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）： 非酒精性脂肪肝病（NAFLD）是一种肝脏脂质代谢紊乱，胆固醇和脂肪在肝细胞内积聚。很大一部分 NAFLD 患者会出现肝脏炎症、坏死和进行性肝纤维化。 NAFLD 现在被认为是美国和退伍军人群体中肝硬化的主要原因；并且，很快将成为肝移植最常见的适应症。除了进展为终末期肝病外，它还经常与糖尿病（胰岛素抵抗）和心血管疾病相关。这些临床表型的聚集现在被称为代谢综合征。 目前治疗 NAFLD 的治疗方法，包括降低胆固醇和甘油三酯的药物、胰岛素增敏剂、抗氧化剂和改变生活方式，尚未发现能有效逆转 NAFLD。目前尚无良好的治疗方法。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疗法至关重要。 肝脏对于全身脂质稳态至关重要。我们的实验室已经确定将胆固醇输送到细胞线粒体进行氧化是调节肝脏脂质代谢的关键步骤。我们发现，肝细胞中线粒体胆固醇递送蛋白 StARD1 的表达增加，会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 StARD1 表达，通过线粒体酶 CYP27A1 启动的途径增加胆固醇氧化；并且，所得的氧甾醇产物是能够介导脂质代谢变化的调节分子。此外，胆汁酸是 CYP27A1 启动胆固醇代谢途径的最终产物，其本身就是重要的调节分子。能够通过激活肠道和肝脏核受体 FXR 介导胆固醇和脂肪的肠道吸收和代谢。 本申请的目的是阐明 StARD1/CYP27A1 胆固醇氧化途径在调节肝脂质和葡萄糖稳态中的作用。这些研究的完成：1) 将确定在 2 个 NAFL 动物模型中，在密切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甾醇和 FXR 激活胆汁酸是否能够逆转脂肪肝； 2) 将用于将胆汁酸对 FXR 介导途径的激活与调节性氧甾醇增加的影响分开； 3) 寻找通过增加 StARD1/CYP27A1 通路表达而产生的未被发现的调节性氧甾醇，这些调节性氧甾醇有助于在西方饮食中显着降低肝脏脂质； 4)寻找控制细胞内调节剂氧甾醇水平的新调节位点； 5) 确定在存在和不存在高脂肪/胆固醇肠道内容物的情况下，天然存在的 FXR 激动剂（即胆汁酸）与合成 FXR 激动剂如何在 Cyp27a1 敲除小鼠模型中差异性地改变肝脏胆固醇、脂肪和葡萄糖代谢;缺乏 CYP27A1 的天然脂肪肝遗传模型会产生氧甾醇。 根据我们的初步研究结果，我们相信，联合使用增加 FXR 的选择性激活和调节性氧甾醇激活途径可以逆转 NAFL，并且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。正如提案中所述，这些研究有可能为 NAFLD 的治疗提供直接的临床前景，不仅适用于我们的退伍军人群体，而且适用于整个美国人口。