CHOLESTEROL HOMEOSTASIS IN THE INBRED MOUSE

肠道是一个独特的器官，为身体提供饮食和再吸收的胆汁胆固醇。 过量的胆固醇会导致胆固醇结石病。 胆石症在食用含高胆固醇的西方饮食的文化中普遍存在，并且可以通过高胆固醇和胆酸饮食在小鼠模型中诱导。 因此，了解胆固醇的吸收对胆固醇结石的预防和治疗具有重要意义。 众所周知，遗传因素显然在近交系小鼠胆固醇结石的发生中起关键作用。 已经发现C57 L和AKR菌株之间胆结石易感性的差异由至少两个Lith（胆结石）基因决定，以及P-糖蛋白的姐妹（Spgp），小管胆盐转运蛋白是Lith 1的候选基因。 最近的一项观察表明，在喂养致石饮食8周时，11种近交系小鼠的胆固醇吸收百分比与胆固醇结石患病率之间存在显着的正相关性，这强烈表明肠道胆固醇吸收的程度可能是胆固醇结石形成的遗传决定步骤。 此外，还观察到胆固醇结石的易感性存在性别差异，男性对女性的比例为2：1。 申请人提出了五个具体目标，以探索胆固醇稳态的遗传和生理机制以及胆固醇吸收的分子机制，以及致石性胆汁和胆固醇胆石症形成的病理生理机制。 目标1：探讨12个品系近交系小鼠胆固醇吸收效率的遗传变异及其在胆固醇结石形成中的作用。 目标二：明确高胆固醇吸收和低胆固醇吸收小鼠之间胆固醇吸收和乳糜微粒形成的分子机制差异。 目的3：研究餐后乳糜微粒代谢及其在胆汁成石中的作用。目标4：本研究利用遗传性胆固醇结石易感小鼠和SR-B1基因敲除小鼠，探讨SR-B1受体在胆固醇分泌和胆固醇结石形成中的作用。 目的5：描述胆结石表型性别差异的激素基础。 这些研究将为我们对胆固醇稳态以及胆固醇结石形成的发病机制的基本理解做出重要贡献。

The intestine is an unique organ providing dietary and re-absorbed biliary cholesterol to the body. Excess cholesterol can result in cholesterol gallstone disease. Cholelithiasis is prevalent in cultures consuming a Western diet with high cholesterol, and can be induced in mouse models by a high cholesterol and cholic acid diet. Therefore, understanding cholesterol absorption is of great importance to both prevention and treatment of cholesterol gallstones. It has been known that genetic factors apparently play a critical role in the development of cholesterol gallstones in inbred mice. It has been found that differences in gallstone susceptibility between C57L and AKR strains are determined by at least two Lith (gallstone) genes, as well as that the sister of P-glycoprotein (Spgp), a canalicular bile salt transporter is a candidate gene for the Lith1. A recent observation that there is a remarkable positive correlation in eleven strains of inbred mice between percent cholesterol absorption and prevalence of cholesterol gallstones at 8 weeks of feeding the lithogenic diet strongly suggests that the extent of cholesterol absorption from the intestine may be a genetically determined step for cholesterol gallstone formation. Furthermore, it has been observed that there are gender differences in susceptibility to cholesterol gallstones, favoring males to females by 2:1. The applicant proposes five specific aims to explore genetic and physiological mechanisms of cholesterol homeostasis as well as molecular mechanisms of cholesterol absorption, and pathophysiological mechanisms of the formation of lithogenic bile and cholesterol cholelithiasis. Aim 1: To investigate genetic variations in cholesterol absorption efficiency and their role in cholesterol gallstone formation among 12 strains of inbred mice. Aim 2: To define differences in molecular mechanisms for cholesterol absorption and chylomicron formation between mice with high and low cholesterol absorption. Aim 3: To study postprandial chylomicron metabolism and its role in the lithogenesis of bile. Aim 4: Using genetically gallstone-susceptible and the SR-B1 att (knockout) mice, to elucidate the role of SR-B 1 (HDL) receptor in biliary cholesterol secretion and cholesterol gallstone formation. Aim 5: To characterize hormonal basis for gender differences in the gallstone phenotypes. These studies should provide important contributions to our basic understanding of cholesterol homeostasis as well as pathogenesis of cholesterol gallstone formation.