HDAC5-mTORC1 Interaction in Differential Regulation of Ghrelin and Nucleobindin 2 (NUCB2)/Nesfatin-1
HDAC5-mTORC1 Interaction in Differential Regulation of Ghrelin and Nucleobindin 2 (NUCB2)/Nesfatin-1
复制标题
HDAC5-mTORC1 相互作用对 Ghrelin 和核结合素 2 (NUCB2)/Nesfatin-1 的差异调节
DOI：
10.1210/me.2015-1184
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发表时间：
2015-11-01
影响因子：
--
通讯作者：
Zhang, Weizhen
中科院分区：
文献类型：
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作者：
Ma, Liangxiao;Tang, Hong;Zhang, Weizhen
组蛋白去乙酰化酶（HDACs）的广谱抑制剂丙戊酸钠（VPA）可增加正常饮食或高脂饮食小鼠的ghrelin，而降低nesfatin-1。生长素释放肽和nucleobindin 2/nesfatin-1的改变是由HDAC 5介导的，而不是HDAC 4。mTORC 1的激活显著减弱了VPA对ghrelin和nesfatin-1水平的影响。HDAC 5与Raptor共免疫沉淀。通过VPA、阿司他汀A或siHDAC 5抑制HDAC 5显著增加了猛禽Lys 840的乙酰化和随后的猛禽Ser 792的磷酸化，导致mTORC 1信号转导的抑制。缺乏Lys 840乙酰化位点的猛禽突变体表现出猛禽Ser 792磷酸化的减少和随后mTORC 1信号的增加。这些变化与生长素释放肽和nucleobindin 2/nesfatin-1表达的相互变化相关。这些发现揭示了HDAC 5-mTORC 1信号传导作为胃ghrelin和nesfatin-1的差异调节的新机制。
Sodium valporate (VPA), a broad-spectrum inhibitor of histone deacetylases (HDACs), increased ghrelin whereas decreased nesfatin-1 in mice fed normal chow diet or high-fat diet. Alterations in ghrelin and nucleobindin 2/nesfatin-1 were mediated by HDAC5 but not HDAC4. Activation of mTORC1 significantly attenuated the effect of VPA on ghrelin and nesfatin-1 levels. HDAC5 coimmunoprecipitated with raptor. Inhibition of HDAC5 by VPA, trichostatin A, or siHDAC5 markedly increased acetylation of raptor Lys840 and subsequent phosphorylation of raptor Ser792, resulting in suppression of mTORC1 signaling. A raptor mutant lacking the Lys840 acetylation site showed a decrement in phosphorylation of raptor Ser792 and subsequent increase in mTORC1 signaling. These alterations were associated with reciprocal changes in ghrelin and nucleobindin 2/nesfatin-1 expression. These findings reveal HDAC5-mTORC1 signaling as a novel mechanism in the differential regulation of gastric ghrelin and nesfatin-1.