Insulin resistance in the pathogenesis of NASH

NASH 发病机制中的胰岛素抵抗

• 批准号: 7943014
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943014
• 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; Comorbidity; 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; 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）：美国约三分之一的成年人被诊断患有脂肪肝。大约 10% 将继续发展为非酒精性脂肪性肝炎 (NASH) 和相关并发症。因此，必须了解该疾病的病理生理学。 NASH发病机制目前基于“两次打击”假说进行解释，其中肝脏脂肪变性最初发生（第一次打击），并容易发生脂质过氧化和炎症，导致肝炎、细胞凋亡、纤维化，最终导致肝硬化（第二次打击）。该疾病与胰岛素抵抗之间的关联一直存在争议，很大程度上是因为缺乏复制的动物模型。我们描述了一种将 NASH 发病机制与癌胚抗原相关细胞粘附分子 1 (CEACAM1) 联系起来的新机制，CEACAM1 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。它还充当抗炎信号分子。 CEACAM1 的肝脏特异性失活会导致胰岛素抵抗、内脏肥胖以及肝脏甘油三酯的产生和输出增加。在初步数据中，我们表明：（i）内脏肥胖人群中 CEACAM1 水平降低； (ii) 转基因小鼠中 CEACAM1 的显性失活抑制会在引发炎症的条件下（例如高脂肪饮食）产生 NASH 样综合征； (iii) 转基因小鼠肝脏中 CEACAM1 的过度表达可预防高脂肪饮食引起的胰岛素抵抗和内脏肥胖。我们假设肝脏 CEACAM1 的减少构成 NASH 发展的关键机制。为了检验这一假设，我们建议调查 CEACAM1 的肝脏特异性无效突变是否会导致胰岛素抵抗（目标 1）并因高脂肪饮食而导致 NASH 的易感性（目标 2）。在目标 2 中，我们还将通过研究肝脏 Ceacam1 功能丧失和获得的小鼠来寻求确定导致 NASH 发展的信号通路。我们将研究 NASH 模型中 CEACAM1 的恢复是否可以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 CEACAM1 的分子靶点和效应器。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）在此过程中的作用。这些实验的结果将确定胰岛素抵抗与 NASH 相关的肝大脂肪变性、炎症和细胞损伤之间联系的新机制。他们还将确定 CEACAM1 作为 NASH 的分子生物标志物及其预防和治疗的潜在靶点。公共卫生相关性：非酒精性脂肪性肝炎 (NASH) 的发病率预计将与肥胖流行同步上升。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，因此了解其机制势在必行。该疾病的特征是肝脏大脂肪变性、炎症和纤维化。它经常与其他常见的代谢异常相关，例如胰岛素抵抗、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，很大程度上是由于缺乏合适的动物模型。我们提出了一种 NASH 的新机制，该机制与癌胚抗原相关细胞粘附分子 1 (CEACAM1) 有关，CEACAM1 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 CEACAM1 减少构成 NASH 发展早期机制的假设。这些实验的结果将确定胰岛素抵抗与 NASH 相关的肝大脂肪变性、炎症和细胞损伤之间联系的新机制。这将确定肝脏 CEACAM1 的减少作为 NASH 的分子生物标志物及其预防和治疗的潜在目标。