REGULATION OF APOLIPOPROTEIN CIII

载脂蛋白CIII是形成脂蛋白颗粒的十种载脂蛋白之一 负责体内胆固醇和甘油三酯的运输 尸体。载脂蛋白调节合成和分解代谢的功能 不同种类的脂蛋白，因此很重要 血浆胆固醇和甘油三酯水平的决定因素。高架 血脂是动脉粥样硬化的重要危险因素， 心脏病的主要原因。载脂蛋白CIII主要与 富含甘油三酯的脂蛋白颗粒和生理证据 提示它在调节血浆甘油三酯中起重要作用。 级别。最近对过量表达CIII的转基因小鼠的研究， 证明CIII产生率是血浆的重要决定因素 甘油三酯水平。这些结果提出了一种可能性，即 CIII基因的转录调控可能起到重要作用 在调节血浆甘油三酯水平方面。 有几条证据表明CIII基因在 对生理信号的反应也与生理信号的变化有关 脂蛋白水平。初步结果表明，有几个 已知对血浆甘油三酯有影响的细胞间信使 新陈代谢(调节细胞反应的糖皮质激素和细胞因子 至炎症)，在CIII转录活性后 肝细胞。此外，CIII启动子还包含几个转录 与基因诱导有关的调控元件 通过各种刺激来表达。综上所述，这些结果展示了 CIII基因表达受生理调节的可能性 信号，并且这种调节在调制中起着重要作用 血浆甘油三酯水平。拟议研究的总体目标 是了解调控载脂蛋白CIII基因的分子机制 表达，并阐明这一调控在 调节脂蛋白代谢。 具体目的是：1)识别生理信号(荷尔蒙 和细胞因子)在组织培养中调节CIII基因转录 细胞，2)表征转录调控元件和 参与CIII基因调控的蛋白质因子 通过细胞因子和激素的表达，以及3)分析 CIII基因的表达及其与脂蛋白代谢的关系 正常和转基因小鼠。从这些实验中产生的结果 将为CIII的潜在关键作用提供有价值的见解 血浆甘油三酯调节中的转录调控 水平，并将增加我们对生理信号如何 就像荷尔蒙和细胞因子一样，调节转录。

Apo CIII is one of ten apolipoproteins that form the lipoprotein particles responsible for transporting cholesterol and triglyceride throughout the body. Apolipoproteins function to regulate the synthesis and catabolism of the different classes of lipoproteins, and as such are important determinants of plasma cholesterol and triglyceride levels. Elevated plasma lipids are a significant risk factor for atherosclerosis, the leading cause of heart disease. Apo CIII is associated primarily with triglyceride rich lipoprotein particles, and physiological evidence indicates that it plays an important role in regulating plasma triglyceride levels. Recent studies with transgenic mice that over-express CIII, demonstrate that CIII production rate is an important determinant of plasma triglyceride levels. These results present the possibility that the transcriptional regulation of the CIII gene could play a significant role in modulating plasma triglyceride levels. Several lines of evidence suggest that the CIII gene is regulated in response to physiological signals that are also associated with changes in lipoprotein levels. Preliminary results demonstrate that several intercellular messengers known to have an effect on plasma triglyceride metabolism (glucocorticoids and cytokines that mediate cellular responses to inflammation), after CIII transcriptional activity in cultured hepatocytes. In addition, the CIII promoter contains several transcription regulatory elements that have been implicated in the induction of gene expression by a variety of stimuli. Taken together, these results present the possibility that CIII gene expression is regulated by physiological signals and that this regulation plays a significant role in the modulation of plasma triglyceride levels. The overall goal of the proposed research is to understand the molecular mechanisms that regulate apo CIII gene expression, and to elucidate the role that this regulation plays in modulating lipoprotein metabolism. The specific aims are to: 1) Identify physiological signals (hormones and cytokines) that modulate CIII gene transcription in tissue culture cells, 2) Characterize the transcriptional regulatory elements and protein factors that are responsible for the modulation of CIII gene expression by cytokines and hormones, and 3)Analyze the regulation of CIII gene expression and its relationship to lipoprotein metabolism in normal and transgenic mice. Results generated from these experiments will provide valuable insights into the potentially crucial role of CIII transcriptional regulation in the modulation of plasma triglyceride levels, and will increase our understanding of how physiological signals like hormones and cytokines modulate transcription.