Hepatic FOXA3 Links NAFLD to Atherosclerosis

项目摘要 项目概述：非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病之一 全球范围内，包括单纯性脂肪变性（NAFL）和非酒精性脂肪性肝炎（NASH）。NAFLD不仅 导致肝功能障碍，但也诱发肝外并发症。积累的数据表明， 心血管疾病（CVD）是NAFLD患者死亡的主要原因。到目前为止， 对NAFLD的发展知之甚少。此外，目前还不清楚NAFLD患者增加的原因 CAD的发病率。叉头框A3（FOXA 3）是一种转录因子，其在脂质或脂蛋白中的功能是 代谢尚未建立。我们的初步研究表明，肝脏FOXA 3的表达明显高于正常肝脏。 在普通代谢压力下减少。使用过表达或敲低方法，我们表明， 肝脏FOXA 3调节肝脏脂质和血浆HDL水平，以及HDL相关蛋白的表达。 proteins.这些新的数据表明，肝脏FOXA 3的失调可能在肝硬化中起重要作用。 NAFLD和CVD的发病机制。为了检验这一假设，我们将使用功能增益和功能损失 接近。完成拟议的研究可能会揭示肝脏FOXA 3在发展中的新作用。 NAFLD和动脉粥样硬化的关系，并可能为NAFLD作为危险因素的机制提供新的见解 对于CAD。

Project Summary Project Summary: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, which includes simple steatosis (NAFL) and non-alcoholic steatohepatitis (NASH). NAFLD not only causes liver dysfunctions but also induces extra-hepatic complications. Accumulating data indicate that cardiovascular disease (CVD) is the major cause of deaths in NAFLD patients. So far, the mechanism underlying the development of NAFLD is poorly understood. In addition, it is unclear why NAFLD patients have increased incidence of CAD. Forkhead box A3 (FOXA3) is a transcription factor whose function in lipid or lipoprotein metabolism has not been established. Our preliminary studies show that hepatic FOXA3 expression is markedly reduced under common metabolic stress. Using over-expression or knockdown approaches, we show that hepatic FOXA3 regulates hepatic lipid and plasma HDL levels as well as the expression of HDL-associated proteins. These novel data suggest that dysregulation of hepatic FOXA3 may play an important role in the pathogenesis of both NAFLD and CVD. To test this hypothesis, we will use both gain- and loss-of-function approaches. Completion of the proposed studies may uncover a novel role of hepatic FOXA3 in the development of NAFLD and atherosclerosis and may offer novel insights into the mechanism by which NAFLD is a risk factor for CAD.