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.
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.
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.
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.
Baber U, Stone GW, Weisz G, Moreno P, Dangas G, Maehara A, Mintz GS, Cristea E, Fahy M, Xu K, et al. Coronary plaque composition, morphology, and outcomes in patients with and without chronic kidney disease presenting with acute coronary syndromes. JACC Cardiovasc Imaging. 2012;5(3 Suppl):S53–61. CrossRefPubMed
Wu Y, Hou J, Li J, Luo Y, Wu S. Correlation between carotid Intima-media thickness and early-stage chronic kidney disease: results from asymptomatic Polyvascular abnormalities in community study. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2016;25(2):259–65. CrossRef
CDC.GOV: National Chronic Kidney Disease Fact Sheet, 2014 . Edited by CDC.GOV.
Investigators A-H, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67. CrossRef
Saleheen D, Scott R, Javad S, Zhao W, Rodrigues A, Picataggi A, Lukmanova D, Mucksavage ML, Luben R, Billheimer J, et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol. 2015;3(7):507–13. CrossRefPubMedPubMedCentral
Kopecky C, Haidinger M, Birner-Grunberger R, Darnhofer B, Kaltenecker CC, Marsche G, Holzer M, Weichhart T, Antlanger M, Kovarik JJ, et al. Restoration of renal function does not correct impairment of uremic HDL properties. Journal of the American Society of Nephrology : JASN. 2015;26(3):565–75. CrossRefPubMed
Zhu X, Lee JY, Timmins JM, Brown JM, Boudyguina E, Mulya A, Gebre AK, Willingham MC, Hiltbold EM, Mishra N, et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem. 2008;283(34):22930–41. CrossRefPubMedPubMedCentral
Kappus MS, Murphy AJ, Abramowicz S, Ntonga V, Welch CL, Tall AR, Westerterp M. Activation of liver X receptor decreases atherosclerosis in Ldlr(−)/(−) mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells. Arterioscler Thromb Vasc Biol. 2014;34(2):279–84. CrossRefPubMed
Skali H, Uno H, Levey AS, Inker LA, Pfeffer MA, Solomon SD. Prognostic assessment of estimated glomerular filtration rate by the new chronic kidney disease epidemiology collaboration equation in comparison with the modification of diet in renal disease study equation. Am Heart J. 2011;162(3):548–54. CrossRefPubMed
Klansek JJ, Yancey P, St Clair RW, Fischer RT, Johnson WJ, Glick JM. Cholesterol quantitation by GLC: artifactual formation of short-chain steryl esters. J Lipid Res. 1995;36(10):2261–6. PubMed
Yancey PG, Jerome WG. Lysosomal cholesterol derived from mildly oxidized low density lipoprotein is resistant to efflux. J Lipid Res. 2001;42(3):317–27. PubMed
Kopecky C, Ebtehaj S, Genser B, Drechsler C, Krane V, Antlanger M, Kovarik JJ, Kaltenecker CC, Parvizi M, Wanner C, et al. HDL cholesterol efflux does not predict cardiovascular risk in Hemodialysis patients. J Am Soc Nephrol . 2015;26(3):565–75.
Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Perkovic V, Hegbrant J, Strippoli GF. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. The Cochrane database of systematic reviews. 2014;5:CD007784.
Levin N, Bischoff ED, Daige CL, Thomas D, Vu CT, Heyman RA, Tangirala RK, Schulman IG. Macrophage liver X receptor is required for antiatherogenic activity of LXR agonists. Arterioscler Thromb Vasc Biol. 2005;25(1):135–42. PubMed
Asquith DL, Ballantine LE, Nijjar JS, Makdasy MK, Patel S, Wright PB, Reilly JH, Kerr S, Kurowska-Stolarska M, Gracie JA, et al. The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release. Ann Rheum Dis. 2013;72(12):2024–31. CrossRefPubMed
- Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism
Patricia G. Yancey
Agnes B. Fogo
Mac Rae F. Linton
Talat Alp Ikizler
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II