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）： 非酒精性脂肪肝疾病（NAFLD）是一种肝脂质代谢疾病，其中胆固醇和脂肪在肝细胞中均积累。 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被认为是美国和退伍军人人口的主要原因。并且，有望很快代表肝移植的最常见指征。除了发展为末期肝病外，它还经常与糖尿病（胰岛素抵抗）和心血管疾病有关。这些临床表型的聚类现在称为代谢综合征。 目前尚未发现当前的NAFLD治疗NAFLD，包括胆固醇和甘油三酸酯降低剂，胰岛素敏化剂，抗氧化剂和生活方式的修饰有效，可有效逆转NAFLD。目前没有良好的治疗方法。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。 肝脏对总体脂质稳态是核心。我们的实验室已将胆固醇递送到细胞的线粒体中以氧化是肝脂质代谢调节的关键步骤。我们发现，线粒体胆固醇递送蛋白Stard1在肝细胞（肝细胞）中的表达增加，下调了胆固醇生物合成的途径，同时上调胆固醇降解和分泌的途径。肝脏Stard1表达的增加会通过线粒体酶（CYP27A1）引发的途径增加胆固醇的氧化。并且，由此产生的氧蛋白酶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的最终产物引发的胆固醇代谢途径，它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介导胆固醇和脂肪肠吸收和代谢。 该应用的目的是阐明胆固醇氧化在肝脂质和葡萄糖稳态调节中的Stard1/CYP27A1途径的作用。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性氧甲醇中和FXR激活胆汁酸是否能够在2个NAFL动物模型中逆转脂肪肝，这些条件紧密模拟了典型的美国生活方式； 2）将使用胆汁酸从增加的调节氧甲醇的作用中拉开激活OFXR介导的途径； 3）寻找通过增加Stard1/cyp27a1途径的表达而产生的未发现的调节性氧甲醇，这些途径有助于面对西方饮食时提到的深刻的肝脂质降低； 4）搜索控制细胞内调节剂氧化酚水平的新型调节部位； 5）在存在和不存在高脂肪/胆固醇肠含量的情况下，在CYP27A敲除小鼠模型中，自然发生的FXR激动剂（即胆汁酸）与合成FXR激动剂的自然发生如何自然发生的FXR激动剂（即胆汁酸）与合成FXR激动剂的方式如何不同。缺乏CYP27A1的脂肪肝的天然遗传模型会产生氧甲醇。 根据我们的初步发现，我们认为在协调中使用的是增加了FXR的选择性激活和调节性氧甲醇激活的途径可以用来逆转NAFL，并且可能是动脉粥样硬化的。该建议提出了基础科学发现，导致了新的治疗方法。如该提案中概述的那样，这些研究有可能提供直接的临床承诺来治疗NAFLD，不仅在我们的退伍军人人口中，而且在整个美国人口中。