IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization
IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization
复制标题
IDH1 缺乏会损害氨基酸的利用，从而减弱小鼠肝脏中的糖异生作用。
DOI：
10.1073/pnas.1618605114
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发表时间：
2017-01-10
影响因子：
11.1
通讯作者：
Mak, Tak W.
中科院分区：
文献类型：
--
作者：
Ye, Jing;Gu, Yu;Mak, Tak W.
虽然异柠檬酸脱氢酶1（IDH 1）的酶活性在几十年前就被定义，但其在体内的功能尚未完全了解。胞质IDH 1将异柠檬酸转化为α-酮戊二酸（α-KG），这是一种在分解代谢途径中调节氮稳态的关键代谢物。人们认为IDH 1可能通过产生NADPH来增强肝脏或脂肪组织中的脂质生物合成，但我们在这里表明，使用CRISPR-Cas9系统产生的IDH 1缺失小鼠肝脏和IDH 1缺陷型HepG 2细胞中的脂质含量相对不变。相反，我们发现IDH 1对肝脏氨基酸（AA）利用至关重要。喂食高蛋白饮食（HPD）的IDH 1缺失小鼠的体重异常低。在长时间禁食后，IDH 1-null小鼠与野生型（WT）对照组相比，血糖降低，但血液丙氨酸和甘氨酸升高。类似地，在IDH 1缺陷型HepG 2细胞中，葡萄糖消耗增加，但丙氨酸利用和细胞内α-KG和谷氨酸水平降低。在IDH 1缺陷的原代肝细胞中，异生以及氨和尿素的产生减少。在IDH 1缺陷的整个肝脏中，参与AA代谢的基因的表达水平降低，而参与再生的基因的表达水平上调。因此，IDH 1对于AA在体内的利用是关键的，并且其缺乏主要通过损害生糖AA如丙氨酸的α-KG依赖性转氨作用来减弱糖原合成。
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 alpha-ketoglutarate (alpha-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 alpha-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.