Project 3 - The role of HMGCR in Modulating TCDD-induced, AHR-mediated NAFLD

项目总结/摘要 高胆固醇血症、肥胖、非酒精性脂肪性肝病（NAFLD）和糖尿病的发病率在2010年增加。 美国人口达到流行病的比例。累积流行病学证据和啮齿动物研究 环境污染物和膳食化学品对NAFLD进展的影响。许多环境污染物， 包括2，3，7，8-四氯二苯并-对-二恶英（TCDD）和相关化合物是芳基的配体， 碳氢化合物受体（AhR）。TCDD还破坏了参与代谢的基因的表达，如3- 羟基-3-甲基戊二酰辅酶A还原酶（HMGCR），胆固醇生物合成的限速步骤。 有趣的是，环境暴露于TCDD和相关化合物会降低血清胆固醇水平， 在人类中，它与代谢功能障碍、肝毒性和NAFLD进展有关。初步 研究还表明，通过他汀类药物联合治疗抑制HMGCR活性， 肝脂肪变性，但加剧了TCDD诱导的毒性。总的来说，这些结果表明， AHR激活、胆固醇稳态和NAFLD进展之间的关系。这使我们 假设胆固醇稳态变化改变了对TCDD和相关化合物的敏感性 引起肝毒性和NAFLD发病机制。具体目标1将使用体外实验检查 AHR信号传导、HMGCR活性和中间代谢之间的联系。具体目标2将审查 在AHR期间，在存在和不存在辛伐他汀的情况下，TCDD对HMGCR活性的影响。 介导从脂肪变性进展为伴有纤维化的脂肪性肝炎。这些具体目标的结果将是 整合以阐明影响TCDD诱导的肝毒性和NAFLD的细胞特异性代谢变化 进展与项目1（Kaminski）和项目2（约翰逊）的合作将进一步表征该角色 的浸润免疫细胞群和TCDD对肝细胞线粒体和能量的影响。 这些研究还将确定处方的他汀类药物是否会增加肝毒性和NAFLD的风险 由于持续暴露于TCDD和相关化合物，目前，超过4000万 美国人每年都服用他汀类药物。因此，评估这一风险的重要性不容忽视。 言过其实，值得进一步调查。

PROJECT SUMMARY/ABSTRACT Hypercholesterolemia, obesity, non-alcoholic fatty liver disease (NAFLD), and diabetes have increased in the US population to epidemic proportions. Accumulating epidemiological evidence and rodent studies link environmental pollutants and dietary chemicals to NAFLD progression. Many environmental contaminants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds are ligands for the aryl hydrocarbon receptor (AhR). TCDD also disrupts the expression of genes involved in metabolism such as 3- Hydroxy-3-Methylglutaryl-Coenzyme A Reductase (HMGCR), the rate-limiting step in cholesterol biosynthesis. Interestingly, environmental exposure to TCDD and related compounds decrease serum cholesterol levels in humans which has been linked to metabolic dysfunction, hepatotoxicity and NAFLD progression. Preliminary studies also show that inhibition of HMGCR activity via statin co-treatment decreased TCDD-induced hepatosteatosis, but exacerbated TCDD-induced toxicity. Collectively, these results suggest a strong relationship between AHR activation, cholesterol homeostasis and NAFLD progression. This has led us to hypothesize that changes in cholesterol homeostasis alters sensitivity to TCDD and related compound elicited hepatotoxicity and NAFLD pathogenesis. Specific Aim 1 will use in vitro experiments examining the link between AHR signaling, HMGCR activity, and intermediate metabolism. Specific Aim 2 will examine the effects of TCDD on HMGCR activity in the absence and presence of simvastatin co-exposure, during AHR- mediated progression from steatosis to steatohepatitis with fibrosis. Results from these specific aims will be integrated to elucidate the cell-specific metabolic changes that affect TCDD-induced hepatotoxicity and NAFLD progression. Collaborations with Project 1 (Kaminski) and Project 2 (Johnson), will further characterize the role of infiltrating immune cell populations and the impact of TCDD on hepatocyte mitochondria and energetics. These studies will also determine if prescribed statin type drugs increase the risk of hepatotoxicity and NAFLD development due to persistent exposure to TCDD and related compounds. Currently, more than 40 million Americans are prescribed statins every year. Consequently, the importance of assessing this risk cannot be overstated, and warrants further investigation.