Extracellular Visfatin Activates Gluconeogenesis in HepG2 Cells Through the Classical PKA/CREB-Dependent Pathway
Extracellular Visfatin Activates Gluconeogenesis in HepG2 Cells Through the Classical PKA/CREB-Dependent Pathway
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DOI：
10.1055/s-0034-1370907
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发表时间：
2014-04-01
影响因子：
2.2
通讯作者：
Kim, H. J.
中科院分区：
文献类型：
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作者：
Choi, Y. J.;Choi, S-E;Kim, H. J.
据报道，脂肪因子影响肝脏新生，并且已知脂肪因子内脂素与胰岛素抵抗和2型糖尿病有关。然而，内脂素是否有助于肝硬化的发生仍不清楚。内脂素，也称为烟酰胺磷酸核糖转移酶（NAMPT），通过调节烟酰胺腺嘌呤二核苷酸（NAD）来调节沉默调节蛋白1（SIRT 1）。因此，我们研究了细胞外内脂素对HepG 2细胞中葡萄糖产生的影响，并评估了细胞外内脂素是否通过NAD（+）-SIRT 1依赖性途径影响肝细胞生成。内脂素处理后，HepG 2细胞的葡萄糖产量、磷酸烯醇式丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6-phosphatase，G6-phosphatase）的mRNA表达和蛋白水平均呈时间和浓度依赖性增加。SIRT 1的敲除对visfatin诱导的胚胎发生无明显影响。随后，我们评估了细胞外内脂素是否通过经典的蛋白激酶A（PKA）/环腺苷酸反应元件（CRE）结合蛋白（CREB）依赖性过程刺激促血管生成酶的产生。HepG 2细胞经内脂素处理后CREB和PKA的磷酸化水平明显升高。此外，CREB和PKA的敲低抑制visfatin诱导的HepG 2细胞中的凋亡。总之，细胞外内脂素通过PKA/CREB途径而不是通过SIRT 1信号调节HepG 2细胞中的葡萄糖产生。本文的支持信息可在http://www.thieme-connect.de/ejournals/toc/hmr上获得
Adipokines reportedly affect hepatic gluconeogenesis, and the adipokine visfatin is known to be related to insulin resistance and type 2 diabetes. However, whether visfatin contributes to hepatic gluconeogenesis remains unclear. Visfatin, also known as nicotinamide phosphoribosyltransferase (NAMPT), modulates sirtuin1 (SIRT1) through the regulation of nicotinamide adenine dinucleotide (NAD). Therefore, we investigated the effect of extracellular visfatin on glucose production in HepG2 cells, and evaluated whether extracellular visfatin affects hepatic gluconeogenesis via an NAD(+)-SIRT1-dependent pathway. Treatment with visfatin significantly increased glucose production and the mRNA expression and protein levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in HepG2 cells in a time-and concentration-dependent manner. Knockdown of SIRT1 had no remarkable effect on the induction of gluconeogenesis by visfatin. Subsequently, we evaluated if extracellular visfatin stimulates the production of gluconeogenic enzymes through the classical protein kinase A (PKA)/cyclic AMP-responsive element (CRE)-binding protein (CREB)-dependent process. The phosphorylation of CREB and PKA increased significantly in HepG2 cells treated with visfatin. Additionally, knockdown of CREB and PKA inhibited visfatin-induced gluconeogenesis in HepG2 cells. In summary, extracellular visfatin modulates glucose production in HepG2 cells through the PKA/CREB pathway, rather than via SIRT1 signaling. Supporting Information for this article is available online at http://www.thieme-connect.de/ejournals/toc/hmr