CHOLESTEROL HOMEOSTASIS IN THE INBRED MOUSE

肠道是一个独特的器官，为身体提供饮食和重新吸收的胆汁胆固醇。过量的胆固醇会导致胆固醇结石。胆石症在食用高胆固醇西方饮食的文化中很常见，高胆固醇和胆酸饮食可以在小鼠模型中诱发胆石症。因此，了解胆固醇的吸收对于预防和治疗胆固醇结石具有重要意义。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着关键作用。研究发现，C57L株和AKR株之间的胆结石易感性差异是由至少两个Lith(胆结石)基因决定的，而且胆汁盐转运蛋白P-糖蛋白(SPGP)的姊妹基因是Lith1的候选基因。最近的一项观察表明，喂食致石饮食8周的11个品系近交系小鼠的胆固醇吸收率与胆固醇结石的患病率之间存在显着的正相关，这有力地表明，从肠道吸收胆固醇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，男性与女性之比为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结石形成的病理生理机制。目的：研究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。目的2：明确高胆固醇吸收小鼠和低胆固醇吸收小鼠在胆固醇吸收和乳糜粒形成的分子机制上的差异。目的：研究餐后乳糜粒代谢及其在胆汁结石形成中的作用。目的：利用胆结石易感和SR-B1基因敲除小鼠，探讨SR-B1受体在胆汁胆固醇分泌和胆固醇结石形成中的作用。目的5：确定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机制的基本了解提供重要的贡献。

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.