Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: Effects of liver X receptor agonism

Ryohei Kaseda, Yohei Tsuchida, Hai Chun Yang, Patricia G. Yancey, Jianyong Zhong, Huan Tao, Aihua Bian, Agnes B. Fogo, Mac Rae F. Linton, Sergio Fazio, Talat Alp Ikizler, Valentina Kon

    Research output: Contribution to journalArticle

    Abstract

    Background: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. Methods: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDLCKD and HDLCont, respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1β), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist. Results: There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HDCKD was significantly less effective than HDLCont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1-23.7] vs control (26.5% [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDLCKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1β, and NF-κB) versus HDLCont. The heightened cytokine response to HDLCKD was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2. Conclusions: Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDLCKD. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDLCKD. However, LXR agonism actually increases the pro-inflammatory effects of HDLCKD through activation of TLRs and ERK1/2 pathways.

    LanguageEnglish (US)
    Article number17
    JournalBMC Nephrology
    Volume19
    Issue number1
    DOIs
    StatePublished - Jan 27 2018

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    Chronic Renal Insufficiency
    Macrophages
    Lipids
    Cholesterol
    Mitogen-Activated Protein Kinase 3
    Protein Kinases
    Toll-Like Receptor 2
    Liver X Receptors
    Tumor Necrosis Factor-alpha
    Cytokines
    Foam Cells
    Toll-Like Receptor 4
    Interleukin-1alpha
    Ultracentrifugation
    Kidney Diseases
    Interleukin-1
    LDL Cholesterol
    Lipoproteins
    Adenosine Triphosphate
    Western Blotting

    Keywords

    • Cholesterol efflux
    • CKD
    • HDL
    • LXR
    • Macrophages

    ASJC Scopus subject areas

    • Nephrology

    Cite this

    Kaseda, R., Tsuchida, Y., Yang, H. C., Yancey, P. G., Zhong, J., Tao, H., ... Kon, V. (2018). Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: Effects of liver X receptor agonism. BMC Nephrology, 19(1), [17]. DOI: 10.1186/s12882-018-0814-8

    Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages : Effects of liver X receptor agonism. / Kaseda, Ryohei; Tsuchida, Yohei; Yang, Hai Chun; Yancey, Patricia G.; Zhong, Jianyong; Tao, Huan; Bian, Aihua; Fogo, Agnes B.; Linton, Mac Rae F.; Fazio, Sergio; Ikizler, Talat Alp; Kon, Valentina.

    In: BMC Nephrology, Vol. 19, No. 1, 17, 27.01.2018.

    Research output: Contribution to journalArticle

    Kaseda, R, Tsuchida, Y, Yang, HC, Yancey, PG, Zhong, J, Tao, H, Bian, A, Fogo, AB, Linton, MRF, Fazio, S, Ikizler, TA & Kon, V 2018, 'Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: Effects of liver X receptor agonism' BMC Nephrology, vol 19, no. 1, 17. DOI: 10.1186/s12882-018-0814-8
    Kaseda R, Tsuchida Y, Yang HC, Yancey PG, Zhong J, Tao H et al. Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: Effects of liver X receptor agonism. BMC Nephrology. 2018 Jan 27;19(1). 17. Available from, DOI: 10.1186/s12882-018-0814-8
    Kaseda, Ryohei ; Tsuchida, Yohei ; Yang, Hai Chun ; Yancey, Patricia G. ; Zhong, Jianyong ; Tao, Huan ; Bian, Aihua ; Fogo, Agnes B. ; Linton, Mac Rae F. ; Fazio, Sergio ; Ikizler, Talat Alp ; Kon, Valentina. / Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages : Effects of liver X receptor agonism. In: BMC Nephrology. 2018 ; Vol. 19, No. 1.
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    abstract = "Background: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. Methods: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDLCKD and HDLCont, respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1β), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist. Results: There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HDCKD was significantly less effective than HDLCont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8{\%} [IQR 16.1-23.7] vs control (26.5{\%} [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDLCKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1β, and NF-κB) versus HDLCont. The heightened cytokine response to HDLCKD was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2. Conclusions: Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDLCKD. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDLCKD. However, LXR agonism actually increases the pro-inflammatory effects of HDLCKD through activation of TLRs and ERK1/2 pathways.",
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    AU - Kaseda,Ryohei

    AU - Tsuchida,Yohei

    AU - Yang,Hai Chun

    AU - Yancey,Patricia G.

    AU - Zhong,Jianyong

    AU - Tao,Huan

    AU - Bian,Aihua

    AU - Fogo,Agnes B.

    AU - Linton,Mac Rae F.

    AU - Fazio,Sergio

    AU - Ikizler,Talat Alp

    AU - Kon,Valentina

    PY - 2018/1/27

    Y1 - 2018/1/27

    N2 - Background: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. Methods: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDLCKD and HDLCont, respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1β), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist. Results: There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HDCKD was significantly less effective than HDLCont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1-23.7] vs control (26.5% [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDLCKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1β, and NF-κB) versus HDLCont. The heightened cytokine response to HDLCKD was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2. Conclusions: Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDLCKD. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDLCKD. However, LXR agonism actually increases the pro-inflammatory effects of HDLCKD through activation of TLRs and ERK1/2 pathways.

    AB - Background: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. Methods: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDLCKD and HDLCont, respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1β), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist. Results: There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HDCKD was significantly less effective than HDLCont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1-23.7] vs control (26.5% [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDLCKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1β, and NF-κB) versus HDLCont. The heightened cytokine response to HDLCKD was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2. Conclusions: Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDLCKD. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDLCKD. However, LXR agonism actually increases the pro-inflammatory effects of HDLCKD through activation of TLRs and ERK1/2 pathways.

    KW - Cholesterol efflux

    KW - CKD

    KW - HDL

    KW - LXR

    KW - Macrophages

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