Effect of dietary fat on the hepatotoxicity of environmental arsenic

描述（由申请人提供）：膳食脂肪的高摄入和环境砷（As）的长期暴露是肝病的独立危险因素，但这两个危险因素如何相互作用损害肝脏尚无研究。在美国，大多数肥胖者患有脂肪变性（脂肪肝），但只有不到20%的脂肪变性患者会发展为更为严重的脂肪性肝炎（伴有炎症和肝损伤的脂肪肝），这表明其他环境因素对炎症性肝损伤也有影响。目前的建议检查环境中的作用，从脂肪变性到脂肪性肝炎的进展。高脂肪的饮食会给肝脏带来代谢负担，使其容易受到第二次伤害。在这里提出的研究中，需要验证的假设是慢性砷暴露通过改变与炎症相关的代谢途径来促进肝脏疾病的进展。具体来说，该团队将研究他们最近观察到的结果的基础，即在高脂肪饮食的小鼠中暴露于砷会导致炎症性肝损伤，而在低脂肪饮食的小鼠中，相同浓度的砷没有毒性。该计划是通过测量肝脏代谢组学和蛋白质组学特征水平上的变化来确定高脂肪、As以及两者结合所改变的途径。通过构建一个整合酶活性和代谢物的模型，人们将能够确定这两种胁迫相互作用的途径。这些研究旨在揭示饮食-环境相互作用模型中与炎症性肝损伤相关的代谢、信号传导和调节途径，该模型与美国人群相关，在美国，高脂肪饮食很常见，砷暴露水平通常低于明显肝毒性的阈值。这一新信息将作为未来研究as分子靶点的基础，这些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a相关的疾病，如心血管疾病和癌症，这些疾病是由慢性炎症引起的。

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.