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专家访谈 基础研究 作者:G.H.Boden 来源:国际糖尿病 2011/6/17 17:33:00    加入收藏
内容概要:Guenther H.Boden 美国天普大学医学院医学部内分泌、糖尿病与代谢病科。其研究方向为碳水化合物与脂代谢

     Guenther H. Boden  美国天普大学医学院医学部内分泌、糖尿病与代谢病科。其研究方向为碳水化合物与脂代谢

      <International Diabetes>:  The prevailing presumption is that ER stress, oxidative stress and inflammation are all relevant to insulin resistance. What is the relationship among those three factors and specifically, is the relationship explained in the mechanism of their effect on diabetes?


    Dr Boden: Let me first explain what ER stress is. The endoplasmic reticulum is a tubular structure which is every living cell. One of its main actions is to recognize misfolded or unfolded proteins and then correct the misfolding or unfolding. This is very important because if it doesn’t happen, the proteins get out of the cell to their targets and severe disease will ensue and kill the organism. This is a life and death situation that needs to be corrected. Every cell makes zillions of proteins that have to be correctly folded in a tertiary form and if that doesn’t happen as I have explained, there will be problems. This is one of the main functions of the ER.

    Dr Boden:首先让我来解释一下ER应激是什么。内质网是每个活细胞中的一种管状结构。其主要作用之一就是识别错误折叠或未折叠蛋白质,并继而纠正这种错误折叠或未折叠。这是非常重要的,因为如果这未发生,蛋白质从细胞中出来进到其靶位置,严重疾病将会因而产生并杀伤有机体。这是一种需要加以纠正的生死攸关的状态。每个细胞都生成难以计数的必须以三维形式被正确折叠的蛋白质,如果未如我已经解释的那样发生,就会有问题。这是ER的主要功能之一。(内质网应激的定义

    As far as diabetologists are concerned, that did not create a lot of attention until around  2004 when there was a paper in Science by a group from Boston, the Hotamisligil group, which showed that there was ER stress in fat and in liver tissue of genetic- as well as diet-induced obese mice. Furthermore, they showed that that led to the development of insulin resistance in these animals. That is when, certainly I, became interested in that because the pathogenesis of insulin resistance is, of course, of utmost importance for diabetes and particularly type 2 diabetes. Then the question was if this happens in mice, what about humans? The first thing we did was obtain fat by subcutaneous biopsy from obese people and from lean people, but neither had diabetes. They are normal people except one group was obese and the other was not. We looked for markers of endoplasmic reticulum stress and sure enough we found plenty of it. We published this work in Diabetes in 2008 and the work was confirmed several months later by another group from the University of Kentucky. At that point, we were pretty sure that this ER stress situation doesn’t just happen in rodents but also in obese humans.

    对糖尿病专家而言,这并未引起很多关注,直至2004年左右当来自波士顿的Hotamisligil 团队在Science上发表了一篇文章时,该文章显示,在遗传以及饮食诱导的肥胖小鼠的脂肪和肝脏组织中存在ER应激。另外,他们证明,在这些动物中这导致胰岛素抵抗的发生。当然,那时我开始对此感兴趣,因为胰岛素抵抗的发病机制对糖尿病尤其是2型糖尿病来说当然最为重要。然后,问题是如果这在小鼠中发生,人类中是怎样?我们所做的第一件事情是通过从均无糖尿病的肥胖以及苗条者的皮下活检来获取脂肪。除了一组是肥胖,另一组不是之外,他们都是正常人。我们寻找内质网应激的标志物,果然发现了很多。我们于2008年在Diabetes上发表这一工作成果,该成果在几个月后被来自肯塔基大学的另一团队所证实。在当时,我们相当肯定,这种ER应激状态不仅仅发生于啮齿类动物中还发生在人类中。(ER应激的研究史

    The next question was how and why is it there? Why do obese people have ER stress? We are still working on that. There are many possibilities as the ER does a lot of things, for instance, it controls calcium metabolism. Firstly we looked at the question of, could it be the lack of oxygen or anoxia that we know occurs in the fat of obese people (simply because the expanded adipose tissue overextends its arterial supply). We also know that there is a low grade state of inflammation in the fat of obese people. Could it be that these two conditions could lead to ER stress? One thing that has been shown very clearly in cell cultures is that the redox state has great influence on ER stress because once you run short of oxygen there are going to be problems and one of the problems is ER stress.

    When there are unfolded proteins in any cell (in this case we are talking about fat cells and liver cells), the ER will recognize that, and so far there have been three sensors identified that can tell if there are unfolded or misfolded proteins. When you activate these sensors, there is a cascade of reactions at the end of which are three different actions. The first action is translation inhibition, which is the slowing down of protein synthesis. That makes good sense because the misfolded proteins make up a proportion of all manufactured proteins due to inevitable mistakes in synthesis and slowing down the process reduces the number of errors present and gives the cell time to repair the ones that are there. The second action initiated by the sensors is to make more chaperones. These are usually proteins that help in correctly folding misfolded proteins. The third action is, if all else fails, these proteins need to be destroyed as it is undesirable for them to escape the cell.

    I look at this in a very primitive way. You have an automobile factory with an assembly line. If people make mistakes, these errors move along the conveyor belt and the guy standing at the end decides that the best option is to slow the belt down to give the workers along the line time to fix the problems. If that doesn’t work, you put more people on the belt. If nothing works, you take the car off the assembly line and trash it because you don’t want it getting out to the dealers. So, there is ER stress in the fat of obese people and the process of the three actions to fix the ER stress I have just described is generally called the unfolded protein response (UPR). Why is the ER stress in the fat of obese people? Could the reason be that because there is anoxia and inflammation in adipose tissue and both are known to cause ER stress? 


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