Molecular Physiology of Hepatic Transport

说明（申请人提供）：胆汁盐分泌是胆汁形成的主要动力。胆盐是两亲性分子，可在肠道吸收之前溶解脂质和疏水营养物质，增强肝胆分泌，防止胆固醇胆结石形成，并转录调节许多参与脂质代谢的肝脏和肠道基因。肝细胞胆汁盐运输的限速步骤是atp依赖的小管分泌，而Abcb11 （BSEP）是编码这种转运体的基因。在人类中，Abcb11的个体间变异性很大。然而，Abcb11在正常生理和病理生理状态下的体内作用仍然知之甚少。首席研究员最近开发了转基因转甲状腺素启动子abcb1 （trr -Abcb11）小鼠，该小鼠在肝小管膜中功能性地过表达Abcb11。这种小鼠可以让人们对abcb1的生理作用进行新的体内研究。因此，该提案的具体目的是：具体目的1：确定Abcb11调节肝脏和肠肝循环中基因表达的机制，以及由此对肝胆和全身脂质代谢的影响。具体目标2：通过喂养trr -Abcb11小鼠作为这些疾病的营养模型的小鼠饮食，确定Abcb11诱导脂肪性肝病和胆石症的机制。具体目的3：通过采用“经典”小鼠高胆固醇血症模型，确定肝脏Abcb11调节全身脂质代谢、高脂血症和动脉粥样硬化的机制。本研究利用最先进的小鼠遗传学、分子生物学和脂质生化技术来研究脂肪肝、胆石症和全身脂质紊乱等疾病的分子机制。这些研究将进一步加深我们对abcb1在肝胆盐转运以及肝胆和全身脂质代谢中的功能的了解。这些数据对于开发针对常见脂质代谢全身性疾病以及胆囊和肝脏疾病的合理疗法至关重要。

DESCRIPTION (provided by applicant): Bile salt secretion is the major driving force for bile formation. Bile salts are amphipathic molecules that solubilize lipids and hydrophobic nutrients prior to gut absorption, enhance hepatobiliary secretion, prevent cholesterol gallstone formation and transcriptionally regulate many hepatic and intestinal genes involved in lipid metabolism. The rate-limiting step for hepatocellular bile salt transport is ATP-dependent canalicular secretion, and Abcb11 (BSEP) is the gene that encodes for this transporter. In humans, the inter-individual variability of Abcb11 is large. However, the in vivo effects of Abcb11 in both normal physiology and pathophysiologic states remain poorly understood. The Principal Investigator has recently developed transgenic transthyretin promoter-Abcbl 1 (TTR-Abcb11) mice that functionally over-express Abcb11 in the liver canalicular membrane. This mouse can allow one to perform novel in vivo investigations into the physiologic role of Abcbl 1. Thus, the Specific Aims of the proposal are: Specific Aim 1: To determine the mechanism(s) by which Abcb11 regulates gene expression in the liver and enterohepatic circulation, with the resultant effects on hepatobiliary and systemic lipid metabolism. Specific Aim 2: To define the mechanism(s) with which Abcb11 induces: fatty liver diseases and cholelithiasis, by feeding TTR-Abcb11 mice well-characterized murine diets that are nutritional models of these diseases. Specific Aim 3: To determine mechanisms by which hepatic Abcb11 regulates systemic lipid metabolism, hyperlipidemia and atherosclerosis by employing "classic" murine models of hypercholesterolemia. This proposal utilizes state-of-the-art mouse genetics, molecular biology and lipid biochemical techniques to examine the molecular mechanisms responsible for diseases including fatty liver, cholelithiasis and systemic lipid disorders. These studies will further our understanding of Abcbl 1 function on hepatic bile salt transport as well as hepatobiliary and systemic lipid metabolism. These data are critical for the development of rational therapies for common systemic disorders of lipid metabolism and diseases of the gallbladder and liver.