Role of Cholesterol in Non Alcoholic Fatty Liver

非酒精性脂肪性肝病（NAFLD）是一种肝脏脂质代谢紊乱，其中胆固醇和脂肪酸均升高。 脂肪在肝细胞中积累。很大一部分NAFLD患者进展为肝脏炎症， 坏死和进行性肝纤维化。NAFLD现在被认为是美国肝硬化的主要原因。 在退伍军人人群中;并且，即将成为肝脏最常见的适应症 移植除了进展为终末期肝病外，它还经常与以下因素相关： 糖尿病（胰岛素抵抗）和心血管疾病。这些临床表型的聚类现在是 称为代谢综合症 目前治疗NAFLD（包括胆固醇和甘油三酯）的治疗方法 降血糖剂、胰岛素增敏剂、抗氧化剂和生活方式改变剂尚未发现 有效逆转NAFLD。目前还没有好的治疗方法。更好地理解 肝细胞胆固醇，脂肪，葡萄糖和胆汁酸代谢的相互作用是至关重要的，以发展更多 有效的治疗。 肝脏是全身脂质稳态的中心。我们的实验室已经确定了胆固醇的输送到 细胞的线粒体氧化作为肝脏脂质代谢调节的关键步骤。我们发现 增加肝细胞中线粒体胆固醇传递蛋白StARD 1的表达， 下调胆固醇生物合成途径，同时上调胆固醇降解途径 和分泌物。增加肝脏StARD 1表达通过以下途径增加胆固醇氧化： 线粒体酶CYP 27 A1;并且，所得的氧固醇产物是能够 介导脂质代谢的变化。此外，胆汁酸，CYP 27 A1的终产物，启动 胆固醇代谢途径，是重要的调节分子本身的权利;能够介导 胆固醇和脂肪的肠道吸收和代谢通过激活肠和肝核 受体，FXR。 本申请的目的是阐明胆固醇的StARD 1/CYP 27 A1途径的作用 氧化在调节肝脏脂质和葡萄糖稳态中的作用。这些研究的完成：1）将 确定是否增加细胞内胆固醇降解为调节性氧化固醇和FXR激活胆汁 酸能够在2种NAFL动物模型中逆转脂肪肝， 典型的美国生活方式; 2）将用于分离胆汁酸介导的FXR通路的激活 从增加的调节性氧固醇的影响; 3）寻找未发现的调节性氧固醇 通过增加StARD 1/CYP 27 A1途径的表达产生，该途径有助于肝脏脂质的深层代谢， 降低注意到在面对西方饮食; 4）寻找新的网站的调节，控制细胞内 调节氧固醇水平;和，5）确定在存在和不存在高脂肪/胆固醇肠 内容天然存在的FXR激动剂（即胆汁酸）与合成FXR激动剂如何差异性地改变 Cyp 27 a1基因敲除小鼠模型中肝脏胆固醇、脂肪和葡萄糖代谢;一种天然存在的 缺乏CYP 27 A1的脂肪肝遗传模型产生氧化固醇。 根据我们的初步发现，我们认为，在音乐会上使用增加选择性激活的 FXR和调节性氧化固醇激活途径可用于逆转NAFL，并且可能逆转动脉粥样硬化形成。 这项提案带来了基础科学发现，导致新的治疗方法。中概述的 这些研究有可能为NAFLD的治疗提供直接的临床承诺， 只有在我们的退伍军人群体中，但在整个美国人口中。

Non-alcoholic fatty liver disease (NAFLD) is a disorder of liver lipid metabolism in which both cholesterol and fat accumulate in liver cells. A significant fraction of patients with NAFLD progress to liver inflammation, necrosis, and progressive liver fibrosis. NAFLD is now recognized as a leading cause of cirrhosis in the U.S. and in the Veteran's population; and, is poised to soon represent the most common indication for liver transplantation. In addition to its progression to end-stage liver disease, it is frequently associated with diabetes (insulin resistance) and cardiovascular disease. The clustering of these clinical phenotypes is now known as Metabolic Syndrome. Current therapeutic approaches for the treatment of NAFLD inclusive of cholesterol and triglyceride lowering agents, insulin sensitizing agents, anti-oxidants, and life-style modifications have not been found effective in reversing NAFLD. No good treatment approach currently exists. A better understanding of the interplay of liver cell cholesterol, fat, glucose, and bile acid metabolism is crucial in order to develop more effective therapies. The liver is central to total body lipid homeostasis. Our laboratory has identified delivery of cholesterol into the cell's mitochondria for oxidation as a crucial step in the regulation of liver lipid metabolism. We have found that increased expression of the mitochondrial cholesterol delivery protein, StARD1, in hepatocytes (liver cells), down-regulates pathways of cholesterol biosynthesis while up-regulating pathways of cholesterol degradation and secretion. Increasing liver StARD1 expression increases cholesterol oxidation via pathways initiated by mitochondrial enzyme, CYP27A1; and, the resulting oxysterol products are regulatory molecules capable of mediating changes in lipid metabolism. Furthermore, bile acids, the end product of the CYP27A1 initiated pathway of cholesterol metabolism, are important regulatory molecules in their own right; capable of mediating cholesterol and fat intestinal absorption and metabolism through activation of an intestinal and liver nuclear receptor, FXR. The objective of this application is to elucidate the role of the StARD1/CYP27A1 pathway of cholesterol oxidation in the regulation of hepatic lipid and glucose homeostasis. The completion of these studies: 1) will determine if increasing intracellular cholesterol degradation into regulatory oxysterols and FXR activating bile acids is capable of reversing fatty liver in 2 NAFL animal models under conditions which closely simulate a typical American lifestyle; 2) will be used to pull apart the activation of FXR mediated pathways by bile acids from the effects of increased regulatory oxysterols; 3) to search for undiscovered regulatory oxysterols generated by increasing expression of the StARD1/CYP27A1 pathway that contribute to the profound liver lipid lowering noted in the face of a Western diet; 4) to search for novel sites of regulation which control intracellular regulatory oxysterol levels; and, 5) to determine in the presence and absence of high fat/cholesterol intestinal content how naturally occurring FXR agonists (i.e bile acids) vs. synthetic FXR agonists may differentially alter hepatic cholesterol, fat, and glucose metabolism in a Cyp27a1 knockout mouse model; a naturally occurring genetic model of fatty liver lacking CYP27A1 generated oxysterols. Based on our preliminary findings, we believe that used in concert increased selective activation of the FXR and regulatory oxysterol activated pathways can be utilized to reverse NAFL, and, likely, atherogenesis. This proposal brings forth basic science discoveries that lead to novel treatment approaches. As outlined in the proposal, these studies have the potential to offer immediate clinical promise for treatment of NAFLD not only in our Veterans population, but in the U.S. population as a whole.