Pathogenic Mechanisms of Fatty Liver Disease

脂肪肝的发病机制

基本信息

批准号：
7806889
负责人：
Mohammad S Siddiqui
金额：
$ 5.17万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7806889
关键词：
ADD-1 protein Adenoviruses Affect Agonist American Apoptotic Applications Grants Atherosclerosis Cell Nucleus Chemistry Complementary DNA Cryptogenic cirrhosis Data Diet Disease Endoplasmic Reticulum Enzymes Fatty Acids Fatty Liver Fatty acid glycerol esters Fibrosis Functional disorder Gene Expression Genes Genetic Transcription Heavy Drinking Hepatic Hepatitis C Hepatocyte Hyperinsulinism Hyperlipidemia Hypertriglyceridemia Incidence Individual Inflammatory Injury Insulin Resistance Knockout Mice Link Lipids Liver Liver Failure Liver diseases Mediating Metabolic syndrome Modeling Molecular Chaperones Mus Nutritional Obesity Organelles PPAR gamma Pathogenesis Pathway interactions Peroxisome Proliferator-Activated Receptors Play Portal Hypertension Prevalence Production Protein Binding Proteins Recombinants Regulation Risk Factors Role Serum Signal Pathway Signal Transduction Testing Translations Triglycerides United States Wild Type Mouse alpha 1-Antitrypsin Deficiency endoplasmic reticulum stress feeding genetic regulatory protein glucose metabolism in vivo lipid metabolism liver transplantation non-alcoholic fatty liver nonalcoholic steatohepatitis prevent problem drinker protein degradation protein folding protein misfolding protein transport public health relevance response rosiglitazone stressor transcription factor

项目摘要

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disorders (NAFLD) are the most common cause of abnormal serum liver chemistry tests in the United States and are the leading causes of cryptogenic cirrhosis. Although NAFLD is associated with the metabolic syndrome, obesity, hyperlipidemia and insulin resistance, the pathophysiology of fatty liver disorders remains poorly understood. There is increasing evidence that endoplasmic reticulum (ER) stress may be involved in the progression of the hepatic injury that occurs with NAFLD. The ER is an intracellular organelle involved in protein folding, packaging and secretion. Pathophysiologic conditions such as obesity, fatty liver and hyperinsulinemia result in excess misfolding of proteins and ER stress. The cellular response to ER stress is activation of the Unfolded Protein Response (UPR); a cellular signaling mechanism that reduces protein translation, increases ER associated protein degradation and increases production of chaperone molecules to enhance protein trafficking. Prolonged UPR activation can then induce inflammatory and apoptotic pathways. SREBP-lc is a hepatic protein that regulates hepatic lipid and glucose metabolism. The high-fat, high calorie (HFHC) diet is a well accepted nutritional model for causing non-alcoholic fatty liver disorders in mice. When mice are fed a HFHC diet, hepatic triglycerides increase, producing ER stress and activation of SREBP-lc pathway, lnsig-1 and lnsig-2 are regulatory proteins that bind to SREBP-lc and prevents its translocation to the nucleus. I hypothesize that when mice are fed a HFHC diet, lnsig-1 and lnsig-2 levels decline thereby allowing SREBP-lc to translocate to nucleus and increase hepatic triglyceride synthesis and hepatic steatosis. Thus, I will examine the role of Insig in the pathogenesis of murine fatty liver by feeding C57BL/6J mice a high fat, high calorie (HFHC) diet and determining the role of Insig signaling and hepatic steatosis (Specific Aim #1A). To demonstrate a direct role of Insig in hepatic steatosis, I will feed Insig 2-null and wild-type mice a HFHC diet and study the resulting effects on hepatic steatosis (Specific Aim #1B). To further investigate the importance of lnsig-1 and lnsig-2 in averting hepatic steatosis in mice fed a HFHC, I will upregulate insig expression in vivo by activating PPAR-gamma pathway which has been shown to increase insig expression. This will be done via gene-mediated therapy and phamacologically with Rosiglitazone, a PPAR-g agonist (Specific Aim #2). PUBLIC HEALTH RELEVANCE: These studies will help delineate the role of the Insig pathway in non-alcoholic fatty liver disorders and enhance our understanding of these common hepatic diseases, especially with the increasing incidence of obesity and metabolic syndrome in the United States.

描述（由申请人提供）：非酒精性脂肪肝病 (NAFLD) 是美国血清肝脏化学测试异常的最常见原因，也是隐源性肝硬化的主要原因。尽管 NAFLD 与代谢综合征、肥胖、高脂血症和胰岛素抵抗相关，但脂肪肝疾病的病理生理学仍知之甚少。越来越多的证据表明，内质网 (ER) 应激可能与 NAFLD 引起的肝损伤的进展有关。 ER 是参与蛋白质折叠、包装和分泌的细胞内细胞器。肥胖、脂肪肝和高胰岛素血症等病理生理状况会导致蛋白质过度错误折叠和内质网应激。细胞对内质网应激的反应是激活未折叠蛋白反应（UPR）；一种细胞信号传导机制，可减少蛋白质翻译、增加内质网相关蛋白质降解并增加伴侣分子的产生以增强蛋白质运输。延长的 UPR 激活可以诱导炎症和细胞凋亡途径。 SREBP-lc是一种调节肝脏脂质和葡萄糖代谢的肝蛋白。高脂肪、高热量（HFHC）饮食是一种公认的导致小鼠非酒精性脂肪肝疾病的营养模型。当小鼠喂食 HFHC 饮食时，肝脏甘油三酯增加，产生 ER 应激并激活 SREBP-lc 通路，lnsig-1 和 lnsig-2 是与 SREBP-lc 结合并防止其转位至细胞核的调节蛋白。我推测，当小鼠喂食 HFHC 饮食时，lnsig-1 和 lnsig-2 水平下降，从而使 SREBP-lc 易位至细胞核，增加肝脏甘油三酯合成和肝脏脂肪变性。因此，我将通过给 C57BL/6J 小鼠喂食高脂肪、高热量 (HFHC) 饮食并确定 Insig 信号传导和肝脂肪变性的作用（具体目标 #1A）来研究 Insig 在小鼠脂肪肝发病机制中的作用。为了证明 Insig 在肝脂肪变性中的直接作用，我将用 HFHC 饮食喂养 Insig 2-null 和野生型小鼠，并研究由此产生的对肝脂肪变性的影响（具体目标 #1B）。为了进一步研究 lnsig-1 和 lnsig-2 在避免饲喂 HFHC 的小鼠肝脂肪变性中的重要性，我将通过激活 PPAR-gamma 途径来上调体内 insig 表达，该途径已被证明可以增加 insig 表达。这将通过基因介导的治疗和 PPAR-g 激动剂罗格列酮的药理学来完成（具体目标#2）。公共健康相关性：这些研究将有助于描述 Insig 通路在非酒精性脂肪肝疾病中的作用，并增强我们对这些常见肝脏疾病的了解，特别是在美国肥胖和代谢综合征发病率不断增加的情况下。