Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis
Autor: | John S. Millar, Swapnil V. Shewale, Raymond N. Sequeira, Daniel J. Rader, Minal B. Mehta, Nicholas J. Hand |
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Rok vydání: | 2017 |
Předmět: |
Blood Glucose
0301 basic medicine medicine.medical_specialty Phosphatase Biology Biochemistry Gene Expression Regulation Enzymologic Energy homeostasis Glycogen debranching enzyme Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Phosphatase 1 Internal medicine medicine Animals Glucose homeostasis Glycogen synthase Molecular Biology Mice Knockout Glycogen Gluconeogenesis Fasting Cell Biology Metabolism 030104 developmental biology Endocrinology Liver chemistry Organ Specificity 030220 oncology & carcinogenesis Glucose-6-Phosphatase biology.protein Phosphorylation Energy Metabolism Phosphoenolpyruvate carboxykinase Phosphoenolpyruvate Carboxykinase (ATP) |
Zdroj: | Journal of Biological Chemistry. 292:10444-10454 |
ISSN: | 0021-9258 |
Popis: | 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, PPP1R3B (protein phosphatase 1 regulatory subunit 3B), encodes a protein (GL) that regulates glycogen metabolism in the liver. We therefore sought to test the hypothesis that hepatic PPP1R3B is associated with glycemic traits. We generated mice with either liver-specific deletion (Ppp1r3bΔhep) or liver-specific overexpression of Ppp1r3b. The Ppp1r3b 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 Ppp1r3b 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 Ppp1r3bΔhep 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 Ppp1r3b 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 Ppp1r3bΔhep mice. These findings indicate a major role for Ppp1r3b in regulating hepatic glycogen stores and whole-body glucose/energy homeostasis. |
Databáze: | OpenAIRE |
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