Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation.
Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation.
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DOI：
10.1016/j.cmet.2010.02.002
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发表时间：
2010-03-03
期刊：
影响因子：
29
通讯作者：
Zhao JJ
中科院分区：
文献类型：
--
作者：
Sopasakis VR;Liu P;Suzuki R;Kondo T;Winnay J;Tran TT;Asano T;Smyth G;Sajan MP;Farese RV;Kahn CR;Zhao JJ
IA类磷脂酰肌醇3-激酶（PI3Ks）在胰岛素代谢途径中形成一个关键节点；然而，这种酶的不同同种异构体的确切作用仍然难以捉摸。通过组织特异性基因失活，我们证明PI3K的p110α催化亚基是肝脏中胰岛素代谢作用的关键介质。因此，肝脏中p110α的缺失导致胰岛素信号明显减弱，PIP3的产生减少，Akt的胰岛素激活丧失，这些缺陷不能通过p110β的过表达来弥补。结果，肝脏敲除p110α的小鼠表现出胰岛素敏感性降低、糖耐量受损、糖异生、低血脂和高瘦素血症增加。肝脏p110α缺失引起的糖尿病综合征对二甲双胍治疗无应答。综上所述，这些数据表明PI3K的p110α亚型在胰岛素信号传导和肝脏糖脂代谢控制中起着重要作用。
The class IA phosphatidylinsositol 3-kinases (PI3Ks) form a critical node in the insulin metabolic pathway; however, the precise roles of the different isoforms of this enzyme remain elusive. Using tissue-specific gene inactivation, we demonstrate that p110α catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110α in liver results in markedly blunted insulin signaling with decreased generation of PIP3 and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110β. As a result, mice with hepatic knockout of p110α display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110α in liver did not respond to metformin treatment. Together, these data indicate that the p110α isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism.
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