@article {26560,
	title = {HDL-apoA-I induces the expression of angiopoietin like 4 (ANGPTL4) in endothelial cells via a PI3K/AKT/FOXO1 signaling pathway},
	journal = {MetabolismMetabolismMetabolism},
	volume = {87},
	year = {2018},
	note = {Theofilatos, DimitrisFotakis, PanagiotisValanti, EfiSanoudou, DespinaZannis, VassilisKardassis, DimitrisengResearch Support, Non-U.S. Gov{\textquoteright}t2018/06/22 06:00Metabolism. 2018 Oct;87:36-47. doi: 10.1016/j.metabol.2018.06.002. Epub 2018 Jun 18.},
	month = {Oct},
	pages = {36-47},
	abstract = {BACKGROUND: High Density Lipoprotein (HDL) and its main protein component, apolipoprotein A-I (apoA-I), have numerous atheroprotective functions on various tissues including the endothelium. Therapies based on reconstituted HDL containing apoA-I (rHDL-apoA-I) have been used successfully in patients with acute coronary syndrome, peripheral vascular disease or diabetes but very little is known about the genomic effects of rHDL-apoA-I and how they could contribute to atheroprotection. OBJECTIVE: The present study aimed to understand the endothelial signaling pathways and the genes that may contribute to rHDL-apoA-I-mediated atheroprotection. METHODS: Human aortic endothelial cells (HAECs) were treated with rHDL-apoA-I and their total RNA was analyzed with whole genome microarrays. Validation of microarray data was performed using multiplex RT-qPCR. The expression of ANGPTL4 in EA.hy926 endothelial cells was determined by RT-qPCR and Western blotting. The contribution of signaling kinases and transcription factors in ANGPTL4 gene regulation by HDL-apoA-I was assessed by RT-qPCR, Western blotting and immunofluorescence using chemical inhibitors or siRNA-mediated gene silencing. RESULTS: It was found that 410 transcripts were significantly changed in the presence of rHDL-apoA-I and that angiopoietin like 4 (ANGPTL4) was one of the most upregulated and biologically relevant molecules. In validation experiments rHDL-apoA-I, as well as natural HDL from human healthy donors or from transgenic mice overexpressing human apoA-I (TgHDL-apoA-I), increased ANGPTL4 mRNA and protein levels. ANGPTL4 gene induction by HDL was direct and was blocked in the presence of inhibitors for the AKT or the p38 MAP kinases. TgHDL-apoA-I caused phosphorylation of the transcription factor forkhead box O1 (FOXO1) and its translocation from the nucleus to the cytoplasm. Importantly, a FOXO1 inhibitor or a FOXO1-specific siRNA enhanced ANGPTL4 expression, whereas administration of TgHDL-apoA-I in the presence of the FOXO1 inhibitor or the FOXO1-specific siRNA did not induce further ANGPTL4 expression. These data suggest that FOXO1 functions as an inhibitor of ANGPTL4, while HDL-apoA-I blocks FOXO1 activity and induces ANGPTL4 through the activation of AKT. CONCLUSION: Our data provide novel insights into the global molecular effects of HDL-apoA-I on endothelial cells and identify ANGPTL4 as a putative mediator of the atheroprotective functions of HDL-apoA-I on the artery wall, with notable therapeutic potential.},
	keywords = {Angiopoietin-like 4 Protein/*biosynthesis/drug effects/genetics, Animals, Apolipoprotein A-I/*pharmacology, Endothelial Cells/*metabolism, Forkhead Box Protein O1/drug effects/genetics/*metabolism, Gene Expression/drug effects, Gene Silencing, Healthy Volunteers, Humans, Lipoproteins, HDL/*pharmacology, Mice, Mice, Transgenic, Microarray Analysis, Oncogene Protein v-akt/drug effects/*metabolism, Phosphatidylinositol 3-Kinases/drug effects/*metabolism, Protein Transport/drug effects, RNA, Small Interfering/pharmacology, Signal Transduction/*drug effects},
	isbn = {1532-8600 (Electronic)0026-0495 (Linking)},
	author = {Theofilatos, D. and Fotakis, P. and Valanti, E. and Sanoudou, D. and Zannis, V. and Kardassis, D.}
}
