Hepatic Leptin Signaling Improves Hyperglycemia by Stimulating MAPK Phosphatase-3 Protein Degradation via STAT3.
Hepatic Leptin Signaling Improves Hyperglycemia by Stimulating MAPK Phosphatase-3 Protein Degradation via STAT3.
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肝脏瘦素信号传导通过 STAT3 刺激 MAPK 磷酸酶 3 蛋白降解来改善高血糖
DOI：
10.1016/j.jcmgh.2022.07.010
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发表时间：
2022
影响因子：
7.2
通讯作者：
Feng, Bin
中科院分区：
文献类型：
--
作者：
Huang, Xiaohua;He, Qin;Zhu, Heng;Fang, Zhengfeng;Che, Lianqiang;Lin, Yan;Xu, Shengyu;Zhuo, Yong;Hua, Lun;Wang, Jianping;Zou, Yuanfeng;Huang, Chao;Li, Lixia;Xu, Haiyan;Wu, De;Feng, Bin
肥胖相关的高血糖症，伴随肝脏胰岛素抵抗，已成为一种流行病。据报道，中枢神经瘦素信号传导可改善高血糖。本研究的目的是探讨肝脏瘦素信号转导在控制高血糖中的作用。首先，在原代小鼠肝细胞和肝癌细胞中研究了瘦素信号传导对肿瘤发生的影响。第二，在过度表达肝脏OBRb的肥胖小鼠中分析葡萄糖耐量、胰岛素耐量、血糖水平和肝脏促血管生成基因表达。第三，在肝细胞和小鼠肝脏中分析丝裂原活化蛋白激酶磷酸酶（MKP）-3的表达、信号转导和转录激活因子（STAT）3的磷酸化水平以及细胞外调节蛋白激酶（ERK）。第四，分析了MKP-3在肝脏瘦素信号转导调节肝脏新生中的作用。最后，分析了ERK和STAT 3在瘦素信号调节MKP-3蛋白中的作用。肝脏瘦素信号的激活抑制了肝细胞和肥胖小鼠肝脏的新生血管形成，并改善了肥胖小鼠的高血糖、胰岛素耐受和葡萄糖耐受。在肝细胞和小鼠肝脏中，瘦素信号降低了可以促进胚胎发生的MKP-3的蛋白水平。Mkp-3缺乏可消除肝脏瘦素信号对肝细胞内新生血管形成的抑制作用。STAT 3降低了MKP-3蛋白水平，而STAT 3的失活消除了瘦素信号对肝细胞中MKP-3蛋白水平降低的作用。STAT 3可与MKP-3和磷酸化ERK 1/2联合收割机，诱导MKP-3降解，瘦素信号可促进STAT 3与MKP-3的结合。肝脏瘦素信号至少部分地通过STAT 3增强的MKP-3和ERK 1/2的组合降低MKP-3蛋白水平来抑制肝细胞再生。
Obesity-related hyperglycemia, with hepatic insulin resistance, has become an epidemic disease. Central neural leptin signaling was reported to improve hyperglycemia. The aim of this study was to investigate the effect of hepatic leptin signaling on controlling hyperglycemia. First, the effect of leptin signaling on gluconeogenesis was investigated in primary mouse hepatocytes and hepatoma cells. Second, glucose tolerance, insulin tolerance, blood glucose levels, and hepatic gluconeogenic gene expression were analyzed in obese mice overexpressing hepatic OBRb. Third, expression of mitogen-activated protein kinase phosphatase (MKP)-3, phosphorylation level of signal transducer and activator of transcription (STAT) 3, and extracellular regulated protein kinase (ERK) were analyzed in hepatocytes and mouse liver. Fourth, the role of MKP-3 in hepatic leptin signaling regulating gluconeogenesis was analyzed. Lastly, the role of ERK and STAT3 in the regulation of MKP-3 protein by leptin signaling was analyzed. Activation of hepatic leptin signaling suppressed gluconeogenesis in both hepatocytes and obese mouse liver, and improved hyperglycemia, insulin tolerance, and glucose tolerance in obese mice. The protein level of MKP-3, which can promote gluconeogenesis, was decreased by leptin signaling in both hepatocytes and mouse liver. Mkp-3 deficiency abolished the effect of hepatic leptin signaling on suppressing gluconeogenesis in hepatocytes. STAT3 decreased the MKP-3 protein level, while inactivation of STAT3 abolished the effect of leptin signaling on reducing the MKP-3 protein level in hepatocytes. Moreover, STAT3 could combine with MKP-3 and phospho-ERK1/2, which induced the degradation of MKP-3, and leptin signaling enhanced the combination. Hepatic leptin signaling could suppress gluconeogenesis at least partially by decreasing the MKP-3 protein level via STAT3-enhanced MKP-3 and ERK1/2 combination.
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影响因子：
4.8
作者：
Meek, Thomas H.;Matsen, Miles E.;Morton, Gregory J.
通讯作者：
Morton, Gregory J.
影响因子：
7.7
作者：
Feng B;Jiao P;Helou Y;Li Y;He Q;Walters MS;Salomon A;Xu H
通讯作者：
Xu H
影响因子：
7.7
作者：
Denroche HC;Levi J;Wideman RD;Sequeira RM;Huynh FK;Covey SD;Kieffer TJ
通讯作者：
Kieffer TJ
DOI：
10.1073/pnas.93.13.6231
发表时间：
1996-06-25
影响因子：
11.1
作者：
Ghilardi, N;Ziegler, S;Skoda, RC
通讯作者：
Skoda, RC
DOI：
10.1152/ajpheart.00379.2008
发表时间：
2008-10-01
影响因子：
4.8
作者：
Bouhidel, Omar;Pons, Sandrine;Ghaleh, Bijan
通讯作者：
Ghaleh, Bijan