Xenobiotic Receptors Modulate PCB-induced Steatohepatitis

异生素受体调节 PCB 诱导的脂肪性肝炎

• 批准号: 9256484
• 负责人: Heather B Clair
• 金额: $ 4.9万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2020-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256484
• 关键词: AHR gene; Acute; Address; Adolescent; Adult; Affect; Affinity; Animals; Aryl Hydrocarbon Receptor; Biological Markers; Body Weight; Cessation of life; Chemicals; Chronic; Cirrhosis; Comorbidity; Complex; Computer Simulation; Data; Diabetes Mellitus; Diet; Disease; Dose; Energy Intake; Environmental Exposure; Environmental Risk Factor; Enzymes; Etiology; Exposure to; Fatty Change; Fatty Liver; Gene Expression; Gene Targeting; General Population; Genes; Genetic; Genetic Transcription; Hepatic; Hepatocyte; High Fat Diet; Human; Individual; Industrialization; Inflammation; Inflammatory; Insulin Resistance; Investigation; Knockout Mice; Laboratories; Ligands; Lipids; Liver; Liver diseases; Mediating; Metabolic Diseases; Metabolic syndrome; Metabolism; Microarray Analysis; Modeling; Molecular Weight; Mus; National Health and Nutrition Examination Survey; Nutritional; Obesity; Odds Ratio; Overweight; Participant; Pathologic; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Pollution; Polychlorinated Biphenyls; Population; Pregnanes; Prevalence; Primary carcinoma of the liver cells; Receptor Activation; Research; Role; Sampling; Serum; Specificity; Steatohepatitis; Structure; Testing; Toxic Environmental Substances; Toxic effect; Transcript; Transgenic Mice; Transplantation; Wild Type Mouse; Xenobiotics; acute liver injury; base; carbohydrate metabolism; cardiovascular risk factor; cohort; constitutive androstane receptor; cytokine; design; exposed human population; improved; liver injury; mRNA Expression; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; persistent organic pollutants; population based; public health relevance; receptor; receptor function; response; transcription factor; transcriptome; transcriptomics; wasting

 DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is intimately associated with obesity, diabetes and the metabolic syndrome. Traditionally, NAFLD has been associated with caloric excess on a susceptible genetic background, however recent studies from our laboratory and others have pointed out a role for environmental toxicants, including polychlorinated biphenyls (PCBs), in the etiology of steatosis and steatohepatitis, particularly in the context of hypercaloric diet coexposure. Our proposed study uses exposure parameters informed by our recent analysis of serum samples from a previously-described cohort of individuals residing in Anniston, AL who were exposed to high levels of PCB-containing waste. Although many of these individuals have serum levels of PCBs above that found in the general population of the US, their exposures remain well below the levels implicated in acute liver injury. Nevertheless, these individuals have significantly elevated biomarkers of liver injury as well as elevated inflammatory cytokines, elevated prevalence of diabetes, and increased BMI when compared to an unexposed population. A frustrating finding of previous toxicity studies has been the very different pathological response of mice and humans to such subacute, chronic, and environmentally relevant PCB exposures. Our preliminary data in a mouse model of subacute PCB exposure shows paradoxical elevations of liver injury biomarkers, fatty change, and inflammatory cytokines at lower exposure vs. higher exposure to a PCB mixture (20mg Aroclor 1260/kg body weight vs. 200mg/kg body weight Aroclor 1260). In two knockout mouse models that lack the constitutive androstane receptor (CAR) or the pregnane and xenobiotic receptor (PXR), our laboratory has found differential transcription of the gene targets of these receptors in response to Aroclor 1260 and high-fat diet exposure. These patterns of pathological and phenotypic responses are consistent with a transcription-factor based mechanism of PCB toxicity. The differences in disease endpoints may therefore be due to differences in ligand specificity and target gene cohort between the human and mouse forms of these receptors. We therefore propose to expand our investigation of receptor-based mechanisms of PCB toxicity with the use of a novel triple-transgenic mouse model expressing human forms of AhR, PXR, and CAR. We hypothesize that using both an acute-exposure primary hepatocyte culture, and a whole animal chronic exposure model, we will find that differences in the structure and function of these receptors will drive a differential transcriptioal response to PCBs and ultimately, differences in PCB-associated disease endpoints.

 描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)与肥胖、糖尿病和代谢综合征密切相关。传统上，NAFLD在易感遗传背景下与热量过剩有关，然而，我们实验室和其他人最近的研究指出，环境毒物，包括多氯联苯(PCBS)，在脂肪变性和脂肪性肝炎的病因学中所起的作用，特别是在 高热量饮食共同暴露的背景。我们建议的研究使用暴露参数，这些参数来自我们最近对居住在美国安尼斯顿的一群人的血清样本的分析，这些人暴露在高水平的含有多氯联苯的废物中。尽管这些人中的许多人的血清多氯联苯水平高于美国普通人群的水平，但他们的暴露水平仍然远低于急性肝脏损伤的水平。然而，与非暴露人群相比，这些个体肝脏损伤的生物标志物显著增加，炎性细胞因子增加，糖尿病患病率增加，体重指数增加。先前毒性研究的一个令人沮丧的发现是，小鼠和人类对这种亚急性、慢性和与环境相关的多氯联苯暴露的病理反应截然不同。我们在亚急性多氯联苯暴露的小鼠模型中的初步数据显示，与高暴露于多氯联苯混合物(20 mg Aroclor 1260/kg体重对200 mg/kg体重Aroclor 1260)相比，低暴露与高暴露相比肝脏损伤生物标记物、脂肪变化和炎症细胞因子的异常升高。在两个缺乏构成雄烷受体(CAR)或孕烷和异源受体(PXR)的基因敲除小鼠模型中，我们的实验室发现这些受体的基因靶标差异转录对Aroclor 1260和高脂饮食暴露的反应。这些病理和表型反应模式与基于转录因子的多氯联苯毒性机制是一致的。因此，疾病终点的差异可能是由于这些受体的人和小鼠之间在配体特异性和靶基因队列方面的差异。因此，我们建议使用一种新的表达人形式的AhR、PXR和CAR的三重转基因小鼠模型来扩大我们对多氯联苯毒性的基于受体的机制的研究。我们假设，使用急性暴露的原代肝细胞培养和整个动物的慢性暴露模型，我们将发现这些受体的结构和功能的差异将驱动对多氯联苯的不同转录反应，最终导致多氯联苯相关疾病终点的差异。