Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Diabetes. 2011 May;60(5):1435-45. doi: 10.2337/db10-1663. Epub 2011 Apr 6.
Most animals experience fasting-feeding cycles throughout their lives. It is well known that the liver plays a central role in regulating glycogen metabolism. However, how hepatic glycogenesis is coordinated with the fasting-feeding cycle to control postprandial glucose homeostasis remains largely unknown. This study determines the molecular mechanism underlying the coupling of hepatic glycogenesis with the fasting-feeding cycle.
Through a series of molecular, cellular, and animal studies, we investigated how PPP1R3G, a glycogen-targeting regulatory subunit of protein phosphatase 1 (PP1), is implicated in regulating hepatic glycogenesis and glucose homeostasis in a manner tightly orchestrated with the fasting-feeding cycle.
PPP1R3G in the liver is upregulated during fasting and downregulated after feeding. PPP1R3G associates with glycogen pellet, interacts with the catalytic subunit of PP1, and regulates glycogen synthase (GS) activity. Fasting glucose level is reduced when PPP1R3G is overexpressed in the liver. Hepatic knockdown of PPP1R3G reduces postprandial elevation of GS activity, decreases postprandial accumulation of liver glycogen, and decelerates postprandial clearance of blood glucose. Other glycogen-targeting regulatory subunits of PP1, such as PPP1R3B, PPP1R3C, and PPP1R3D, are downregulated by fasting and increased by feeding in the liver.
We propose that the opposite expression pattern of PPP1R3G versus other PP1 regulatory subunits comprise an intricate regulatory machinery to control hepatic glycogenesis during the fasting-feeding cycle. Because of its unique expression pattern, PPP1R3G plays a major role to control postprandial glucose homeostasis during the fasting-feeding transition via its regulation on liver glycogenesis.
大多数动物在其一生中都会经历禁食-进食循环。众所周知，肝脏在调节糖原代谢中起着核心作用。然而，肝糖原生成如何与禁食-进食循环协调，以控制餐后血糖稳态，在很大程度上仍不清楚。本研究确定了将肝糖原生成与禁食-进食循环偶联的分子机制。
通过一系列分子、细胞和动物研究，我们研究了糖原靶向蛋白磷酸酶 1（PP1）调节亚基 PPP1R3G 如何在与禁食-进食循环紧密协调的方式下调节肝糖原生成和血糖稳态。
肝脏中的 PPP1R3G 在禁食期间上调，在进食后下调。PPP1R3G 与糖原颗粒结合，与 PP1 的催化亚基相互作用，并调节糖原合酶（GS）活性。当 PPP1R3G 在肝脏中过表达时，空腹血糖水平降低。肝 PPP1R3G 敲低可降低餐后 GS 活性升高，减少餐后肝糖原积累，并减缓餐后血糖清除。其他糖原靶向 PP1 调节亚基，如 PPP1R3B、PPP1R3C 和 PPP1R3D，在肝脏中通过禁食下调，通过进食上调。
我们提出，PPP1R3G 与其他 PP1 调节亚基的相反表达模式构成了一种复杂的调节机制，以控制禁食-进食循环期间的肝糖原生成。由于其独特的表达模式，PPP1R3G 通过其对肝糖原生成的调节，在禁食-进食转换期间发挥主要作用来控制餐后血糖稳态。
