Effects of Dietary Fat on the Hepatotoxicity of Environmental Arsenic

膳食脂肪对环境砷肝毒性的影响

• 批准号: 8813884
• 负责人: WALTER H WATSON
• 金额: $ 18.47万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813884
• 关键词: Acetylation; Adult; Affect; American; Animal Model; Arginine; Arsenic; Arsenites; Benign; Binding; Cells; Centers of Research Excellence; ChIP-seq; Chemicals; Cirrhosis; Clinical; Consumption; Cysteine; DNA; DNA Binding; DNA Binding Domain; Diet; Dietary Fats; Disease; Disease Progression; Disease model; Environment; Etiology; FDA approved; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Gene Expression; Genes; Genetic; Hepatic; Hepatotoxicity; High Fat Diet; In Vitro; Incubated; Individual; Inflammation; Inflammatory; Injury; Knowledge; Liver; Liver diseases; Lysine; Mediating; Methylation; Modeling; Modification; Mus; Obesity; Pathway interactions; Play; Population; Post-Translational Protein Processing; Process; Proteins; Proteomics; Request for Proposals; Response Elements; Risk Factors; Role; Signal Pathway; Staging; Steatohepatitis; Techniques; Testing; Tissues; Toxic effect; Toxicology; Transactivation; Translating; United States; Zinc; Zinc Fingers; cell injury; contaminated drinking water; drinking water; feeding; follow-up; genetic regulatory protein; innovation; lipid metabolism; liver injury; non-alcoholic fatty liver; novel; oxidation; promoter; research study; response; saturated fat; transcription factor; transcriptome sequencing

One of every three American adults is obese and is afflicted with some form of non-alcoholic fatty liver disease (NAFLD). The majority of obese individuals will have steatosis (fatty liver), but only about 20% will have the more serious condition of steatohepatitis (fatty liver with inflammation and liver injury). There is still no FDA- approved therapy for any stage of NAFLD. Therefore, it is critical that we understand the multiple factors that promote progression from steatosis to steatohepatitis in NAFLD. Our previous studies have shown that consumption of arsenic-contaminated drinking water is an important risk factor for progression of NAFLD. Preliminary proteomic analysis demonstrated that the abundance of a number of proteins that are controlled at the transcriptional level by HNF-4a was decreased in the livers of mice with arsenic-enhanced NAFLD. Mechanistic studies showed that the expression of this zinc finger transcription factor was not altered, but that its DNA binding activity was inhibited at the post-translational level. HNF-4a is known to be regulated by post- translational modifications (PTMs), and arsenic has the potential to affect zinc binding, cysteine oxidation, arginine methylation and lysine acetylation. Very little is known about how PTMs of HNF-4a are regulated, or how disruption of these regulatory processes contributes to liver disease. To follow up on these important findings, the objective of the current proposal is to delineate the mechanisms by which environmental arsenic exposure promotes the progression from steatosis to steatohepatitis in mice fed a Western-style diet that is high in saturated fat. The central hypothesis to be tested is that alterations in HNF-4a-mediated gene expression induced by arsenic play a critical role in the progression of NAFLD from steatosis to steatohepatitis in this model. This hypothesis will be tested in three Specific Aims. First, we will define the specific molecular interactions of arsenic with the zinc finger domain of HNF-4a. Second, we will analyze the mechanisms by which arsenic affects PTMs of HNF-4a, and how these changes translate into altered DNA binding activity and transactivation potential. Third, we will define the post-translational modifications of hepatic HNF-4a in mice fed a high fat diet and exposed to arsenic-contaminated drinking water, and relate these changes to the occupancy of HNF-4a-response elements in genes involved in lipid metabolism and inflammation. This model of inflammatory liver injury is relevant to the United States population, where high fat diets are common and arsenic exposure levels are typically below the threshold for overt hepatotoxicity. The new information obtained from these studies will delineate pathways that are altered by arsenic and that are important in the etiology of NAFLD.

每三个美国成年人中就有一个肥胖，并患有某种形式的非酒精性脂肪性肝病 (NAFLD)。大多数肥胖的人会有脂肪变性(脂肪肝)，但只有大约20%的人会有 脂肪性肝炎(脂肪肝合并炎症和肝损伤)的情况更严重。仍然没有FDA- 批准用于NAFLD任何阶段的治疗。因此，至关重要的是，我们要了解 促进非酒精性脂肪性肝病从脂肪变性进展为脂肪性肝炎。我们之前的研究表明， 饮用受砷污染的饮用水是NAFLD进展的重要危险因素。 初步的蛋白质组学分析表明，一些蛋白质的丰度控制在 砷增强型非酒精性脂肪肝小鼠肝脏HNF-4a转录水平降低。 机制研究表明，这种锌指转录因子的表达没有改变，但 其DNA结合活性在翻译后水平受到抑制。已知HNF-4a受POST-2调节 翻译修饰(PTM)，砷有可能影响锌结合，半胱氨酸氧化， 精氨酸甲基化和赖氨酸乙酰化。关于HNF-4a的PTM是如何被调控的，或者 这些调控过程的破坏如何导致肝病。跟进这些重要的 调查结果，当前提案的目标是描述环境砷 暴露促进喂食西式饮食的小鼠从脂肪变性进展为脂肪性肝炎 饱和脂肪含量高。需要检验的中心假设是HNF-4a介导的基因的变化 砷诱导的表达在NAFLD从脂肪变性到脂肪性肝炎的进展中起关键作用 在这个模型中。这一假设将在三个具体目标上得到检验。首先，我们将定义特定的分子 砷与hnf-4a锌指结构域的相互作用。第二，我们将通过以下方式来分析这些机制 哪些砷影响HNF-4a的PTM，以及这些变化如何转化为改变的DNA结合活性和 激活潜能。第三，我们将确定喂食小鼠肝脏hnf-4a的翻译后修饰。 高脂肪饮食和接触受砷污染的饮用水，并将这些变化与入住率联系起来 参与脂类代谢和炎症的基因中的HNF-4a反应元件。这一模式 炎症性肝损伤与美国人口有关，在美国，高脂肪饮食很常见， 砷暴露水平通常低于公开肝脏毒性的阈值。获得的新信息 这些研究将描绘出被砷改变的途径，这些途径在癌症的病因中是重要的。 NAFLD。