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Article: IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization

TitleIDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization
Authors
KeywordsTransamination
α-ketoglutarate
Liver
Isocitrate dehydrogenase 1
Gluconeogenesis
Issue Date2017
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2017, v. 114, n. 2, p. 292-297 How to Cite?
AbstractAlthough the enzymatic activity of isocitrate dehydrogenase 1 (IDH1) was defined decades ago, its functions in vivo are not yet fully understood. Cytosolic IDH1 converts isocitrate to a-ketoglutarate (a-KG), a key metabolite regulating nitrogen homeostasis in catabolic pathways. It was thought that IDH1 might enhance lipid biosynthesis in liver or adipose tissue by generating NADPH, but we show here that lipid contents are relatively unchanged in both IDH1-null mouse liver and IDH1-deficient HepG2 cells generated using the CRISPR-Cas9 system. Instead, we found that IDH1 is critical for liver amino acid (AA) utilization. Body weights of IDH1-null mice fed a high-protein diet (HPD) were abnormally low. After prolonged fasting, IDH1-null mice exhibited decreased blood glucose but elevated blood alanine and glycine compared with wildtype (WT) controls. Similarly, in IDH1-deficient HepG2 cells, glucose consumption was increased, but alanine utilization and levels of intracellular a-KG and glutamate were reduced. In IDH1-deficient primary hepatocytes, gluconeogenesis as well as production of ammonia and urea were decreased. In IDH1-deficient whole livers, expression levels of genes involved in AA metabolism were reduced, whereas those involved in gluconeogenesis were up-regulated. Thus, IDH1 is critical for AA utilization in vivo and its deficiency attenuates gluconeogenesis primarily by impairing a-KG-dependent transamination of glucogenic AAs such as alanine.
Persistent Identifierhttp://hdl.handle.net/10722/292990
ISSN
2020 Impact Factor: 11.205
2020 SCImago Journal Rankings: 5.011
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYe, Jing-
dc.contributor.authorGua, Yu-
dc.contributor.authorZhang, Feng-
dc.contributor.authorZhao, Yuanlin-
dc.contributor.authorYuan, Yuan-
dc.contributor.authorHao, Zhenyue-
dc.contributor.authorSheng, Yi-
dc.contributor.authorLi, Wanda Y.-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorCairns, Rob A.-
dc.contributor.authorMak, Tak W.-
dc.date.accessioned2020-11-17T14:57:38Z-
dc.date.available2020-11-17T14:57:38Z-
dc.date.issued2017-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2017, v. 114, n. 2, p. 292-297-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/292990-
dc.description.abstractAlthough the enzymatic activity of isocitrate dehydrogenase 1 (IDH1) was defined decades ago, its functions in vivo are not yet fully understood. Cytosolic IDH1 converts isocitrate to a-ketoglutarate (a-KG), a key metabolite regulating nitrogen homeostasis in catabolic pathways. It was thought that IDH1 might enhance lipid biosynthesis in liver or adipose tissue by generating NADPH, but we show here that lipid contents are relatively unchanged in both IDH1-null mouse liver and IDH1-deficient HepG2 cells generated using the CRISPR-Cas9 system. Instead, we found that IDH1 is critical for liver amino acid (AA) utilization. Body weights of IDH1-null mice fed a high-protein diet (HPD) were abnormally low. After prolonged fasting, IDH1-null mice exhibited decreased blood glucose but elevated blood alanine and glycine compared with wildtype (WT) controls. Similarly, in IDH1-deficient HepG2 cells, glucose consumption was increased, but alanine utilization and levels of intracellular a-KG and glutamate were reduced. In IDH1-deficient primary hepatocytes, gluconeogenesis as well as production of ammonia and urea were decreased. In IDH1-deficient whole livers, expression levels of genes involved in AA metabolism were reduced, whereas those involved in gluconeogenesis were up-regulated. Thus, IDH1 is critical for AA utilization in vivo and its deficiency attenuates gluconeogenesis primarily by impairing a-KG-dependent transamination of glucogenic AAs such as alanine.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectTransamination-
dc.subjectα-ketoglutarate-
dc.subjectLiver-
dc.subjectIsocitrate dehydrogenase 1-
dc.subjectGluconeogenesis-
dc.titleIDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1618605114-
dc.identifier.pmid28011762-
dc.identifier.pmcidPMC5240724-
dc.identifier.scopuseid_2-s2.0-85009259942-
dc.identifier.volume114-
dc.identifier.issue2-
dc.identifier.spage292-
dc.identifier.epage297-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000391439300041-
dc.identifier.issnl0027-8424-

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