Glycogen storage disease phenotypes accompanying the perturbation of the methionine cycle in NDRG3-deficient mouse livers

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Title
Glycogen storage disease phenotypes accompanying the perturbation of the methionine cycle in NDRG3-deficient mouse livers
Author(s)
Hyun Ahm Sohn; Dong Chul Lee; Anna Park; Minho KangByoung-Ha YoonChul-Ho LeeYong-Hoon KimKyoung-Jin Oh; Cha Yeon Kim; Seong-Hwan Park; Han Koo; Hyoung-Chin KimWoon Kee Yoon; D S Lim; D Kim; Kyung Chan ParkYoung Il Yeom
Bibliographic Citation
Cells, vol. 11, no. 9, pp. 1536-1536
Publication Year
2022
Abstract
N-Myc downstream regulated gene 3 (NDRG3) is a unique pro-tumorigenic member among NDRG family genes, mediating growth signals. Here, we investigated the pathophysiological roles of NDRG3 in relation to cell metabolism by disrupting its functions in liver. Mice with liver-specific KO of NDRG3 (Ndrg3 LKO) exhibited glycogen storage disease (GSD) phenotypes including excessive hepatic glycogen accumulation, hypoglycemia, elevated liver triglyceride content, and several signs of liver injury. They suffered from impaired hepatic glucose homeostasis, due to the suppression of fasting-associated glycogenolysis and gluconeogenesis. Consistently, the expression of glycogen phosphorylase (PYGL) and glucose-6-phosphate transporter (G6PT) was significantly down-regulated in an Ndrg3 LKO-dependent manner. Transcriptomic and metabolomic analyses revealed that NDRG3 depletion significantly perturbed the methionine cycle, redirecting its flux towards branch pathways to upregulate several metabolites known to have hepatoprotective functions. Mechanistically, Ndrg3 LKO-dependent downregulation of glycine N-methyltransferase in the methionine cycle and the resultant elevation of the S-adenosylmethionine level appears to play a critical role in the restructuring of the methionine metabolism, eventually leading to the manifestation of GSD phenotypes in Ndrg3 LKO mice. Our results indicate that NDRG3 is required for the homeostasis of liver cell metabolism upstream of the glucose-glycogen flux and methionine cycle and suggest therapeutic values for regulating NDRG3 in disorders with malfunctions in these pathways.
Keyword
NDRG3Glycogen storage diseasePYGLMethionine cycleReprogrammingGNMT
ISSN
2073-4409
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/cells11091536
Type
Article
Appears in Collections:
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
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