The Role of Iron in the Pathogenesis of NAFLD

铁在 NAFLD 发病机制中的作用

• 批准号: 8106057
• 负责人: KRIS KOWDLEY
• 金额: $ 77.31万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-20 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8106057
• 关键词: Adult; American; Ancillary Study; Apoptosis; Area; Biological Assay; Biological Markers; Biology; Candidate Disease Gene; Cells; Chronic; Cirrhosis; Clinical Data; Clinical Research; Complement Factor B; Deposition; Disease; Disease Progression; Enrollment; Feasibility Studies; Fibrosis; Funding; Gene Expression; Gene Targeting; General Population; Genomics; Genotype; Goals; Hemochromatosis; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Histologic; IL8 gene; Immunohistochemistry; In Situ; Inflammation; Inflammatory; Injury; Insulin Resistance; Interleukin-2; Interleukin-6; International; Iron; Iron Overload; Kupffer Cells; Laboratories; Lead; Liver; Liver diseases; MADH4 gene; Molecular; Molecular Profiling; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; Nonesterified Fatty Acids; Nuclear; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Pilot Projects; Population; Production; Publishing; Reactive Oxygen Species; Regulation; Regulator Genes; Resources; Reticuloendothelial System; Risk; Role; Serum; Severities; Severity of illness; Site; Societies; Staging; Staining method; Stains; Systems Biology; TFR2 gene; TNF gene; Up-Regulation; Variant; base; cytokine; cytotoxic; effective therapy; fibrogenesis; genome wide association study; genome-wide; hepcidin; interest; macrophage; metal transporting protein 1; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; stellate cell; success; symposium

DESCRIPTION (provided by applicant): Non alcoholic fatty liver disease (NAFLD) is the most common liver disease in the USA and may be present in up to 30% of the general population. A subset of patients with NAFLD has non-alcoholic steatohepatitis (NASH), a more severe form of this disease associated with hepatocellular injury, inflammation and varying levels of fibrosis. Patients with NASH are at increased risk of progression to cirrhosis and end-stage liver disease. It is estimated that about 6 million Americans are at risk of developing cirrhosis due to NAFLD. Thus, there is an urgent need to understand the mechanisms whereby patients with NAFLD develop NASH. The "two-hit" hypothesis suggests that the primary insult in NAFLD is insulin resistance and increased circulating free fatty acid levels; NASH may develop in the presence of a "second hit" leading to increased oxidative stress in the liver. A large body of laboratory and clinical data suggests that hepatic iron overload results in production of reactive oxygen species, which may lead to increased liver injury and hepatic fibrogenesis via induction of a number of pathways, many of which involve the redox-sensitive nuclear factor-:B (NF-:B). In a preliminary study of more than 800 subjects enrolled in the NASH Clinical Research Network (CRN), we have found that hepatic iron deposition is present in 35% of NAFLD patients, or an estimated 15 million adult Americans, and that the presence of hepatic iron deposition in reticuloendothelial cells is associated with NASH and advanced fibrosis. By contrast, hepatocellular iron deposition is associated with less severe histologic disease. We are proposing a systems biology approach to identify genomic variants, gene expression profiles and serum and immunohistochemical biomarkers which may explain these dichotomous hepatic iron phenotypes. The proposed studies are feasible, will harness the vast resources of the NASH CRN and will provide an extraordinarily unique opportunity to determine the pathways and mechanisms involved in the pathogenesis of NASH, including but not limited to role of hepatic iron. We believe our results could lead to a greater understanding of the mechanism causing this common but poorly understood liver disease and may lead to novel therapeutic interventions. PUBLIC HEALTH RELEVANCE: NAFLD is the most common liver disease in Western societies. It is estimated that about 6 million Americans are at risk of developing cirrhosis from nonalcoholic fatty liver disease (NAFLD). We have identified that more than one third of patients with NAFLD have hepatic iron deposition (an estimated 15 million adult Americans) which may contribute to disease progression. The goal of this study is to determine the mechanisms leading to hepatic iron deposition and more severe NAFLD.

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）是美国最常见的肝病，可能存在多达30％的普通人群。 NAFLD患者的一部分患有非酒精性脂肪性肝炎（NASH），这种疾病与肝细胞损伤，炎症和纤维化水平变化有关。 NASH患者的进展风险增加了肝硬化和终末期肝病。据估计，由于NAFLD，大约有600万美国人有肝硬化的风险。因此，迫切需要了解NAFLD患者纳什患者的机制。 “两击”假设表明，NAFLD中的主要侮辱是胰岛素抵抗，循环自由脂肪酸水平升高。在存在“第二次命中”的情况下，纳什可能会发展，从而导致肝脏中氧化应激增加。大量的实验室和临床数据表明，肝铁超负荷会导致活性氧的产生，这可能通过诱导多种途径而导致肝损伤和肝纤维发生增加，其中许多途径涉及氧化还原敏感的核因子 - ：b（nf-：b）。在对NASH临床研究网络（CRN）中800多名受试者的初步研究中，我们发现35％的NAFLD患者或估计有1500万成年美国人存在肝铁沉积，并且存在肝的存在网状内皮细胞中的铁沉积与NASH和晚期纤维化有关。相比之下，肝细胞铁沉积与不太严重的组织学疾病有关。我们正在提出一种系统生物学方法，以鉴定基因组变异，基因表达谱和血清以及免疫组织化学生物标志物，可以解释这些二分法肝铁表型。拟议的研究是可行的，将利用Nash CRN的庞大资源，并将提供一个非常独特的机会来确定NASH发病机理所涉及的途径和机制，包括但不限于肝铁的作用。我们认为，我们的结果可能会导致对导致这种常见但知之甚少的肝病的机制有更深入的了解，并可能导致新的治疗干预措施。 公共卫生相关性：NAFLD是西方社会中最常见的肝病。据估计，大约有600万美国人有非酒精性脂肪肝病（NAFLD）患肝硬化的风险。我们已经确定，有超过三分之一的NAFLD患者患有肝铁沉积（估计1500万成年美国人），这可能导致疾病进展。这项研究的目的是确定导致肝铁沉积和更严重的NAFLD的机制。