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

项目摘要/摘要 高胆固醇血症、肥胖、非酒精性脂肪性肝病(NAFLD)和糖尿病在 美国人口达到流行病的比例。积累流行病学证据与啮齿动物研究的联系 环境污染物和饮食化学物质对NAFLD进展的影响。很多环境污染物， 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 烃受体(AhR)。TCDD还干扰新陈代谢相关基因的表达，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，环境中暴露于TCDD和相关化合物可降低 这与代谢功能障碍、肝毒性和非酒精性脂肪肝进展有关。初步 研究还表明，通过他汀类药物共同处理抑制HMGCR活性可以减少TCDD诱导的 肝脏骨质疏松症，但加剧了TCDD的毒性。总体而言，这些结果表明， AHR激活、胆固醇稳态与NAFLD进展的关系这让我们找到了 假设胆固醇稳态的改变改变了对TCDD及相关化合物的敏感性 诱发肝毒性和NAFLD的发病机制。特定目标1将使用体外实验来检验 AHR信号、HMGCR活性和中间代谢之间的联系。《特定目标2》将考察 TCDD在无辛伐他汀联合暴露和联合辛伐他汀存在时对AHR-HMGCR活性的影响 调节从脂肪变性到脂肪性肝炎伴纤维化的进展。这些具体目标的结果将是 综合阐明影响TCDD诱导的肝毒性和NAFLD的细胞特异性代谢变化 进步。与项目1(Kaminski)和项目2(Johnson)的合作将进一步确定该角色的特征 以及TCDD对肝细胞线粒体和能量学的影响。 这些研究还将确定开出的他汀类药物是否会增加肝毒性和非酒精性脂肪肝的风险。 由于持续接触TCDD和相关化合物而发生的疾病。目前，有4000多万 美国人每年都会服用他汀类药物。因此，评估这一风险的重要性不能 言过其实了，需要进一步调查。

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.