A MACROPHAGE ENDOGENOUS FACTOR THAT SUPPRESSES ANABOLISM

我们的目标是追踪和调查分子事件 这会引发感染的生化后遗症。其中一位临床医生 患有慢性感染或肿瘤的动物的特征是存在一种 分解代谢状态，可导致恶病质、休克和死亡。这个 这种现象的生化基础尚不清楚，但可能只有一次 触发是一种普遍的性质。为了深入了解 这一过程的机制，我们选择内毒素血症作为模型系统 并将组织培养技术应用于其研究。 体外培养的小鼠腹膜巨噬细胞条件培养液 内毒素被用作一种介质的来源，当添加到 培养、分化的3T3-L1细胞显著抑制其活性 脂蛋白脂肪酶、脂肪酸合成酶和乙酰辅酶A羧基酶。这 效果，至少在一定程度上是由于对其 综合。我们的目标是描述 介体与细胞相互作用，调节新陈代谢。我们计划 通过检查调解人对关键监管的影响来实现这一点 事件包括：胰岛素可刺激的两个核糖体的磷酸化 和细胞蛋白，通常是细胞蛋白的磷酸化，DNA KEY的甲基化、细胞激素反应和化学修饰 调节酶。使用纯化的介体，我们计划表征 它与细胞相互作用的机制，通过测试特定的 感受器。除了脂肪组织，我们怀疑介体可能 还能调节肝脏代谢。为此，我们将描述 介体对体外培养肝细胞的影响 对脂肪生成和糖异生的影响。 中介体构成了细胞之间通信系统的一部分 免疫系统和身体的能量储存组织。在……里面 对感染的反应，介体警告能量储存组织 需要能量来对抗入侵。目标细胞通过以下方式响应 从存储模式切换到供应模式。如果入侵的时间很短， 动物可以迅速恢复和补充商店，然而，如果 侵袭是慢性的，完全耗尽会导致恶病质和 死亡可能会导致死亡。 这些研究具有临床、诊断和药理学上的相关性 代表着朝着理解并可能改善的重要一步 传染病的新陈代谢后遗症。

It is our objective to pursue and investigation of the molecualr events that trigger the biochemical sequelae of infection. One of the clinical hallmarks of animals with chronic infections or tumors is the presence of a catabolic state which can proceed to cachexia, shock, and death. The biochemical basis for this phenomenon is not understood but presumably once triggered is of a universal nature. In order to gain insight into the mechanism of this process, we have selected endotoxemia as a model system and have applied tissue culture techniques to its investigation. Conditioned medium from cultured mouse peritoneal macrophages exposed to endotoxin is utilized as a source of a mediator that when added to cultured, differentiating 3T3-L1 cells markedly suppresses the activity of lipoprotein lipase, fatty acid synthetase and acetyl CoA carboxylase. This effect, at least in part, appears due to a specific effect on their synthesis. It is our objective to characterize the mechanism by which the mediator interacts with cells and regulates metabolism. We plan to accomplish this by examining the effect of the mediator on key regulatory events including; insulin stimulatable phosphorylation of both ribosomal and cellular protein, phosphorylation of cellular protein in general, DNA methylation, cellular hormonal response and chemical modification of key regulatory enzymes. Using purified mediator, we plan to characterize the mechanism by which it interacts with the cell by testing for specific receptors. In addition to adipose tissue, we suspect that the mediator may also regulate hepatic metabolism. To that end we will characterize the effect of the mediator on cultured hepatocytes specifically looking at its effect on lipogenesis and gluconeogenesis. The mediator constitutes part of a communication system between the cells of the immune system and the energy storage tissues of the body. In response to infection, the mediator warns energy storage tissues of the need for energy to combat the invasion. The target cells respond by switching from a storage to a supply mode. If the invasion is short, the animal can quickly recover and replenish the stores, however, if the invasion is of a chronic nature, complete depletion leading to cachexia and death can result. These studies have clinical, diagnostic and pharmacologic relevance and represent a significant step toward understanding and perhaps ameliorating the metabolic sequelae of infectious diseases.