Activation of liver X receptor suppresses angiogenesis via induction of ApoD

• Published in: The FASEB journal 2017-12, Vol.31 (12), p.5568-5576
• Main Authors: Lai, Chih‐Jen, Cheng, Hsu‐Chen, Lin, Ching‐Yu, Huang, Shih‐Han, Chen, Ting‐Huan, Chung, Chi‐Jung, Chang, Chung‐Ho, Wang, Horng‐Dar, Chuu, Chih‐Pin
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Akt; AKT protein; Angiogenesis; Apolipoproteins; Apolipoproteins D - metabolism; Cardiovascular diseases; Cell activation; Cell Movement - drug effects; Cholesterol; Chorioallantoic membrane; Endothelial cells; Fatty acids; Gene expression; Heart diseases; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; HUVEC; Hydrocarbons, Fluorinated - pharmacology; In vivo methods and tests; Interleukin 8; Interleukin-8 - metabolism; Liver; Liver X receptors; Liver X Receptors - agonists; Liver X Receptors - metabolism; Matrix metalloproteinase; Metalloproteinase; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Neovascularization, Physiologic - drug effects; Nitric Oxide Synthase Type III - metabolism; Proteins; Rapamycin; Receptors; Regulators; Scavenger receptors; Scavenger Receptors, Class B - metabolism; Signal Transduction - drug effects; Signaling; Sulfonamides - pharmacology; T0901317; TOR protein; TOR Serine-Threonine Kinases - metabolism; Umbilical vein; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor C - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201700374R

ABSTRACT Liver X receptors (LXRs) are important sensors and regulators for cholesterol, fatty acid, and glucose. LXRs play essential roles in the development and progression of cardiovascular diseases. We examined the effects of T0901317, a potent LXR agonist, on angiogenesis of human umbilical vein endothelial cells (HUVECs). Treatment with T0901317 inhibited the tube formation and migration of HUVECs and reduced the in vivo angiogenesis, as determined by chorioallantoic membrane assay. T0901317 stimulated gene and protein expression of LXR target gene apolipoprotein D (ApoD). Overexpression of ApoD suppressed the tube formation of HUVECs. ApoD interacted with scavenger receptor class B member 1 (SR‐B1), while knockdown of SR‐B1 blocked suppressive effects of T0901317 on HUVEC migration. T0901317 treatment or overexpression of ApoD lessened expression of proteins regulating angiogenesis, including phospho–eNOS S1177, phospho–Akt T308, phospho–Akt S473, eNOS, mammalian target of rapamycin, VEGF‐A, VEGF‐C, IL‐8, RhoB, matrix metalloproteinase (MMP)‐8, ‐9, and monocyte chemoattractant protein 1. Our study suggested that activation of LXR interferes with angiogenesis through induction of LXR target gene ApoD, which in turn suppresses PI3K‐Akt‐eNOS signaling, an essential pathway regulating angiogenesis. ApoD may be a potential therapeutic target for tumor angiogenesis.—Lai, C.‐J., Cheng, H.‐C., Lin, C.‐Y., Huang, S.‐H., Chen, T.‐H., Chung, C.‐J., Chang, C.‐H., Wang, H.‐D., Chuu, C.‐P. Activation of liver X receptor suppresses angiogenesis via induction of ApoD. FASEB J. 31, 5568–5576 (2017). www.fasebj.org