Fasting-Induced Protein Phosphatase 1 Regulatory Subunit Contributes to Postprandial Blood Glucose Homeostasis via Regulation of Hepatic Glycogenesis

Abstract

OBJECTIVEMost 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.RESEARCH DESIGN AND METHODSThrough 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.RESULTSPPP1R3G 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.CONCLUSIONSWe 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.

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

“…4B), or food intake (Fig. 4C), which was consistent with the notion that animal models with enhanced glycogen synthesis reveal little change in body weight (15,19,20,46).…”

Ethanol-induced hepatic steatosis is modulated by glycogen level in the liver

“…According to the GenBank database, there are seven genes encoding G subunits (PPP1R3A to PPP1R3G), all of which possess a PP1-binding domain and a glycogen-binding domain ( 14 ). Recent studies in our laboratory indicate that PPP1R3G is changed along the fasting-feeding cycle and plays a critical role in postprandial glucose homeostasis ( 15 ). In addition, we found that PPP1R3G overexpression in the liver can impact on liver triglyceride metabolism via its regulation on hepatic glycogenesis ( 16 ).…”

“…The antibodies used in the assay were as follows: anti-tubulin and ␤ -actin antibodies from Sigma-Aldrich; anti-green fl uorescence protein (GFP) and anti-SREBP-1 antibodies from Santa Cruz Biotechnology (Santa Cruz, CA); anti-FAS antibody from BD Pharmingen (San Diego, CA). The anti-PPP1R3G antibody was generated in our laboratory as previous reported ( 15 ).…”

Obese Mice Fed a Diet Supplemented with Enzyme-Treated Wheat Bran Display Marked Shifts in the Liver Metabolome Concurrent with Altered Gut Bacteria

“…However, not all gene expression differences were consistent with a fasted phenotype. The glycogen-targeting regulatory subunits of protein phosphatases, Ppp1r3b and Ppp1r3c, were increased in the ETWB group; these transcripts have been previously reported to increase in the liver during feeding and to decrease during feed deprivation (64).…”