Testosterone stimulates cholesterol clearance from human macrophages by activating LXRα

KILBY, Elizabeth L., KELLY, Daniel M. and JONES, T. Hugh (2021). Testosterone stimulates cholesterol clearance from human macrophages by activating LXRα. Life Sciences, 269.

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Link to published version:: https://doi.org/10.1016/j.lfs.2021.119040
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    Abstract

    Aims Low testosterone in men is associated with increased cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors including cholesterol, endothelial dysfunction and inflammation as key mediators of atherosclerosis. Although evidence suggests testosterone is anti-atherogenic, its mechanism of action is unknown. The present study investigates whether testosterone exerts anti-atherogenic effects by stimulating cholesterol clearance from macrophages via activation of liver X receptor (LXRα), a nuclear master regulator of cellular cholesterol homeostasis, lipid regulation, and inflammation. Main methods Using human monocyte THP-1 cells differentiated into macrophages, the effect of testosterone (1–10 nM) treatment (24–72 h) on the expression of LXRα and LXR- targets apolipoprotein E (APOE), ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding transcription factor 1 (SREBF1) and fatty acid synthase (FAS), was investigated via qPCR and western blotting, with or without androgen receptor blockade with flutamide or LXR antagonism with CPPSS-50. Cholesterol clearance was measured by monitoring fluorescent dehydroergosterol (DHE) cellular clearance and ABCA1 cellular translocation was observed via immunocytochemistry in testosterone treated macrophages. Key findings Testosterone increased mRNA and protein expression of LXRα, APOE, ABCA1, SREBF1 and FAS. These effects were blocked by flutamide and independently by LXR antagonism with CPPSS-50. Furthermore testosterone stimulated cholesterol clearance from the macrophages and promoted the translocation of ABCA1 toward the cell membrane. Significance Testosterone acts via androgen receptor-dependent pathways to stimulate LXRα and downstream targets to induce cholesterol clearance in human macrophages. This may, in part, explain the anti-atherogenic effects of testosterone frequently seen clinically.

    Item Type: Article
    Uncontrolled Keywords: 0601 Biochemistry and Cell Biology; 1115 Pharmacology and Pharmaceutical Sciences; Pharmacology & Pharmacy
    Identification Number: https://doi.org/10.1016/j.lfs.2021.119040
    SWORD Depositor: Symplectic Elements
    Depositing User: Symplectic Elements
    Date Deposited: 22 Jan 2021 11:37
    Last Modified: 22 Jan 2021 15:45
    URI: http://shura.shu.ac.uk/id/eprint/27995

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