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Activation of liver X receptor suppresses angiogenesis via induction of ApoD

Chih-Jen Lai1,2, Hsu-Chen Cheng3, Ching-Yu Lin1

  • 1Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|August 27, 2017
PubMed

Insights

Activation of Liver X Receptors (LXRs) suppresses angiogenesis by increasing apolipoprotein D (ApoD). This process inhibits endothelial cell function and may offer a new target for anti-angiogenesis therapies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cardiovascular Biology

Background:

  • Liver X receptors (LXRs) are key regulators of lipid, fatty acid, and glucose metabolism.
  • LXRs play a significant role in the pathogenesis of cardiovascular diseases.
  • Angiogenesis, the formation of new blood vessels, is crucial in both physiological and pathological contexts, including cardiovascular disease and tumor growth.

Purpose of the Study:

  • To investigate the effect of a potent LXR agonist, T0901317, on angiogenesis.
  • To elucidate the molecular mechanisms by which LXR activation influences endothelial cell function and blood vessel formation.
  • To explore the potential role of LXR target genes, specifically apolipoprotein D (ApoD), in mediating these effects.

Main Methods:

  • Treatment of human umbilical vein endothelial cells (HUVECs) with T0901317.
  • Assessment of HUVEC tube formation and migration in vitro.
  • In vivo angiogenesis assay using the chorioallantoic membrane model.
  • Gene and protein expression analysis of LXR target genes and signaling pathway components.
  • Overexpression and knockdown studies for ApoD and scavenger receptor class B member 1 (SR-B1).

Main Results:

  • T0901317 significantly inhibited HUVEC tube formation and migration, and reduced in vivo angiogenesis.
  • T0901317 upregulated the expression of its target gene, apolipoprotein D (ApoD).
  • Overexpression of ApoD mimicked the anti-angiogenic effects of T0901317, while ApoD interaction with SR-B1 was critical for T0901317's inhibitory effects on HUVEC migration.
  • T0901317 and ApoD overexpression reduced the levels of key pro-angiogenic proteins, including phospho-eNOS, phospho-Akt, VEGF-A, VEGF-C, and MMPs, by suppressing the PI3K-Akt-eNOS signaling pathway.

Conclusions:

  • LXR activation inhibits angiogenesis through the induction of its target gene, ApoD.
  • ApoD mediates the anti-angiogenic effects by suppressing the PI3K-Akt-eNOS signaling pathway.
  • ApoD represents a potential therapeutic target for modulating angiogenesis, particularly in the context of tumor growth.
Keywords:
AktHUVECT0901317

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