Insulin resistance in the pathogenesis of NASH

NASH 发病机制中的胰岛素抵抗

• 批准号: 7755556
• 负责人: Sonia M. Najjar
• 金额: $ 37.45万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755556
• 关键词: ADD-1 protein; Address; Adipose tissue; Adult; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoproteins B; Apoptosis; Biochemical; Biological Markers; Biological Preservation; CEACAM1; Cell Adhesion Molecules; Central obesity; Cholesterol; Choline Deficiency; Chylomicrons; Cirrhosis; Clinical; Country; Data; Development; Diagnosis; Diet; Disease; Disputes; Dominant-Negative Mutation; Dyslipidemias; Endoplasmic Reticulum; Epidemic; Exhibits; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Genes; Hepatic; Hepatitis; Hepatocyte; Human; Hyperinsulinism; Hypertriglyceridemia; Incidence; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Link; Lipid Peroxidation; Liver; Liver Cirrhosis; Liver diseases; Mediating; Metabolic; Methionine; Mitochondria; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Output; Pathogenesis; Peripheral; Phenotype; Play; Prevention; Process; Production; Proteins; Rodent; Role; Serum; Signal Pathway; Signaling Molecule; Steatohepatitis; Surface; Syndrome; T-Cell Activation; Testing; Transgenic Mice; Transgenic Organisms; Triglycerides; United States; Very low density lipoprotein; base; cell injury; choline deficient diet; embryonic antigen; feeding; gain of function; insulin sensitivity; interest; lipid transfer protein; liver transplantation; microsomal triglyceride transfer protein; mutant; nonalcoholic steatohepatitis; novel; null mutation; overexpression; prevent; public health relevance; receptor; research study; response; restoration; therapeutic target

DESCRIPTION (provided by applicant): About one third of adults in the United States are diagnosed with fatty liver disease. About 10% will proceed to develop nonalcoholic steatohepatitis (NASH), and associated co-morbidities. Thus, it is imperative to understand the pathophysiology of the disease. NASH pathogenesis is currently explained on the basis of the "two-hit" hypothesis, in which hepatic steatosis develops initially (first hit) and predisposes to lipid peroxidation and inflammation, leading to hepatitis, apoptosis, fibrosis and ultimately, cirrhosis (second hit). Association between the disease and insulin resistance has been disputed, largely because of the lack of a replicate animal model. We describe a novel mechanism linking NASH pathogenesis to the Carcino-Embryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), a protein that regulates insulin sensitivity by mediating hepatic insulin clearance. It also acts as an anti-inflammatory signaling molecule. Liver-specific inactivation of CEACAM1 causes insulin resistance, visceral obesity and increased triglyceride production and output from liver. In preliminary data, we show that: (i) CEACAM1 levels are reduced in humans with visceral obesity; (ii) dominant-negative inhibition of CEACAM1 in transgenic mice yields a NASH-like syndrome under conditions that trigger inflammation, such as high-fat diet; while (iii) overexpression of CEACAM1 in liver of transgenic mice prevents insulin resistance and visceral obesity in response to high fat diet. We hypothesize that reduction in hepatic CEACAM1 constitutes a key mechanism in NASH development. To test this hypothesis, we propose to investigate whether liver-specific null mutation of CEACAM1 causes insulin resistance (Aim 1) and predisposes to NASH in response to high-fat diet (Aim 2). In Aim 2, we will also seek to identify the signaling pathways responsible for NASH development by studying mice with hepatic Ceacam1 loss- and gain-of-function. We will examine whether CEACAM1 restoration in NASH models reverses hepatic insulin resistance, inflammation, lipid peroxidation and fibrosis. In Aim 3, we will investigate the molecular target(s) and effector(s) of CEACAM1 responsible for NASH development. Based on a novel hypothesis, we will test the role of Mitochondrial Triglyceride Transfer Protein (MTP) in this process. The results of these experiments will define novel mechanisms linking insulin resistance with hepatic macrosteatosis, inflammation and cell injury associated with NASH. They will also identify CEACAM1 as a molecular biomarker of NASH as well as a potential target for its prevention and treatment. PUBLIC HEALTH RELEVANCE: The incidence of Nonalcoholic Steatohepatitis (NASH) is expected to rise in parallel to the obesity epidemic. Because NASH frequently progresses to liver cirrhosis, and is becoming the leading cause of liver transplant in the US, it is imperative to understand its mechanisms. The disease is characterized by hepatic macrosteatosis, inflammation and fibrosis. It is frequently associated with other common metabolic abnormalities, such as insulin resistance, visceral obesity and liver steatosis, but the role of insulin resistance in the pathogenesis of NASH has been disputed, largely owing to the lack of a suitable animal model. We propose a novel mechanism of NASH, linked to the Carcino-Embryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1), a protein the inactivation of which causes insulin resistance, dyslipidemia, liver steatosis and inflammation. The proposal seeks to test the hypothesis that reduction in hepatic CEACAM1 constitutes an early mechanism in NASH development. The results of these experiments will define novel mechanisms linking insulin resistance and hepatic macrosteatosis, inflammation and cell injury associated with NASH. This will identify reduction in hepatic CEACAM1 as a molecular biomarker of NASH as well as a potential target for its prevention and treatment.

描述（由申请人提供）：在美国，大约三分之一的成年人被诊断患有脂肪肝。大约10%的人会发展为非酒精性脂肪性肝炎（NASH）和相关的合并症。因此，必须了解疾病的病理生理学。NASH发病机制目前基于“两次打击”假说来解释，其中肝脂肪变性最初发展（第一次打击）并倾向于脂质过氧化和炎症，导致肝炎、细胞凋亡、纤维化并最终导致肝硬化（第二次打击）。这种疾病和胰岛素抵抗之间的联系一直存在争议，主要是因为缺乏可复制的动物模型。我们描述了NASH发病机制与癌胚抗原相关细胞粘附分子1（CEACAM 1）的新机制，CEACAM 1是一种通过介导肝脏胰岛素清除来调节胰岛素敏感性的蛋白质。它也是一种抗炎信号分子。CEACAM 1的肝脏特异性失活导致胰岛素抵抗、内脏肥胖和增加的甘油三酯产生和肝脏输出。在初步数据中，我们表明：（i）CEACAM 1水平在内脏肥胖的人中降低;（ii）在转基因小鼠中CEACAM 1的显性负抑制在触发炎症的条件下产生NASH样综合征，如高脂饮食;而（iii）转基因小鼠肝脏中CEACAM 1的过表达可预防胰岛素抵抗和内脏肥胖。我们假设肝脏CEACAM 1的减少是NASH发展的关键机制。为了验证这一假设，我们建议研究CEACAM 1的肝脏特异性无效突变是否会导致胰岛素抵抗（目的1），并在高脂饮食中易患NASH（目的2）。在目标2中，我们还将通过研究肝脏Ceacam 1功能丧失和获得的小鼠，寻求确定负责NASH发展的信号通路。我们将研究NASH模型中CEACAM 1的恢复是否逆转肝脏胰岛素抵抗、炎症、脂质过氧化和纤维化。在目标3中，我们将研究负责NASH发展的CEACAM 1的分子靶标和效应物。基于一个新的假设，我们将测试线粒体甘油三酯转移蛋白（MTP）在这一过程中的作用。这些实验的结果将定义将胰岛素抵抗与NASH相关的肝脏大脂肪变性、炎症和细胞损伤联系起来的新机制。他们还将确定CEACAM 1作为NASH的分子生物标志物以及预防和治疗NASH的潜在靶点。公共卫生相关性：预计非酒精性脂肪性肝炎（NASH）的发病率将与肥胖流行病平行上升。由于NASH经常进展为肝硬化，并且正在成为美国肝移植的主要原因，因此必须了解其机制。该疾病的特征在于肝脏巨大脂肪变性、炎症和纤维化。它经常与其他常见的代谢异常相关，如胰岛素抵抗、内脏肥胖和肝脏脂肪变性，但胰岛素抵抗在NASH发病机制中的作用一直存在争议，主要是由于缺乏合适的动物模型。我们提出了NASH的一种新机制，与癌胚抗原相关细胞粘附分子1（CEACAM 1）有关，CEACAM 1是一种蛋白质，其失活会导致胰岛素抵抗、血脂异常、肝脏脂肪变性和炎症。该提案旨在检验肝脏CEACAM 1减少构成NASH发展早期机制的假设。这些实验的结果将定义连接胰岛素抵抗和与NASH相关的肝脏大脂肪变性、炎症和细胞损伤的新机制。这将确定肝脏CEACAM 1的减少作为NASH的分子生物标志物以及其预防和治疗的潜在靶点。