Molecular Physiology of Hepatic Transport

说明(申请人提供)：胆盐分泌是胆汁形成的主要驱动力。胆盐是一种两亲性分子，能在肠道吸收之前溶解脂肪和疏水性营养物质，促进肝胆分泌，防止胆固醇结石形成，并在转录水平上调节许多参与脂质代谢的肝脏和肠道基因。肝细胞胆盐转运的限速步骤是ATP依赖的小管分泌，而Abcb11(BSEP)是该转运蛋白的编码基因。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。首席研究人员最近开发了转基因反义甲状腺激素启动子Abcb11(TTR-Abcb11)小鼠，该小鼠在肝小管膜上功能性地过表达Abcb11。这只小鼠可以在体内对Abcb11的生理作用进行新的研究。因此，该提案的具体目标是：特定的目标1：确定Abcb11调节肝脏和肠肝循环中基因表达的机制(S)，从而对肝胆和全身脂质代谢产生影响。具体目的2：通过给TTRAbcb11小鼠饲喂具有良好特色的小鼠饲料作为这些疾病的营养模型，明确Abcb11诱发脂肪肝和胆石症的机制(S)。具体目标3：利用“经典”的高胆固醇血症小鼠模型，确定肝脏Abcb11调节系统脂代谢、高脂血症和动脉粥样硬化的机制。这项建议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、胆石症和全身性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Abcbl-1在肝脏胆盐转运以及肝胆和全身脂质代谢中的作用的了解。这些数据对于开发合理的治疗常见的全身性脂代谢紊乱以及胆囊病和肝病的方法至关重要。

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.