Project 3: TCDD-Elicited Steatosis: The Role of Aryl Hydrocarbon Receptor

项目总结（见说明）： 代谢综合征（MetS）是一种多因素疾病，可从脂肪变性发展而来，并导致非酒精性脂肪性肝病、心血管疾病、糖尿病和肝细胞癌的病因。其特征在于血脂异常、肥胖和由于脂肪分解引起的脂质蓄积和膳食脂肪吸收增加而导致的肝甘油三酯（TRG）增加。2，3，7，8-四氯二苯并-对-二恶英（TCDD）和相关化合物与代谢综合征的发展以及糖尿病和血脂异常有关。TCDD通过增加脂肪酸和TRG水平、抑制脂肪细胞增殖、减少葡萄糖转运、破坏脂质和碳水化合物代谢和转运诱导肝脂肪变性。在这个建议中，我们将调查芳香烃受体（AhR）介导的脂质代谢和运输的全身性改变，有助于肝脂肪变性，在大都会发展的第一步。更具体地说，我们将测试的假设，AhR介导的肠道，循环和肝脏的脂质摄取，代谢和运输的影响，导致肝脂肪变性，涉及二恶英反应元件（DRE）的独立机制。我们的初步数据表明，AhR介导的脂质转运和代谢的变化涉及非经典AhR介导的基因表达。我们的具体目标将研究（1）膳食脂肪作为AhR介导的肝脂肪变性中的脂质来源，（2）AhR过氧化物酶体增殖物激活受体（PPAR）信号通路相互作用，其破坏有助于肝脂肪积累的脂质转运和代谢基因表达，（3）AhR/COUP-TF介导的肝细胞核因子4 α（HNF 4a）调节的脂质转运和代谢基因表达的抑制，（4）人和小鼠原代肝细胞中的脂质组成和转运基因表达，和（5）AhR-配体对小鼠血清脂质水平和组成的影响。这些研究不仅将阐明AhR介导的机制参与脂肪变性，但也提供了进一步的证据表明，TCDD和相关化合物暴露发挥了贡献作用的MetS及其相关疾病的病因学使用非经典的DRE独立的机制。这些研究还补充了项目4（Hashsham），该项目检查了对肠和肝脏中胆碱摄取和代谢的影响。此外，与项目2（托马斯）和研究支持核心A（Zhang/Conolly）的合作将确定与AhR介导的血脂异常相关的其他遗传性状，并提供数据以支持AhR调控的生物能量计算模型的开发。

PROJECT SUMMARY (See Instructions): Metabolic syndrome (MetS) is a multi-factorial disease that can develop from steatosis and contribute to the etiology of non-alcoholic fatty liver disease, cardiovascular disease, diabetes, and hepatocellular carcinoma. It is characterized by dyslipidemia, obesity, and increased hepatic triglycerides (TRGs) due to the accumulation of lipids from adipose lipolysis and increased absorption of dietary fat. 2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds have been implicated in MetS development, as well as diabetes and dyslipidemia. TCDD induces hepatic steatosis by increasing fatty acid and TRG levels, inhibiting adipocyte proliferation, decreasing glucose transport, and disrupting lipid and carbohydrate metabolism and transport. In this proposal, we will investigate aryl hydrocarbon receptor (AhR)-mediated systemic alterations in lipid metabolism and transport that contribute to hepatic steatosis, the initial step in Mets development. More specifically, we will test the hypothesis that AhR-mediates intestinal, circulatory and hepatic lipid uptake, metabolism, and transport effects leading to hepatic steatosis that involve dioxin response element (DRE)-independent mechanisms. Our preliminary data suggest that AhR-mediated changes in lipid transport and metabolism involve non-canonical AhR-mediated gene expression. Our specific aims will examine (1) dietary fat as a lipid source in AhR-mediated hepatic steatosis, (2) AhR peroxisome proliferator activated receptor (PPAR) signaling pathways interactions that disrupt lipid transport and metabolism gene expression contributing to hepatic fat accumulation, (3) AhR/COUP-TF-mediated inhibition of hepatocyte nuclear factor 4 alpha (HNF4a)-regulated lipid transport and metabolism gene expression, (4) lipid composition and transport gene expression in human and mouse primary hepatocytes, and (5) the effects of AhR-ligands on serum lipid levels and composition in mice. These studies will not only elucidate the AhR-mediated mechanisms involved in steatosis, but also provide further evidence that TCDD and related compound exposure plays a contributory role in the etiology of MetS and its related diseases using non-canonical DRE-independent mechanisms. These studies also complement Project 4 (Hashsham) which examines effects on choline uptake and metabolism in the intestine and liver. In addition, collaborations with Project 2 (Thomas) and Research Support Core A (Zhang/Conolly) will identify other genetic traits relevant to AhR-mediated dyslipidemia and provide data to support the development of bioenergetic computational models regulated by the AhR, respectively.