Bile Acid Activated Cell Signaling in the Liver and Nutrition

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。它们的合成是清除体内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许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（如FXR、PXR、维生素D）和细胞信号通路（如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通路表现出一定程度的特异性，这表明胆汁酸池的组成可能是肝脏代谢的重要调节剂。当前续期申请的具体目的是：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共轭胆酸信号转导到ERK1/2和AKT通路。确定百日咳毒素敏感GPCR信号引起原代肝细胞ERBB1和胰岛素受体激活的分子机制。2)确定胆汁酸在啮齿动物原代肝细胞和体内激活JNK1/2通路的机制。测定不同胆汁酸如何在体外激活酸性鞘磷脂酶（ASM）。3）. 表征不同胆汁酸对慢性胆瘘大鼠和小鼠JNK1/2、ERK1/2和AKT信号通路的激活作用。测定不同胆汁酸输注（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关键基因mRNA水平的影响。

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.