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。部分NAFLD患者患有非酒精性脂肪性肝炎(NASH)，这是一种更严重的疾病，与肝细胞损伤、炎症和不同程度的纤维化有关。NASH患者进展为肝硬变和终末期肝病的风险增加。据估计，约有600万美国人因NAFLD而面临发展为肝硬变的风险。因此，迫切需要了解NAFLD患者发生NASH的机制。“二次打击”假说表明，NAFLD的主要损害是胰岛素抵抗和循环中游离脂肪酸水平的增加；NASH可能是在“二次打击”导致肝脏氧化应激增加的情况下发生的。大量的实验室和临床数据表明，肝脏铁超载导致产生的活性氧物种，可能通过诱导多个途径导致肝损伤和肝纤维化的加重，其中许多途径涉及氧化还原敏感的核因子-：B(NF-：B)。在一项对NASH临床研究网络(CRN)注册的800多名受试者的初步研究中，我们发现35%的NAFLD患者或大约1500万美国成年人存在肝脏铁沉积，网状内皮细胞中肝脏铁沉积的存在与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。我们提出了一种系统生物学方法来识别基因组变异、基因表达谱以及血清和免疫组织化学生物标记物，这些生物标记物可能解释这些二分性肝铁表型。建议的研究是可行的，将利用NASH CRN的大量资源，并将提供一个非常独特的机会来确定NASH发病机制和途径，包括但不限于肝铁的作用。我们相信，我们的结果可能有助于更好地理解这种常见但知之甚少的肝病的发病机制，并可能导致新的治疗干预措施。 公共卫生相关性：非酒精性脂肪肝是西方社会最常见的肝病。据估计，约有600万美国人面临患上非酒精性脂肪性肝病(NAFLD)导致的肝硬变的风险。我们已经确认，超过三分之一的NAFLD患者有肝脏铁沉积(估计有1500万美国成年人)，这可能有助于疾病的进展。本研究的目的是确定导致肝脏铁沉积和更严重的NAFLD的机制。

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.