期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：2
页码：292-297
DOI：10.1073/pnas.1618605114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
