The Role of Iron in the Pathogenesis of NAFLD

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是美国最常见的肝病，可能存在于高达30%的普通人群中。一部分NAFLD患者患有非酒精性脂肪性肝炎（NASH），这是一种与肝细胞损伤、炎症和不同水平的纤维化相关的更严重的疾病形式。NASH患者进展为肝硬化和终末期肝病的风险增加。据估计，约有600万美国人因NAFLD而有发生肝硬化的风险。因此，迫切需要了解NAFLD患者发展NASH的机制。“二次打击”假说表明，NAFLD的主要损伤是胰岛素抵抗和循环游离脂肪酸水平增加; NASH可能在“二次打击”的存在下发展，导致肝脏中氧化应激增加。大量的实验室和临床数据表明，肝铁超负荷导致活性氧的产生，这可能通过诱导许多途径导致肝损伤和肝纤维化的增加，其中许多途径涉及氧化还原敏感的核因子-：B（NF-：B）。在NASH临床研究网络（CRN）招募的800多名受试者的初步研究中，我们发现35%的NAFLD患者或估计1500万成年美国人中存在肝脏铁沉积，并且网状内皮细胞中存在肝脏铁沉积与NASH和晚期纤维化相关。相比之下，肝细胞铁沉积与不太严重的组织学疾病相关。我们提出了一种系统生物学方法，以确定基因组变异，基因表达谱和血清和免疫组化生物标志物，这可能会解释这些二分肝铁表型。拟议的研究是可行的，将利用NASH CRN的巨大资源，并将提供一个非常独特的机会来确定NASH发病机制中涉及的途径和机制，包括但不限于肝铁的作用。我们相信，我们的研究结果可以更好地了解导致这种常见但知之甚少的肝脏疾病的机制，并可能导致新的治疗干预措施。

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.