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: 9055552
• 负责人: Heather B Clair
• 金额: $ 3.43万
• 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/9055552
• 关键词: AHR gene; Acute; Address; Adolescent; Adult; Affect; Affinity; Animals; Aryl Hydrocarbon Receptor; Biological Markers; Body Weight; Cessation of life; Chemicals; Chronic; Comorbidity; Complex; Computer Simulation; Data; Diabetes Mellitus; Diet; Disease; Dose; Energy Intake; Environmental Exposure; 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; Inflammation; Inflammatory; Insulin Resistance; Investigation; Knockout Mice; Laboratories; Ligands; Lipids; Liver Cirrhosis; 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; Pollution; Polychlorinated Biphenyls; Population; Pregnanes; Prevalence; Primary carcinoma of the liver cells; Receptor Activation; Research; Risk; Role; Sampling; Serum; Specificity; Steatohepatitis; 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; feeding; improved; liver injury; mRNA Expression; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; persistent organic pollutants; population based; public health relevance; receptor; receptor structure 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（由申请人提供）：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与易感遗传背景下的热量过剩有关，然而，我们实验室和其他人最近的研究指出了环境毒物（包括多氯联苯（PCB））在脂肪变性和脂肪性肝炎病因学中的作用，特别是在 高热量饮食共同暴露的背景。我们提出的研究使用暴露参数通知我们最近的血清样本分析，从先前描述的队列的个人居住在安尼斯顿，AL谁暴露于高水平的含PCB的废物。虽然这些人中有许多人的血清中多氯联苯的水平高于美国一般人群中发现的水平，但他们的暴露水平仍远低于急性肝损伤的水平。然而，与未暴露人群相比，这些个体具有显著升高的肝损伤生物标志物以及升高的炎性细胞因子、升高的糖尿病患病率和增加的BMI。以往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、慢性和与环境有关的多氯联苯接触的病理反应非常不同。我们在亚急性PCB暴露小鼠模型中的初步数据显示，在较低暴露量与较高暴露量的PCB混合物（20 mg Aroclor 1260/kg体重与200 mg/kg体重Aroclor 1260）下，肝损伤生物标志物、脂肪变化和炎性细胞因子的矛盾升高。在两个缺乏组成型雄烷受体（CAR）或异源生物素受体（PXR）的基因敲除小鼠模型中，我们的实验室发现了这些受体的基因靶点在Aroclor 1260和高脂饮食暴露中的差异转录。这些模式的病理和表型反应是一致的转录因子为基础的机制PCB毒性。因此，疾病终点的差异可能是由于这些受体的人和小鼠形式之间的配体特异性和靶基因群的差异。因此，我们建议扩大我们的调查与使用一种新的三重转基因小鼠模型表达人类形式的AhR，PXR和CAR的PCB毒性的受体为基础的机制。我们假设使用急性暴露的原代肝细胞培养物和整个动物慢性暴露模型，我们将发现这些受体的结构和功能差异将驱动对PCB的差异转录反应，并最终导致PCB相关疾病终点的差异。