Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic β-cell survival and function via CREB.
Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic β-cell survival and function via CREB.
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DOI：
10.1016/j.jnutbio.2012.03.008
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Liu D
中科院分区：
文献类型：
--
作者：
Zhang Y;Zhen W;Maechler P;Liu D
慢性高脂血症导致β细胞凋亡和功能障碍，从而促进T2 D的发病机制。因此，寻找促进胰腺β细胞存活并改善其功能的药物可能是预防和治疗T2 D的有希望的策略。我们研究了从银杏叶中分离的小分子山奈酚对β细胞凋亡和功能的影响，并进一步确定了其作用机制。山奈酚治疗促进活力，抑制细胞凋亡，并降低半胱天冬酶-3在INS-1 E细胞和人类胰岛长期暴露于棕榈酸酯的活性。此外，山奈酚防止脂毒性诱导的抗凋亡蛋白Akt和Bcl-2的下调。山奈酚的细胞保护作用与改善胰岛素分泌、合成和PDX-1表达有关。慢性高脂血症显著减少β细胞中cAMP的产生、PKA的活化和CREB的磷酸化及其调节的转录活性，所有这些都可以通过山奈酚治疗恢复。通过在INS-1 E细胞中转染CREB siRNA或在人胰岛中腺病毒转移显性阴性形式的CREB来破坏CREB表达，消除了棕榈酸酯引起的β细胞凋亡和功能障碍的山奈酚保护作用。INS-1 E细胞或人胰岛与山奈酚孵育48小时诱导PDX-1表达。山奈酚对PDX-1表达的这种作用不被结构上相关的类黄酮化合物所共享。PDX-1基因敲低降低INS-1 E细胞中山奈酚刺激的cAMP生成和CREB激活。这些结果表明，山奈酚是一种新的胰腺β细胞的存活因子，通过上调PDX-1/cAMP/PKA/CREB信号级联。
Chronic hyperlipidemia causes β-cell apoptosis and dysfunction, thereby contributing to the pathogenesis of T2D. Thus, searching for agents to promote pancreatic β-cell survival and improve its function could be a promising strategy to prevent and treat T2D. We investigated the effects of kaempferol, a small molecule isolated from ginkgo biloba, on apoptosis and function of β-cells and further determined the mechanism underlying its actions. Kaempferol treatment promoted viability, inhibited apoptosis, and reduced caspase-3 activity in INS-1E cells and human islets chronically exposed to palmitate. In addition, kaempferol prevented the lipotoxicity-induced down-regulation of anti-apoptotic proteins Akt and Bcl-2. The cytoprotective effects of kaempferol were associated with improved insulin secretion, synthesis, and PDX-1 expression. Chronic hyperlipidemia significantly diminished cAMP production, PKA activation, and CREB phosphorylation and its regulated transcriptional activity in β-cells, all of which were restored by kaempferol treatment. Disruption of CREB expression by transfection of CREB siRNA in INS-1E cells or adenoviral transfer of dominant-negative forms of CREB in human islets ablated kaempferol protection of β-cell apoptosis and dysfunction caused by palmitate. Incubation of INS-1E cells or human islets with kaempferol for 48 h induced PDX-1 expression. This effect of kaempferol on PDX-1 expression was not shared by a host of structurally related flavonoid compounds. PDX-1 gene knockdown reduced kaempferol–stimulated cAMP generation and CREB activation in INS-1E cells. These findings demonstrate that kaempferol is a novel survivor factor for pancreatic β-cells via up-regulating the PDX-1/cAMP/PKA/CREB signaling cascade.
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影响因子：
7.7
作者：
Elsner M;Gehrmann W;Lenzen S
通讯作者：
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影响因子：
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作者：
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DOI：
10.1152/ajpendo.00252.2004
发表时间：
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影响因子：
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影响因子：
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影响因子：
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作者：
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