Abstract
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.
Highlights
Ghrelin is an acetylated 28 amino acid hormone initially identified from the stomach, which induced the release of growth hormone (GH) from the pituitary and regulates food intake, energy homeostasis and adiposity [1,2]
We previously reported that hexarelin, a GH secretagogue that interacts with both CD36 and growth hormone secretagogue receptor 1a (GHS-R1a) receptors, activated the peroxisome proliferator-activated receptor c (PPARc)-liver X receptor a (LXRa)-ABCA1/G1 transporter pathway in macrophages [26]
Our results showed that ghrelin elicited a dose-dependent increase in LXRa, ABCA1, and ABCG1 mRNA expression, as well as for GHS-R1a, with values reaching 1.8, 1.7, 2.2, and 2.1-fold respectively, when treated with 100 nM ghrelin compared to untreated differentiated cells (Figs. 1A and B)
Summary
Ghrelin is an acetylated 28 amino acid hormone initially identified from the stomach, which induced the release of growth hormone (GH) from the pituitary and regulates food intake, energy homeostasis and adiposity [1,2]. In concordance with the peripheral distribution of GHS-R1a, including vascular endothelium, myocardium and monocytes [5,6,7], emerging evidence indicates that ghrelin and its receptor have a variety of GH releasing-independent cardiovascular and anti-inflammatory activities [8,9,10]. Attempts to elucidate the peripheral cardiovascular effects of ghrelin have identified several signaling mechanisms involving both classical G-. Ghrelin inhibited proliferation of human aortic smooth muscle cells through a cAMP/PMA activation pathway [18]. Given such complexity in GHS-R1a signaling, the molecular mechanisms underlying ghrelin downstream effects on macrophage biology have not yet been described
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