Glycogen-targeting subunits and glucokinase differentially affect pathways of glycogen metabolism and their regulation in hepatocytes

Ruojing Yang, Liwei Cao, Rosa Gasa, Matthew J. Brady, A. Dean Sherry, Christopher B. Newgard

Research output: Contribution to journalArticle

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Abstract

Overexpression of the glucose-phosphorylating enzyme glucokinase (GK) or members of the family of glycogen-targeting subunits of protein phosphatase-1 increases hepatic glucose disposal and glycogen synthesis. This study was undertaken to evaluate the functional properties of a novel, truncated glycogen-targeting subunit derived from the skeletal muscle isoform GM/RGI and to compare pathways of glycogen metabolism and their regulation in cells with overexpressed targeting subunits and GK. When overexpressed in hepatocytes, truncated GM/RGI (GMΔC) was approximately twice as potent as full-length GM/RGI in stimulation of glycogen synthesis, but clearly less potent than GK or two other native glycogen-targeting subunits, GL and PTG. We also found that cells with overexpressed GMΔC are unique in that glycogen was efficiently degraded in response to lowering of media glucose concentrations, stimulation with forskolin, or a combination of both maneuvers, whereas cells with overexpressed GL, PTG, or GK exhibited impairment in one or both of these glycogenolytic signaling pathways. 2H NMR analysis of purified glycogen revealed that hepatocytes with overexpressed GK synthesized a larger portion of their glycogen from triose phosphates and a smaller portion from tricarboxylic acid cycle intermediates than cells with overexpressed glycogen-targeting subunits. Additional evidence for activation of distinct pathways of glycogen synthesis by GK and targeting subunits is provided by the additive effect of co-overexpression of the two types of proteins upon glycogen synthesis and a much larger stimulation of glucose utilization, glucose transport, and lactate production elicited by GK. We conclude that overexpression of the novel targeting subunit GMΔC confers unique regulation of glycogen metabolism. Furthermore, targeting subunits and GK stimulate glycogen synthesis by distinct pathways.

Original languageEnglish (US)
Pages (from-to)1514-1523
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number2
DOIs
StatePublished - Jan 11 2002

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ASJC Scopus subject areas

  • Biochemistry

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