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Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis.

Citation
Mehta, M. B., et al. “Hepatic Protein Phosphatase 1 Regulatory Subunit 3B (Ppp1R3B) Promotes Hepatic Glycogen Synthesis And Thereby Regulates Fasting Energy Homeostasis.”. The Journal Of Biological Chemistry, pp. 10444-10454.
Center University of Pennsylvania
Author Minal B Mehta, Swapnil Shewale V, Raymond N Sequeira, John S Millar, Nicholas J Hand, Daniel J Rader
Keywords Alb-Cre, Ppp1r3b, Gluconeogenesis, glycogen, glycogen storage disease, glycogen synthase, glycolysis, liver
Abstract

Maintenance of whole-body glucose homeostasis is critical to glycemic function. Genetic variants mapping to chromosome 8p23.1 in genome-wide association studies have been linked to glycemic traits in humans. The gene of known function closest to the mapped region, (protein phosphatase 1 regulatory subunit 3B), encodes a protein (G) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic is associated with glycemic traits. We generated mice with either liver-specific deletion ( ) or liver-specific overexpression of The deletion significantly reduced glycogen synthase protein abundance, and the remaining protein was predominantly phosphorylated and inactive. As a consequence, glucose incorporation into hepatic glycogen was significantly impaired, total hepatic glycogen content was substantially decreased, and mice lacking hepatic had lower fasting plasma glucose than controls. The concomitant loss of liver glycogen impaired whole-body glucose homeostasis and increased hepatic expression of glycolytic enzymes in mice relative to controls in the postprandial state. Eight hours of fasting significantly increased the expression of two critical gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, above the levels in control livers. Conversely, the liver-specific overexpression of enhanced hepatic glycogen storage above that of controls and, as a result, delayed the onset of fasting-induced hypoglycemia. Moreover, mice overexpressing hepatic Ppp1r3b upon long-term fasting (12-36 h) were protected from blood ketone-body accumulation, unlike control and mice. These findings indicate a major role for in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis.

Year of Publication
2017
Journal
The Journal of biological chemistry
Volume
292
Issue
25
Number of Pages
10444-10454
Date Published
12/2017
ISSN Number
1083-351X
DOI
10.1074/jbc.M116.766329
Alternate Journal
J. Biol. Chem.
PMID
28473467
PMCID
PMC5481556
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