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: 8974226
• 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/8974226
• 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; Dyslipidemias; Enzymes; Extrahepatic; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Genetic; Genetic Models; Glucose; Glucose Intolerance; H218 Protein; Health; 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; 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; receptor; response; western diet

DESCRIPTION (provided by applicant): 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-oxidant, 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 regulaton 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 o 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 regulator 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.

描述（由申请人提供）： 非酒精性脂肪性肝病（NAFLD）是一种肝脏脂质代谢紊乱，其中胆固醇和脂肪在肝细胞中积聚。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现在被认为是美国和退伍军人人群中肝硬化的主要原因;并且即将成为肝移植的最常见适应症。除了进展为终末期肝病外，它还经常与糖尿病（胰岛素抵抗）和心血管疾病有关。这些临床表型的聚集现在被称为代谢综合征。 目前用于治疗NAFLD的治疗方法包括胆固醇和甘油三酯降低剂、胰岛素增敏剂、抗氧化剂和生活方式改变，尚未发现在逆转NAFLD中有效。目前还没有好的治疗方法。更好地了解肝细胞胆固醇，脂肪，葡萄糖和胆汁酸代谢的相互作用对于开发更有效的治疗方法至关重要。 肝脏是全身脂质稳态的中心。我们的实验室已经确定胆固醇进入细胞线粒体进行氧化是调节肝脏脂质代谢的关键步骤。我们已经发现，肝细胞（肝细胞）中线粒体胆固醇递送蛋白StARD 1的表达增加，下调胆固醇生物合成途径，同时上调胆固醇降解和分泌途径。增加肝脏StARD 1表达通过线粒体酶CYP 27 A1启动的途径增加胆固醇氧化;并且，所得氧固醇产物是能够介导脂质代谢变化的调节分子。此外，胆汁酸（CYP 27 A1启动的胆固醇代谢途径的终产物）本身是重要的调节分子;能够通过激活肠和肝核受体FXR介导胆固醇和脂肪肠吸收和代谢。 本申请的目的是阐明胆固醇氧化的StARD 1/CYP 27 A1途径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）将确定在接近模拟典型美国生活方式的条件下，增加细胞内胆固醇降解为调节性氧固醇和FXR活化胆汁酸是否能够逆转2种NAFL动物模型中的脂肪肝; 2）将用于将胆汁酸对FXR介导的途径的活化与增加的调节性氧固醇的作用分开; 3）寻找通过增加StARD 1/CYP 27 A1途径的表达而产生的未发现的调节性氧固醇，其有助于在面对西方饮食时注意到的显著的肝脂质降低;和5）确定在存在和不存在高脂肪/胆固醇肠内容物的情况下，天然存在的FXR激动剂如何（即胆汁酸）与合成FXR激动剂相比，可在Cyp 27 a1敲除小鼠模型中差异性地改变肝胆固醇、脂肪和葡萄糖代谢;缺乏CYP 27 A1产生氧化固醇的脂肪肝的自然发生的遗传模型。 基于我们的初步研究结果，我们认为，协同使用增加FXR和调节性氧固醇激活途径的选择性激活可用于逆转NAFL，并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。正如提案中所概述的，这些研究有可能为NAFLD的治疗提供直接的临床承诺，不仅在我们的退伍军人群体中，而且在整个美国人口中。