The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin
The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin
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DOI：
10.1126/science.1120781
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发表时间：
2005-12-09
期刊：
影响因子：
56.9
通讯作者：
Cantley, LC
中科院分区：
文献类型：
--
作者：
Shaw, RJ;Lamia, KA;Cantley, LC
Peutz-Jegher综合征肿瘤抑制基因编码一种蛋白苏氨酸激酶LKB1，它能磷酸化并激活AMPK[腺苷一磷酸(AMP)激活的蛋白激酶]。成年小鼠肝脏中LKB1的缺失导致AMPK活性几乎完全丧失。LKB1功能丧失导致高血糖，糖异生和脂生基因表达增加。在LKB1缺陷的肝脏中，CREB(cAMP反应元件结合蛋白)的转录共激活因子TORC2被去磷酸化并进入细胞核，驱动过氧化物酶体增殖物激活受体-γ共激活因子1α(PGC-1α)的表达，进而推动糖异生。针对TORC2的腺病毒小发夹RNA(ShRNA)降低了肝脏LKB1缺失小鼠PGC-1α的表达，并使血糖水平正常化，表明TORC2是LKB1/AMPK信号在糖异生调节中的关键靶点。最后，我们表明，二甲双胍是最广泛使用的2型糖尿病治疗药物之一，它需要肝脏中的LKB1来降低血糖水平。
The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)-activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element-binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1 alpha expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 in the liver to lower blood glucose levels.