Hepatic FOXA3 Links NAFLD to Atherosclerosis

项目摘要 项目摘要：非酒精性脂肪性肝病是最常见的慢性肝病之一。 其中包括单纯性脂肪变性(NAFL)和非酒精性脂肪性肝炎(NASH)。NAFLD不仅 会导致肝功能障碍，但也会导致肝外并发症。越来越多的数据表明， 心血管疾病(CVD)是NAFLD患者死亡的主要原因。到目前为止，潜在的机制 对非酒精性脂肪肝的发展了解甚少。此外，非酒精性脂肪肝患者增加的原因尚不清楚 冠心病的发病率。叉头盒A3(Forkhead box A3，FOXA3)是一种转录因子，其在脂类或脂蛋白中起作用 新陈代谢尚未建立起来。我们的初步研究表明，肝脏FOXA3的表达显著 在普通代谢压力下减少。使用过度表达或击倒的方法，我们证明了 肝脏FOXA3调节肝脏脂质和血浆高密度脂蛋白水平及高密度脂蛋白相关蛋白的表达 蛋白质。这些新的数据表明，肝脏FOXA3的异常调节可能在 NAFLD和CVD的共同发病机制。为了检验这一假设，我们将同时使用增益函数和损耗函数 接近了。拟议研究的完成可能会揭示肝脏FOXA3在发育中的一个新角色 NAFLD与动脉粥样硬化的关系，并可能为NAFLD成为危险因素的机制提供新的见解 用于计算机辅助设计。

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.