We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers.
- Authors
Sohn, Hyun Ahm; Lee, Dong Chul; Park, Anna; Kang, Minho; Yoon, Byoung-Ha; Lee, Chul-Ho; Kim, Yong-Hoon; Oh, Kyoung-Jin; Kim, Cha Yeon; Park, Seong-Hwan; Koo, Han; Kim, Hyoung-Chin; Yoon, Won Kee; Lim, Dae-Sik; Kim, Daesoo; Park, Kyung Chan; Yeom, Young Il
- 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.
- Subjects
GLYCOGEN storage disease; METHIONINE; GLYCOGEN phosphorylase; PHENOTYPES; METHIONINE metabolism; LIVER cells
- Publication
Cells (2073-4409), 2022, Vol 11, Issue 9, pN.PAG
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells11091536