Hepatic cytokine-inducible SH2-containing protein (CISH) regulates gluconeogenesis via cAMP-responsive element binding protein (CREB)
Hepatic cytokine-inducible SH2-containing protein (CISH) regulates gluconeogenesis via cAMP-responsive element binding protein (CREB)
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肝细胞因子诱导的 SH2 蛋白 (CISH) 通过 cAMP 反应元件结合蛋白 (CREB) 调节糖异生
DOI：
10.1096/fj.202200870r
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发表时间：
2022-10-01
期刊：
影响因子：
4.8
通讯作者：
Guo，Feifan
中科院分区：
文献类型：
--
作者：
Xiao，Fei;Deng，Jiali;Guo，Feifan
血管生成障碍是导致2型糖尿病患者高血糖的关键因素。CISH是细胞因子信号转导抑制蛋白（suppressors of cytokine signaling，SOCS）家族的重要成员，其生理功能已被广泛报道，但其在肝脏肿瘤发生中的作用尚不清楚。在本研究中，我们观察到禁食野生型（WT）小鼠的肝脏CISH表达降低。CISH的过表达降低小鼠原代肝细胞中葡萄糖的产生，而CISH的沉默具有相反的效果。此外，腺病毒介导的肝脏CISH过表达可改善WT和瘦素受体缺陷型糖尿病（db/db）小鼠的葡萄糖耐量并减少糖异生。相反，腺病毒介导的肝CISH敲低会损害WT小鼠的葡萄糖耐量并增加胚胎发生。我们还产生了肝脏特异性CISH敲除（LV-CISH KO）小鼠，并发现这些小鼠在葡萄糖耐量和造血方面与注射了敲低CISH表达的腺病毒的小鼠具有相似的表型。从机制上讲，我们发现CISH过表达减少，CISH敲低增加了葡萄糖-6-磷酸酶（G6 β）和磷酸烯醇式丙酮酸羧激酶1（PEPCK）的mRNA和蛋白水平，这两种酶在体外和体内参与了胚胎发生。此外，我们发现cAMP反应元件结合蛋白1（CREB）的磷酸化是CISH调控细胞新生所必需的，CREB是G6蛋白酶和Pepck的转录因子。总之，这项研究确定了肝CISH作为一个重要的调节器的胚胎发生。我们的研究结果还为SOCS蛋白家族的代谢功能和糖尿病治疗的潜在靶点提供了重要的见解。
Impairment of gluconeogenesis is a key factor responsible for hyperglycemia in patients with type 2 diabetes. As an important member of the suppressors of cytokine signaling (SOCS) protein family, many physiological functions of cytokine‐inducible SH2‐containing protein (CISH) have been described; however, the role of hepatic CISH in gluconeogenesis is poorly understood. In the present study, we observed that hepatic CISH expression was reduced in fasted wild‐type (WT) mice. Overexpression of CISH decreased glucose production in mouse primary hepatocytes, while silencing of CISH had the opposite effects. In addition, adenovirus‐mediated hepatic CISH overexpression resulted in improved glucose tolerance and decreased gluconeogenesis in WT and leptin receptor‐deficient diabetic (db/db) mice. In contrast, adenovirus‐mediated hepatic CISH knockdown impaired glucose tolerance and increased gluconeogenesis in WT mice. We also generated liver‐specific CISH knockout (LV‐CISH KO) mice and discovered that these mice had a similar phenotype in glucose tolerance and gluconeogenesis as mice injected with adenoviruses that knockdown CISH expression. Mechanistically, we found that CISH overexpression decreased and CISH knockdown increased the mRNA and protein levels of glucose‐6‐phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase 1 (PEPCK), two key enzymes involved in gluconeogenesis, in vitro, and in vivo. Moreover, we discovered that the phosphorylation of cAMP‐responsive element binding protein 1 (CREB), a transcription factor ofG6paseandPepck, was required for regulating gluconeogenesis by CISH. Taken together, this study identifies hepatic CISH as an important regulator of gluconeogenesis. Our results also provide important insights into the metabolic functions of the SOCS protein family and the potential targets for the treatment of diabetes.