucose metabolism.

描述（由申请人提供）：胆汁酸是由肝脏肝细胞中的胆固醇合成的类固醇分子。它们的合成代表了从体内清除胆固醇的主要排泄途径。最近的研究表明，胆汁酸还可以作为强大的调节分子，帮助协调控制肝脏中的胆固醇、脂蛋白和葡萄糖代谢。胆汁酸能够通过两种不同但高度协调的细胞机制调节众多基因的表达和蛋白质的活性。它们可以激活特定的核受体（即 FXR、PXR、维生素 D）和细胞信号传导通路（即 JNK1/2、ERK1/2、AKT、蛋白激酶 C）。每种胆汁酸似乎对其激活的核受体和细胞信号传导途径表现出一定程度的特异性，这表明胆汁酸库成分可能是肝脏代谢的重要调节剂。当前拨款续签申请的具体目标是： 1) 确定 G 蛋白偶联受体 (GPCR) 的身份，该受体通过 ERBB1 和胰岛素受体将原代肝细胞中的结合胆汁酸信号传导至 ERK1/2 和AKT 途径。确定百日咳毒素敏感 GPCR 信号引起原代肝细胞中 ERBB1 和胰岛素受体激活的分子机制。 2)确定原代啮齿动物肝细胞和体内胆汁酸激活JNK1/2途径的机制。确定不同胆汁酸如何在体外激活酸性鞘磷脂酶 (ASM)。 3）。表征慢性胆瘘大鼠和小鼠模型中不同胆汁酸对 JNK1/2、ERK1/2 和 AKT 信号通路的激活。确定不同胆汁酸输注（IV 和 ID）对细胞信号通路激活、选定脂质信号分子水平以及参与胆固醇和葡萄糖代谢的关键基因 mRNA 水平的影响。