Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers
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...
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| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/9/1536 |
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| author | Hyun Ahm Sohn Dong Chul Lee Anna Park Minho Kang Byoung-Ha Yoon Chul-Ho Lee Yong-Hoon Kim Kyoung-Jin Oh Cha Yeon Kim Seong-Hwan Park Han Koo Hyoung-Chin Kim Won Kee Yoon Dae-Sik Lim Daesoo Kim Kyung Chan Park Young Il Yeom |
| author_facet | Hyun Ahm Sohn Dong Chul Lee Anna Park Minho Kang Byoung-Ha Yoon Chul-Ho Lee Yong-Hoon Kim Kyoung-Jin Oh Cha Yeon Kim Seong-Hwan Park Han Koo Hyoung-Chin Kim Won Kee Yoon Dae-Sik Lim Daesoo Kim Kyung Chan Park Young Il Yeom |
| author_sort | Hyun Ahm Sohn |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:15:49Z |
| format | Article |
| id | doaj.art-3ef6680da9b94c32ab9d782cf9fc5cea |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:15:49Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3ef6680da9b94c32ab9d782cf9fc5cea2023-11-23T08:00:40ZengMDPI AGCells2073-44092022-05-01119153610.3390/cells11091536Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse LiversHyun Ahm Sohn0Dong Chul Lee1Anna Park2Minho Kang3Byoung-Ha Yoon4Chul-Ho Lee5Yong-Hoon Kim6Kyoung-Jin Oh7Cha Yeon Kim8Seong-Hwan Park9Han Koo10Hyoung-Chin Kim11Won Kee Yoon12Dae-Sik Lim13Daesoo Kim14Kyung Chan Park15Young Il Yeom16Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, KoreaPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaKorea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, KoreaLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, KoreaDepartment of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, KoreaDepartment of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, KoreaPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaN-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.https://www.mdpi.com/2073-4409/11/9/1536NDRG3glycogen storage diseasePYGLmethionine cyclereprogrammingGNMT |
| spellingShingle | Hyun Ahm Sohn Dong Chul Lee Anna Park Minho Kang Byoung-Ha Yoon Chul-Ho Lee Yong-Hoon Kim Kyoung-Jin Oh Cha Yeon Kim Seong-Hwan Park Han Koo Hyoung-Chin Kim Won Kee Yoon Dae-Sik Lim Daesoo Kim Kyung Chan Park Young Il Yeom Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers Cells NDRG3 glycogen storage disease PYGL methionine cycle reprogramming GNMT |
| title | Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers |
| title_full | Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers |
| title_fullStr | Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers |
| title_full_unstemmed | Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers |
| title_short | Glycogen Storage Disease Phenotypes Accompanying the Perturbation of the Methionine Cycle in NDRG3-Deficient Mouse Livers |
| title_sort | glycogen storage disease phenotypes accompanying the perturbation of the methionine cycle in ndrg3 deficient mouse livers |
| topic | NDRG3 glycogen storage disease PYGL methionine cycle reprogramming GNMT |
| url | https://www.mdpi.com/2073-4409/11/9/1536 |
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