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.

非酒精性脂肪性肝病（NAFLD）是一种肝脏脂质代谢紊乱，其中胆固醇 以及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 现在被认为是美国肝硬化的主要原因。 以及退伍军人人口；并且，很快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 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 称为代谢综合症。 目前治疗 NAFLD 的方法包括胆固醇和甘油三酯 尚未发现降压药、胰岛素增敏剂、抗氧化剂和生活方式改变 有效逆转 NAFLD。目前尚无良好的治疗方法。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对于发展更多功能至关重要 有效的疗法。 肝脏对于全身脂质稳态至关重要。我们的实验室已确定将胆固醇输送到 细胞线粒体的氧化是调节肝脏脂质代谢的关键步骤。我们发现 增加肝细胞（肝细胞）中线粒体胆固醇传递蛋白 StARD1 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。增加肝脏 StARD1 表达可通过以下途径增加胆固醇氧化： 线粒体酶，CYP27A1；并且，所得的氧甾醇产物是能够调节分子 介导脂质代谢的变化。此外，CYP27A1 的最终产物胆汁酸引发 胆固醇代谢途径，本身就是重要的调节分子；有调解能力 通过激活肠和肝核，肠道吸收和代谢胆固醇和脂肪 受体，FXR。 本申请的目的是阐明 StARD1/CYP27A1 胆固醇通路的作用 氧化调节肝脂质和葡萄糖稳态。完成这些研究：1）将 确定是否增加细胞内胆固醇降解为调节性氧甾醇和 FXR 激活胆汁 在两种 NAFL 动物模型中，在非常模拟的条件下，酸能够逆转脂肪肝。 典型的美国生活方式； 2) 将用于分解胆汁酸对 FXR 介导途径的激活 免受调节性氧甾醇增加的影响； 3）寻找未被发现的调节性氧甾醇 通过增加 StARD1/CYP27A1 通路的表达而产生，该通路有助于深层肝脏脂质 面对西方饮食时注意到的降低； 4）寻找控制细胞内的新的调控位点 调节氧甾醇水平； 5) 确定肠道中是否存在高脂肪/胆固醇 天然存在的 FXR 激动剂（即胆汁酸）与合成 FXR 激动剂可能如何差异改变的内容 Cyp27a1 敲除小鼠模型中的肝脏胆固醇、脂肪和葡萄糖代谢；自然发生的 缺乏 CYP27A1 生成氧甾醇的脂肪肝遗传模型。 根据我们的初步发现，我们相信协同使用会增加选择性激活 FXR 和调节性氧甾醇激活途径可用于逆转 NAFL，并可能逆转动脉粥样硬化形成。 该提案带来了基础科学发现，从而带来了新的治疗方法。如中所述 根据该提案，这些研究有可能为 NAFLD 的治疗提供直接的临床前景 不仅在我们的退伍军人人口中，而且在整个美国人口中。