Effect of dietary fat on the hepatotoxicity of environmental arsenic

描述(由申请人提供)：高摄入膳食脂肪和长期暴露于环境砷(As)是肝脏疾病的独立风险因素，但尚未有关于这两个风险因素如何相互作用损害肝脏的研究。在美国，大多数肥胖者患有脂肪变性(脂肪肝)，但只有不到20%的脂肪变性患者进展为严重得多的脂肪性肝炎(脂肪肝伴炎症和肝脏损伤)，这表明其他环境因素对炎症性肝损伤有影响。目前的建议考察了环境AS在从脂肪变性到脂肪性肝炎进展中的作用。高脂肪饮食会给肝脏带来新陈代谢负担，使其容易受到第二次侮辱的伤害。在这里提出的研究中，需要检验的假设是，慢性砷暴露通过改变与炎症相关的代谢途径而促进肝病的进展。具体地说，这个团队将检验他们最近观察到的基础，即AS暴露会导致高脂肪饮食小鼠的炎症性肝损伤，而相同浓度的AS在喂养低脂肪饮食的小鼠中是无毒的。该计划是通过在代谢组学和蛋白质组学的水平上测量肝脏的变化来确定由高脂肪、AS以及两者的组合改变的途径。通过构建一个整合了酶活性和代谢产物的模型，人们将能够确定这两种压力相互作用的途径。这些研究预计将揭示与炎症性肝损伤相关的代谢、信号和调控途径，在一个与美国人群相关的饮食-环境相互作用模型中，高脂肪饮食很常见，而且暴露水平通常低于公开肝毒性的阈值。这一新信息将被用作未来研究AS分子靶点的基础，AS分子靶点负责增加对炎症的敏感性。这些研究可能适用于其他与AS相关的疾病，如由慢性炎症驱动的心血管疾病和癌症。 公共卫生相关性：大多数肥胖者至少在一定程度上患有脂肪肝。拟议的研究将研究环境AS如何促进进展为更严重的肝病。

DESCRIPTION (provided by applicant): High intake of dietary fat and chronic exposure to environmental arsenic (As) are independent risk factors for liver disease, but there have been no studies on how these two risk factors interact to damage the liver. The majority of obese people in the United States have steatosis (fatty liver), but less than 20% of people with steatosis progress to the much more serious condition of steatohepatitis (fatty liver with inflammation and liver injury), indicating that other environmental factors have an impact on inflammatory liver injury. The current proposal examines the role of environmental As in the progression from steatosis to steatohepatitis. A diet high in fat places a metabolic burden on the liver, making it susceptible to injury by a second insult. In the studies proposed here, the hypothesis to be tested is that chronic As exposure contributes to liver disease progression by altering metabolic pathways related to inflammation. Specifically, this team will examine the basis for their recent observation that As exposure results in inflammatory liver injury in mice fe a high fat diet, whereas the same concentration of As is not toxic in mice fed a low fat diet. The plan is to identify pathways altered by high fat, As, and the combination of the two by measuring changes in liver at the level of metabolomics and proteomics signatures. By constructing a model integrating both the enzymatic activities and metabolites, one will be able to identify the pathways where these two stresses interact. These studies are expected to reveal metabolic, signaling and regulatory pathways that are associated with inflammatory liver injury in a model of diet-environment interaction that is relevant to the United States population, where high fat diets are common and As exposure levels are typically below the threshold for overt hepatotoxicity. This new information will be used as a basis for future studies examining the molecular targets of As that are responsible for increased sensitivity to inflammation. These studies may be applicable to other As- associated illnesses such as cardiovascular disease and cancer that are driven by chronic inflammation. PUBLIC HEALTH RELEVANCE: Most obese people have fatty liver disease to at least some extent. The proposed studies will examine how environmental As contributes to progression to more serious forms of liver disease.