PPP1R3G对糖脂代谢的功能研究
文献类型：学位论文
| 作者 | 张永贤 |
| 学位类别 | 博士 |
| 答辩日期 | 2014-05 |
| 授予单位 | 中国科学院上海生命科学研究院营养科学研究所 |
| 授予地点 | 中国科学院上海生命科学研究院 |
| 导师 | 陈雁 |
| 关键词 | PPP1R3G 肝糖原合成 糖原合成酶 肝脂代谢 胰岛素敏感性 |
| 其他题名 | Characterizing role of PPP1R3G in glycogen and lipid metabolism |
| 学位专业 | 生物化学与分子生物学 |
| 中文摘要 | 肝脏中糖原的代谢对血糖稳态的调控起着至关重要的作用。进食时，血糖浓度升高，胰岛素通过增加外周组织对葡萄糖的吸收和减少肝脏葡萄糖异生等方式来恢复餐后血糖，部分葡萄糖被肝脏吸收后，除了提供机体正常代谢所需的能量外，剩余的将以糖原的形式储存起来。而在饥饿时，血糖浓度缓慢下降，肝脏中的糖原被分解为葡萄糖，供机体行使基本的生理功能。肝脏是血糖的感受器，在维持血糖的平衡中起着重要作用。糖原合成和分解的关键酶是糖原合成酶和糖原磷酸化酶，它们在蛋白磷脂酶1（PP1）和糖原定位亚基（G亚基）作用下发生去磷酸化从而影响酶的活性。根据基因序列比对，推测哺乳类动物有7个G亚基，这些亚基在不同组织器官中影响糖原的合成。最近研究报道了蛋白磷脂酶1 的一个新的糖原定位亚基-PPP1R3G，该亚基的表达受饥饿-进食循环的调节，而且可能在维持餐后血糖平衡上发挥了重要作用。 为了深入探讨了PPP1R3G蛋白在糖脂代谢中的生理功能，我们构建了PPP1R3G肝脏特异性转基因小鼠和全身性敲除小鼠。在转基因小鼠的模型中，我们发现PPP1R3G转基因小鼠肝糖原含量明显增加，同时能够加快餐后血糖的清除。此外，PPP1R3G转基因小鼠的体脂成分减少，血液中的甘油三酯含量降低，肝脏中甘油三酯成分减少，同时能够缓解饥饿诱导产生的脂肪肝。若将肝脏特异性表达PPP1R3G蛋白的糖原结合区域删除掉之后，上述的现象将会消失。因此，这一研究不但表明PPP1R3G对糖稳态平衡的具有重要功能，并且提示肝脏糖原代谢与机体脂肪代谢以及脂肪肝形成密切关联。在PPP1R3G KO小鼠模型中，我们发现高脂饮食情况下，PPP1R3G KO小鼠体重减轻、脂肪减少、胰岛素敏感性得到改善。这预示着其他组织的PPP1R3G蛋白对于糖脂稳态平衡发挥了不同的生理功能。 |
| 索取号 | D2014-095 |
| 英文摘要 | Liver glycogen metabolism plays an important role in glucose homeostasis. Upon feeding, the rise of blood glucose level is reduced by increasing glucose uptake in peripheral tissues, mainly regulated by blood glucose concentration and insulin/glucagon ratio. Dysregulation in blood glucose homeostasis is associated with many disorders such as diabetes and cardiovascular diseases. Liver is actively involved in removal of postprandial blood glucose via glycogen synthesis. Glycogen synthesis is mainly regulated by glycogen synthase that is dephosphorylated and activated by protein phosphatase1 (PP1) in combination with glycogen-targeting subunits or G subunits. There are seven G subunits (PPP1R3A to G) that control glycogenesis in different organs. PPP1R3G is a recently discovered G subunit whose expression is changed along the fasting-feeding cycle and is proposed to play a role in postprandial glucose homeostasis. Here we analyzed the physiological function of PPP1R3G using mouse models with liver-specific overexpression of PPP1R3G and whole body knock-out of PPP1R3G. PPP1R3G overexpression increases hepatic glycogen accumulation, stimulates glycogen synthase activity, and accelerates postprandial blood glucose clearance. In addition, the transgenic mice have a reduced fat composition, together with decreased hepatic triglyceride level. Fasting-induced hepatic steatosis is relieved by PPP1R3G overexpression. The glycogen-binding domain is indispensable for the physiological activities of PPP1R3G on glucose metabolism and triglyceride accumulation in the liver. Cumulatively, these data indicate that PPP1R3G plays a critical role in postprandial glucose homeostasis and liver triglyceride metabolism via its regulation on hepatic glycogenesis. Using the mouse model of PPP1R3G knockout, we found that PPP1R3G-deleted mice had reduced body weight, lower fat composition and improved insulin sensitivity under high-fat diet, suggesting the novel physiology functions of PPP1R3G in different tissues in the regulation of glucose and lipid metabolism. |
| 语种 | 中文 |
| 源URL | [http://202.127.25.144/handle/331004/107]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所_信号转导与营养相关疾病研究组 |
| 推荐引用方式 GB/T 7714 | 张永贤. PPP1R3G对糖脂代谢的功能研究[D]. 中国科学院上海生命科学研究院. 中国科学院上海生命科学研究院营养科学研究所. 2014. |
入库方式： OAI收割
来源：上海营养与健康研究所
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