Regulation of glucose homeostasis and lipid metabolism by PPP1R3G-mediated hepatic glycogenesis

Mol Endocrinol. 2014 Jan;28(1):116-26. doi: 10.1210/me.2013-1268. Epub 2013 Jan 1.

Abstract

Liver glycogen metabolism plays an important role in glucose homeostasis. Glycogen synthesis is mainly regulated by glycogen synthase that is dephosphorylated and activated by protein phosphatase 1 (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. In this study, we analyzed the physiological function of PPP1R3G using a mouse model with liver-specific overexpression of PPP1R3G. PPP1R3G overexpression increases hepatic glycogen accumulation, stimulates glycogen synthase activity, elevates fasting blood glucose level, 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. In addition, PPP1R3G overexpression is able to elevate glycogenesis in primary hepatocytes. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Blood Glucose
  • Cells, Cultured
  • Energy Metabolism
  • Glucose / metabolism*
  • Hepatocytes / metabolism
  • Homeostasis*
  • Insulin Resistance
  • Lipid Metabolism*
  • Liver / metabolism*
  • Liver Glycogen / biosynthesis*
  • Mice
  • Mice, Transgenic
  • Organ Specificity
  • Primary Cell Culture
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / metabolism*
  • Triglycerides / metabolism

Substances

  • Blood Glucose
  • Liver Glycogen
  • Triglycerides
  • PPP1R3G protein, mouse
  • Protein Phosphatase 1
  • Glucose

Grants and funding

This work was supported by research grants from National Natural Science Foundation of China (81021002, 81130077, and 81390353 to Y.C. and 30971660 to Y.P.), Ministry of Science and Technology of China (2012CB524900 to Y.C., 2010CB529506 to Y.P. and Z.W., and 2013BAI04B03 to Z.W.), and Chinese Academy of Sciences (KSCX2-EW-R-08 to Y.C.). Susie Chen is a summer student from University of Washington at Seattle, Washington, USA.