CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis
CITED2 links hormonal signaling to PGC-1α acetylation in the regulation of gluconeogenesis
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DOI：
10.1038/nm.2691
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发表时间：
2012-04-01
期刊：
影响因子：
82.9
通讯作者：
Kasuga, Masato
中科院分区：
文献类型：
--
作者：
Sakai, Mashito;Matsumoto, Michihiro;Kasuga, Masato
在禁食期间，诱导肝脏再生对于确保适当的能量稳态至关重要（1）。这种诱导在2型糖尿病中失调，导致空腹高血糖症的发展（2）。禁食期间代谢适应的激素和营养调节主要由转录辅激活因子过氧化物酶体增殖激活受体γ辅激活因子1 α（PGC-1 α）与各种其他转录调节因子共同介导（3-8）。尽管CITED 2（CBP和p300相互作用的反式激活因子，具有富含谷氨酸和天冬氨酸的COOH末端结构域2）与许多这些分子相互作用（9-11），但该蛋白在肝细胞生成调节中的作用以前是未知的。在这里，我们表明CITED 2是通过PGC-1 α调节肝脏再生所必需的。CITED 2的丰度在禁食小鼠的肝脏中增加，在培养的肝细胞中通过胰高血糖素-cAMP-蛋白激酶A（PKA）信号传导增加，并且2型糖尿病小鼠肝脏中CITED 2的量高于非糖尿病小鼠。CITED 2通过阻断其与乙酰转移酶氨基酸合成的一般控制5-样2（GCN 5）的相互作用来抑制PGC-1 α的乙酰化。随后下调PGC-1 α乙酰化导致其转录共激活活性的增加和致凋亡基因表达的增加。CITED 2与GCN 5的相互作用被胰岛素以依赖于磷酸肌醇3-激酶（PI 3 K）-胸腺瘤病毒原癌基因（Akt）信号传导的方式破坏。我们的研究结果表明，CITED 2作为胰高血糖素和胰岛素信号传导的转导子，在PGC-1 α活性的调节中发挥作用，PGC-1 α活性与胚胎发生的转录控制相关，并且这种功能是通过调节GCN 5依赖性PGC-1 α乙酰化介导的。我们还发现，肝脏CITED 2功能的丧失抑制了糖尿病小鼠的新生血管形成，这表明它是高血糖症的治疗靶点。
During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis(1). Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia(2). Hormonal and nutrient regulation of metabolic adaptation during fasting is mediated predominantly by the transcriptional coactivator peroxisome proliferative activated receptor gamma coactivator 1 alpha (PGC-1 alpha) in concert with various other transcriptional regulators(3-8). Although CITED2 (CBP- and p300-interacting transactivator with glutamic acid-and aspartic acid-rich COOH-terminal domain 2) interacts with many of these molecules(9-11), the role of this protein in the regulation of hepatic gluconeogenesis was previously unknown. Here we show that CITED2 is required for the regulation of hepatic gluconeogenesis through PGC-1 alpha. The abundance of CITED2 was increased in the livers of mice by fasting and in cultured hepatocytes by glucagon-cAMP-protein kinase A (PKA) signaling, and the amount of CITED2 in liver was higher in mice with type 2 diabetes than in non-diabetic mice. CITED2 inhibited the acetylation of PGC-1 alpha by blocking its interaction with the acetyltransferase general control of amino acid synthesis 5-like 2 (GCN5). The consequent downregulation of PGC-1 alpha acetylation resulted in an increase in its transcriptional coactivation activity and an increased expression of gluconeogenic genes. The interaction of CITED2 with GCN5 was disrupted by insulin in a manner that was dependent on phosphoinositide 3-kinase (PI3K)-thymoma viral proto-oncogene (Akt) signaling. Our results show that CITED2 functions as a transducer of glucagon and insulin signaling in the regulation of PGC-1 alpha activity that is associated with the transcriptional control of gluconeogenesis and that this function is mediated through the modulation of GCN5-dependent PGC-1 alpha acetylation. We also found that loss of hepatic CITED2 function suppresses gluconeogenesis in diabetic mice, suggesting it as a therapeutic target for hyperglycemia.