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Hepatic Steatosis Modulation by Apo B Gene Transcription

Apo B 基因转录调节肝脂肪变性

基本信息

批准号：
8012888
负责人：
JANET DEHOFF SPARKS
金额：
$ 9.99万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-10 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8012888
关键词：
Animal Feed Animals Antibodies Apolipoproteins Apolipoproteins B Applications Grants Arts Betaine Bile Acid Biosynthesis Pathway Binding Biological Assay Biopsy Cells Cholesterol Esters Cirrhosis Clinical Collaborations Consensus Consumption DNA DNA Methylation Development Diet Dissection EMSA Electrophoretic Mobility Shift Assay Energy Intake Energy Metabolism Enhancers Enzymes Epigenetic Process Equilibrium Event Fatty Liver Fatty acid glycerol esters Fructose Functional disorder Funding Gene Expression Genes Genetic Genetic Transcription Goals Hepatic Hepatocyte Homocysteine Homocysteine S-methyltransferase Homocystine Human Hyperphagia Hypertriglyceridemia In Vitro Individual Inflammation Institutes Intervention Journals Laboratories Lead Ligands Ligation Lipids Lipoprotein (a)Lipoproteins Liver Liver diseases Low-Density Lipoproteins Measures Mediating Messenger RNA Metabolic Metabolic syndrome Metabolism Methods Methylation Micronutrients Modeling Modification Mus National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Nonesterified Fatty Acids Nuclear Nuclear Extract Nuclear Orphan Receptor Obesity Organ Oxidative Stress Patients Physiology Pilot Projects Plasma Population Printing Production Proteins Publishing Rattus Regulation Research Research Personnel Risk Rodent Role Run-On Assays Serum Steatohepatitis Supplementation Testing Therapeutic Time Tissues Transactivation Transcriptional Regulation Transfection Triglycerides Very low density lipoprotein Western Blotting Work Zucker Rats base cardiovascular risk factor chromatin immunoprecipitation experience feeding foot gain of function heart disease risk hepatoma cell improved in vivo knock-down lipid biosynthesis meetings member mouse model non-alcoholic fatty liver nonalcoholic steatohepatitis nutrition oxidation problem drinker promoter protein profiling public health relevance response transcription factor very low density lipoprotein triglyceride

项目摘要

DESCRIPTION (provided by applicant): Over 50% of obese individuals with metabolic syndrome have increased hepatic triglycerides (TG) (steatosis) that predisposes them to non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) for which there is no consensus treatment. Human studies indicate that betaine, a naturally occurring micronutrient, alleviates hepatic steatosis, and reduces NASH, however, the mechanism responsible for this effect is not known. We have shown that dietary betaine in rats enhances hepatic apolipoprotein (apo) B synthesis through increased apob gene transcription which favors hepatic TG export in very low density lipoproteins (VLDL) and reduces liver TG content by 45%. This suggests a similar mechanism may be responsible for the reduction of hepatic steatosis observed in humans fed betaine. Aim 1 tests the ability of betaine to reverse hepatic steatosis in two rodent metabolic syndrome models: Zucker (fa/fa) rats and fructose-fed apobec-1-/- mice (B100). Zucker rats model overfeeding and fructose-fed mice model increased consumption of fructose. B100 mice serve as a model of human liver lipoprotein metabolism because B100 mice synthesize and secrete VLDL B100 rather than VLDL B48 and VLDL B100. In vivo VLDL production, hepatic lipid content, lipogenesis, bile acid synthesis, and ¿-oxidation will be measured in rodents fed ¿ betaine. Aim 2 will define the transcription factors (TF) that mediate transactivation of the apob gene using gel shift assays, chromatin immunoprecipitation, and in vitro loss and gain of function studies in rodent hepatocytes. Aim 3 examines the role of DNA methylation in regulating apob gene expression as a potential mechanism of betaine action by assessment of global and promoter DNA hypomethylation and transient transfection assays using methylated promoter constructs. As increasing hepatic production of VLDL can lead to hypertriglyceridemia and increased LDL chol, betaine therapy will be tested in combination with reduced caloric intake. We suggest that induction of apob transcription may be beneficial in treating hepatic steatosis, and reducing the development of NASH and cirrhosis. What is favorable for the liver may not be favorable in the long term for cardiovascular risk, however, understanding the association gives us the ability to balance risk based on each organ's pathophysiology. Fatty liver disease is increasingly common in the obese human population, and can progress to liver disease including cirrhosis. Betaine may reverse fatty liver by favoring the unloading of hepatic fat into circulating lipoproteins. Clinical implications are direct as betaine is an available therapeutic micronutrient. Understanding the mechanism responsible for the action of betaine on apo B and serum lipoproteins could improve therapy by specific intervention by enhancing TG export from the liver. PUBLIC HEALTH RELEVANCE: Fatty liver disease is increasingly common in the obese human population, and can progress to liver disease including cirrhosis. Betaine may reverse fatty liver by favoring the unloading of hepatic fat into circulating lipoproteins. Clinical implications are direct as betaine is an available therapeutic micronutrient, and understanding the mechanism responsible for the action of betaine on apo B and serum lipoproteins could improve therapy by enhancing TG export from the liver.

描述（由申请人提供）：超过50%的代谢综合征肥胖个体的肝脏甘油三酯（TG）（脂肪变性）增加，使其易患非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH），目前尚无一致的治疗方法。人体研究表明，甜菜碱，一种天然存在的微量营养素，减轻肝脏脂肪变性，并减少NASH，然而，负责这种作用的机制尚不清楚。我们已经证明，大鼠饮食中的甜菜碱通过增加apo B基因转录促进肝脏载脂蛋白（apo）B合成，这有利于极低密度脂蛋白（VLDL）中的肝脏TG输出，并使肝脏TG含量降低45%。这表明，类似的机制可能是负责减少肝脏脂肪变性观察到人类饲料甜菜碱。目的1测试甜菜碱逆转两种啮齿动物代谢综合征模型中肝脂肪变性的能力：Zucker（fa/fa）大鼠和果糖喂养的apobec-1-/-小鼠（B100）。Zucker大鼠模型过度喂养和果糖喂养的小鼠模型增加果糖的消耗。B100小鼠用作人肝脂蛋白代谢的模型，因为B100小鼠合成并分泌VLDL B100而不是VLDL B48和VLDL B100。将在饲喂甜菜碱的啮齿动物中测量体内VLDL产生、肝脂质含量、脂肪生成、胆汁酸合成和氧化。目的2将定义转录因子（TF）介导的apob基因的反式激活，使用凝胶迁移试验，染色质免疫沉淀，并在体外丧失和获得的啮齿动物肝细胞的功能研究。目的3通过评估整体和启动子DNA低甲基化和使用甲基化启动子构建体的瞬时转染试验，研究DNA甲基化在调节apob基因表达中的作用，作为甜菜碱作用的潜在机制。由于VLDL的肝脏产生增加可导致高胆固醇血症和LDL胆固醇增加，甜菜碱治疗将与减少热量摄入联合试验。我们认为，诱导apob转录可能有利于治疗肝脂肪变性，并减少NASH和肝硬化的发展。从长远来看，对肝脏有利的可能对心血管风险不利，然而，了解这种关联使我们能够根据每个器官的病理生理学平衡风险。脂肪肝在肥胖人群中越来越常见，并且可以进展为肝病，包括肝硬化。甜菜碱可以通过促进肝脏脂肪卸载到循环脂蛋白中来逆转脂肪肝。甜菜碱是一种有效的治疗性微量营养素，因此具有直接的临床意义。了解甜菜碱对载脂蛋白B和血清脂蛋白的作用机制，可以通过增强TG从肝脏输出的特异性干预来改善治疗。公共卫生相关性：脂肪肝在肥胖人群中越来越常见，并且可以进展为肝病，包括肝硬化。甜菜碱可以通过促进肝脏脂肪卸载到循环脂蛋白中来逆转脂肪肝。临床意义是直接的，因为甜菜碱是一种有效的治疗性微量营养素，了解甜菜碱对载脂蛋白B和血清脂蛋白的作用机制可以通过增强肝脏的TG输出来改善治疗。