title: IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization.
abstract: Although 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 α-ketoglutarate (α-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 wild-type (WT) controls. Similarly, in IDH1-deficient HepG2 cells, glucose consumption was increased, but alanine utilization and levels of intracellular α-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 α-KG-dependent transamination of glucogenic AAs such as alanine.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1; tmak@uhnres.utoronto.ca yejing@fmmu.edu.cn.|Department of Pathology and Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ye
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.|Department of Pathology and Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Pathology and Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
authors.forename: Wanda Y
authors.initials: WY
authors.lastname: Li
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Cairns
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1; tmak@uhnres.utoronto.ca yejing@fmmu.edu.cn.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D005215:Fasting / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D007656:Ketoglutaric Acids; D018698:Glutamic Acid; D007521:Isocitrate Dehydrogenase; D005947:Glucose
keywords: gluconeogenesis; isocitrate dehydrogenase 1; liver; transamination; α-ketoglutarate