A concerted kinase interplay identifies PPARgamma as a molecular target of ghrelin signaling in macrophages.
A concerted kinase interplay identifies PPARgamma as a molecular target of ghrelin signaling in macrophages.
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DOI：
10.1371/journal.pone.0007728
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发表时间：
2009-11-04
期刊：
影响因子：
3.7
通讯作者：
Tremblay A
中科院分区：
文献类型：
--
作者：
Demers A;Caron V;Rodrigue-Way A;Wahli W;Ong H;Tremblay A
过氧化物酶体增殖激活剂受体PPARγ在血管生物学中起重要作用，调节巨噬细胞功能和动脉粥样硬化进展。最近，我们描述了联合激活ghrelin/GHS-R1a受体和清除率受体CD36通过转录激活PPARγ诱导巨噬细胞释放胆固醇的有益作用。虽然CD36和PPARγ在动脉粥样硬化中的相互作用已被公认，但ghrelin受体调节PPARγ的作用尚不清楚。在这里，我们证明了ghrelin通过涉及Erk1/2和Akt激酶的协同信号级联触发PPARγ激活，导致下游效应物LXRα和ABC甾醇转运蛋白在人巨噬细胞中的表达增强。这些作用与PPARγ磷酸化的增强有关，而不依赖于抑制保守丝氨酸-84。Src酪氨酸激酶Fyn被确定为响应ghrelin而被募集到GHS-R1a，但激活的Fyn无法增强PPARγ Ser-84特异性磷酸化依赖于对接蛋白Dok-1的同时募集，这阻碍了Erk1/2途径的最佳激活。此外，Ser-84的替代保留了ghrelin诱导的PPARγ活性和对Src抑制的反应性，支持了PPARγ对ghrelin反应的独立于Ser-84的机制。与此一致的是，我们发现ghrelin以g αq依赖的方式促进PI3-K/Akt通路，导致Akt募集到PPARγ，增强PPARγ磷酸化和活化，独立于Ser-84，增加LXRα和ABCA1/G1的表达。综上所述，这些结果说明了巨噬细胞中Fyn/Dok-1/Erk和g - αq/PI3-K/Akt通路的复杂相互作用，以协调一致的方式转导PPARγ对胃饥饿素的反应。
The peroxisome proliferator-activator receptor PPARγ plays an essential role in vascular biology, modulating macrophage function and atherosclerosis progression. Recently, we have described the beneficial effect of combined activation of the ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release through transcriptional activation of PPARγ. Although the interplay between CD36 and PPARγ in atherogenesis is well recognized, the contribution of the ghrelin receptor to regulate PPARγ remains unknown. Here, we demonstrate that ghrelin triggers PPARγ activation through a concerted signaling cascade involving Erk1/2 and Akt kinases, resulting in enhanced expression of downstream effectors LXRα and ABC sterol transporters in human macrophages. These effects were associated with enhanced PPARγ phosphorylation independently of the inhibitory conserved serine-84. Src tyrosine kinase Fyn was identified as being recruited to GHS-R1a in response to ghrelin, but failure of activated Fyn to enhance PPARγ Ser-84 specific phosphorylation relied on the concomitant recruitment of docking protein Dok-1, which prevented optimal activation of the Erk1/2 pathway. Also, substitution of Ser-84 preserved the ghrelin-induced PPARγ activity and responsiveness to Src inhibition, supporting a mechanism independent of Ser-84 in PPARγ response to ghrelin. Consistent with this, we found that ghrelin promoted the PI3-K/Akt pathway in a Gαq-dependent manner, resulting in Akt recruitment to PPARγ, enhanced PPARγ phosphorylation and activation independently of Ser-84, and increased expression of LXRα and ABCA1/G1. Collectively, these results illustrate a complex interplay involving Fyn/Dok-1/Erk and Gαq/PI3-K/Akt pathways to transduce in a concerted manner responsiveness of PPARγ to ghrelin in macrophages.
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DOI：
10.1152/ajpendo.00570.2006
发表时间：
2007-03-01
影响因子：
5.1
作者：
Iantorno, Micaela;Chen, Hui;Quon, Michael J.
通讯作者：
Quon, Michael J.
影响因子：
20.3
作者：
Dixit, Vishwa D.;Yang, Hyunwon;Taub, Dennis D.
通讯作者：
Taub, Dennis D.
影响因子：
3.3
作者：
Filigheddu, Nicoletta;Gnocchi, Viola F.;Graziani, Andrea
通讯作者：
Graziani, Andrea
影响因子：
4.1
作者：
Demers, A;McNicoll, N;Ong, H
通讯作者：
Ong, H
影响因子：
5.8
作者：
Gnanapavan, S;Kola, B;Korbonits, M
通讯作者：
Korbonits, M