Role of NDRG3 in the regulation of liver glycogen metabolism

Abstract

N-Myc downstream regulated gene 3 (NDRG3) is recently emerged in physiological or pathophysiological role through mediating growth signals. Unlike NDRG1, NDRG2 or NDRG4, understanding of physiological function for NDRG3, except for elucidation as a scaffolding protein regulating growth signaling in cancer, is not enough because of limitation of germ line animal model by embryonic lethality unlike other NDRG family via knockout model. Here, I vindicates that the liver-specific deletion of NDRG3 is involved in impairment of homeostasis including flux of glucose-glycogen and hepatomegaly, and hypoglycemia. Disruption of NDRG3 in mouse liver caused extravagant glycogen synthesis with attenuating mRNA expressions of PYGL and G6PT. Moreover, metabolome analysis elucidated that NDRG3-abolished mice were ruined in balance of adenosylmethionine (SAM) and SAH induced by attenuation of glycine N-methyltransferase (GNMT) governing conversion between two metabolites as primary source of a methyl donor. Suppression of GNMT induced alteration of methionine cycle, redirecting its flux towards branch pathways to upregulate several metabolites known to have hepatoprotective functions. In addition, abrogation of NDRG3 inhibited transcriptional level of GNMT, an essential enzyme of methionine cycle, accompanying suppressed transcription of G6PT and PYGL, a rate-limiting enzyme for glycogen degradation. To summarize, these data suggest that NDRG3 is required for homeostasis of liver cell metabolism upstream of the glucose–glycogen flux and methionine cycle and provide therapeutic possibility in relation to disorders of glycogen metabolism.