Role of Cholesterol in Non Alcoholic Fatty Liver

胆固醇在非酒精性脂肪肝中的作用

• 批准号: 8628400
• 负责人: WILLIAM M PANDAK
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628400
• 关键词: Agonist; American; Animal Model; Antioxidants; Atherosclerosis; Attenuated; Basic Science; Behavior Therapy; Bile Acids; CYP7A1 gene; Cardiovascular Diseases; Cells; Cholesterol; Cholesterol Homeostasis; Cirrhosis; Clinical; Cyclophosphamide; Data; Development; Diabetes Mellitus; Diet; Dyslipidemias; Enzymes; Extrahepatic; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Genetic; Genetic Models; Glucose; Glucose Intolerance; H218 Protein; Hepatic; Hepatocyte; Hereditary Disease; Homeostasis; Impairment; Incidence; Inflammation; Insulin; Insulin Resistance; Intestinal Absorption; Intestinal Content; Intestines; Intracellular Accumulation of Lipids; Knockout Mice; Laboratories; Lead; Life; Life Style; Lipids; Liver; Liver Fibrosis; Liver diseases; Mediating; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Necrosis; Neurologic; Nuclear Receptors; Pathogenesis; Pathway interactions; Patient Care; Patients; Population; Prevention; Property; Proteins; Regulation; Research; Risk Factors; Role; Simulate; Site; Staging; Structure; Testing; Therapeutic; Tissues; Transplantation; Triglycerides; Variant; Veterans; atherogenesis; base; blood glucose regulation; cholesterol biosynthesis; clinical phenotype; design; effective therapy; expectation; glucose metabolism; hepatic necrosis; lipid metabolism; liver inflammation; liver injury; liver transplantation; mouse model; non-alcoholic fatty liver; novel; novel strategies; oxidation; prevent; public health relevance; receptor; response

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.

非酒精性脂肪肝疾病（NAFLD）是肝脂质代谢的一种疾病 脂肪积聚在肝细胞中。 NAFLD患者的很大一部分发展为肝脏炎症， 坏死和进行性肝纤维化。现在，NAFLD被认为是美国肝硬化的主要原因 在退伍军人的人口中；而且，准备很快代表肝脏的最常见迹象 移植。除了其发展为末期肝病外，它经常与 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 称为代谢综合征。 当前用于治疗NAFLD的治疗方法包括胆固醇和甘油三酸酯 尚未发现降低剂，胰岛素敏化剂，抗氧化剂和生活方式的修饰 有效逆转NAFLD。目前没有良好的治疗方法。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至关重要 有效的疗法。 肝脏对总体脂质稳态是核心。我们的实验室已经确定将胆固醇的递送到 细胞的线粒体用于氧化，这是调节肝脂质代谢的关键步骤。我们找到了 在肝细胞（肝细胞）中，线粒体胆固醇递送蛋白Stard1的表达增加 下调胆固醇生物合成的途径，同时上调胆固醇降解的途径 和分泌。肝脏Stard1表达的增加可通过通过 线粒体酶，CYP27A1;并且，所得的氧蛋白酶产物是能够的调节分子 介导脂质代谢的变化。此外，胆汁酸是启动CYP27A1的最终产物 胆固醇代谢的途径本身就是重要的调节分子。能够调解 胆固醇和脂肪肠吸收和代谢，通过激活肠道和肝核 受体，fxr。 该应用的目的是阐明胆固醇的stard1/cyp27a1途径的作用 调节肝脂质和葡萄糖稳态的氧化。这些研究的完成：1）将 确定将细胞内胆固醇降解增加到调节氧甲醇和FXR激活胆汁中是否增加 在紧密模拟A 典型的美国生活方式； 2）将使用胆汁酸拉开FXR介导的途径的激活 从增加的调节氧甲醇的作用中； 3）寻找未发现的调节氧甲醇 通过增加stard1/cyp27a1途径的表达而产生的，该途径有助于深度肝脂质 降低面对西方饮食的指出； 4）搜索控制细胞内的新型调节地点 调节氧蛋白酶水平； 5）在存在和不存在高脂肪/胆固醇的情况下确定 内容含有自然发生的FXR激动剂（即胆汁酸）与合成FXR激动剂可能会有所不同 CYP27A1敲除小鼠模型中的肝胆固醇，脂肪和葡萄糖代谢；天然发生的 缺乏CYP27A1的脂肪肝遗传模型产生了氧甲醇。 根据我们的初步发现，我们认为在协作中使用的是增加的选择性激活 FXR和调节性氧固醇活化途径可用于逆转NAFL，并且可能是动脉粥样硬化。 该建议提出了基础科学发现，导致了新的治疗方法。如概述 这些提议，这些研究有可能立即提供临床前景，以治疗NAFLD 仅在我们的退伍军人人口中，但在整个美国人口中。