Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt
Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt
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DOI：
10.1042/bj3490013
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发表时间：
2000-07-01
影响因子：
4.1
通讯作者：
Iynedjian, PB
中科院分区：
文献类型：
--
作者：
Fleischmann, M;Iynedjian, PB
胰岛素刺激肝脏中甾醇调节元件结合蛋白（SREBP） 1/ADD1基因的转录。用原代培养的肝细胞来描述胰岛素信号通路诱导SREBP1基因表达。phosphoinositide 3-kinase （PI 3-kinase）抑制剂wortmannin和LY 294002可以消除SREBP1 mRNA的胰岛素依赖性升高，而丝裂原激活蛋白激酶级联抑制剂PD 98059则没有作用。为了研究蛋白激酶B (PKB)/cAkt在PI 3激酶下游的作用，我们用一种编码PKB雌激素受体融合蛋白的腺病毒转导肝细胞。该重组蛋白的PKB活性在4-羟他莫昔芬（OHT）刺激的肝细胞中迅速激活，内源性PKB在胰岛素刺激的肝细胞中也迅速激活。将OHT添加到转导的肝细胞中导致SREBP1 mRNA的积累，其时间过程和强度与胰岛素在非转导细胞中的作用相似。在表达PKB活性未被OHT激活的重组蛋白突变形式的肝细胞中，SREBP1 mRNA的水平未因OHT而升高。因此，PKB的急性激活足以诱导SREBP1 mRNA在原代肝细胞中积累，并且可能是胰岛素诱导肝脏中SREBP1基因表达的主要信号事件。
Insulin stimulates the transcription of the sterol regulatory-element binding protein (SREBP) 1/ADD1 gene in liver. Hepatocytes in primary culture were used to delineate the insulin signalling pathway for induction of SREBP1 gene expression. The inhibitors of phosphoinositide 3-kinase (PI 3-kinase), wortmannin and LY 294002, abolished the insulin-dependent increase in SREBP1 mRNA, whereas the inhibitor of the mitogen-activated protein kinase cascade, PD 98059, was without effect. To investigate the role of protein kinase B (PKB)/cAkt downstream of PI 3-kinase, hepatocytes were transduced with an adenovirus encoding a PKB oestrogen receptor fusion protein. The PKB activity of this recombinant protein was rapidly activated in hepatocytes challenged with 4-hydroxytamoxifen (OHT), as was endogenous PKB in hepatocytes challenged with insulin. The addition of OHT to transduced hepatocytes resulted in accumulation of SREBP1 mRNA, with a time-course and magnitude similar to the effect of insulin in non-transduced cells. The level of SREBP1 mRNA was not increased by OHT in hepatocytes expressing a mutant form of the recombinant protein whose PKB activity was not activated by OHT. Thus acute activation of PKB is sufficient to induce SREBP1 mRNA accumulation in primary hepatocytes, and might be the major signalling event by which insulin induces SREBP1 gene expression in the liver.