Quercetin protects against ox‑LDL‑induced injury via regulation of ABCAl, LXR‑α and PCSK9 in RAW264.7 macrophages

Li,Shanshan; Cao,Hui; Shen,Dingzhu; Jia,Qingling; Chen,Chuan; Xing,San  Li

doi:10.3892/mmr.2018.9048

Quercetin protects against ox‑LDL‑induced injury via regulation of ABCAl, LXR‑α and PCSK9 in RAW264.7 macrophages

Authors:
- Shanshan Li
- Hui Cao
- Dingzhu Shen
- Qingling Jia
- Chuan Chen
- San Li Xing
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Affiliations: Shanghai Geriatrics Institute of Chinese Medicine, Shanghai 200031, P.R. China
Published online on: May 22, 2018 https://doi.org/10.3892/mmr.2018.9048
Pages: 799-806
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Quercetin is a flavonoid that has anti‑inflammatory, anti‑oxidant and lipid metabolic effects. It has also been reported to reduce the risk of cardiovascular disease. The present study measured the effects of quercetin on the expression of ATP‑binding cassette transporter 1 (ABCAl), ATP‑binding cassette sub‑family G member 1 (ABCG1), liver X receptor‑α (LXR‑α), proprotein convertase subtilisin/kexin type 9 (PCSK9), p53, p21 and p16 induced by oxidized low density lipoprotein (ox‑LDL). RAW264.7 macrophages were exposed to ox‑LDL with or without 20 µmol/l quercetin and cell proliferation and senescence were quantified using β‑gal staining. Superoxide dismutase (SOD), malondialdehyde (MDA) and lipid droplets were measured in the cytoplasm using oil red staining, while intracellular and total cholesterol (TC) were measured using filipin staining and a TC kit. Immunofluorescent studies and western blot analysis were performed to quantify the expression of ABCAl, ABCG1, LXR‑α, PCSK9, p53, p21 and p16. Quercetin increased RAW264.7 cell viability and reduced lipid accumulation, senescence, lipid droplets, intracellular cholesterol and TC. It was concluded that quercetin inhibits ox‑LDL‑induced lipid droplets in RAW264.7 cells by upregulation of ABCAl, ABCG1, LXR‑α and downregulation of PCSK9, p53, p21 and p16.

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1	Getz GS and Reardon CA: The mutual interplay of lipid metabolism and the cells of the immune system in relation to atherosclerosis. Clin Lipidol. 9:657–671. 2014. View Article : Google Scholar : PubMed/NCBI
2	Maranhão RC and Leite AC Jr: Development of anti-atherosclerosis therapy based on the inflammatory and proliferative aspects of the disease. Curr Pharm Des. 21:1196–1204. 2015. View Article : Google Scholar : PubMed/NCBI
3	Yu XH, Fu YC, Zhang DW, Yin K and Tang CK: Foam cells in atherosclerosis. Clin Chim Acta. 424:245–252. 2013. View Article : Google Scholar : PubMed/NCBI
4	Voloshyna I, Seshadri S, Anwar K, Littlefield MJ, Belilos E, Carsons SE and Reiss AB: Infliximab reverses suppression of cholesterol efflux proteins by TNF-α: A possible mechanism for modulation of atherogenesis. Biomed Res Int. 2014:3126472014. View Article : Google Scholar : PubMed/NCBI
5	Cui Q, Ju X, Yang T, Zhang M, Tang W, Chen Q, Hu Y, Haas JV, Troutt JS, Pickard RT, et al: Serum PCSK9 is associated with multiple metabolic factors in a large Han Chinese population. Atherosclerosis. 213:632–636. 2010. View Article : Google Scholar : PubMed/NCBI
6	Paciullo F, Fallarino F, Bianconi V, Mannarino MR, Sahebkar A and Pirro M: PCSK9 at the crossroad of cholesterol metabolism and immune function during infections. J Cell Physiol. 232:2330–2338. 2017. View Article : Google Scholar : PubMed/NCBI
7	Adorni MP, Cipollari E, Favari E, Zanotti I, Zimetti F, Corsini A, Ricci C, Bernini F and Ferri N: Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages. Atherosclerosis. 256:1–6. 2017. View Article : Google Scholar : PubMed/NCBI
8	Lara-Guzman OJ, Tabares-Guevara JH, Leon-Varela YM, Álvarez RM, Roldan M, Sierra JA, Londoño-Londoño JA and Ramirez-Pineda JR: Proatherogenic macrophage activities are targeted by the flavonoid quercetin. J Pharmacol Exp Ther. 343:296–306. 2012. View Article : Google Scholar : PubMed/NCBI
9	Cui Y, Hou P, Li F, Liu Q, Qin S, Zhou G, Xu X, Si Y and Guo S: Quercetin improves macrophage reverse cholesterol transport in apolipoprotein E-deficient mice fed a high-fat diet. Lipids Health Dis. 16:92017. View Article : Google Scholar : PubMed/NCBI
10	Mbikay M, Sirois F, Simoes S, Mayne J and Chrétien M: Quercetin-3-glucoside increases low-density lipoprotein receptor (LDLR) expression, attenuates proprotein convertase subtilisin/kexin 9 (PCSK9) secretion and stimulates LDL uptake by Huh7 human hepatocytes in culture. FEBS Open Bio. 4:755–762. 2014. View Article : Google Scholar : PubMed/NCBI
11	Lu Y and Jia Y: Quercetin upregulates ABCA1 expression through liver X receptor alpha signaling pathway in THP-1 macrophages. Eur Rev Med Pharmacol Sci. 20:3945–3952. 2016.PubMed/NCBI
12	Yvan-Charvet L, Pagler T, Gautier EL, Avagyan S, Siry RL, Han S, Welch CL, Wang N, Randolph GJ, Snoeck HW and Tall AR: ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science. 328:1689–1693. 2010. View Article : Google Scholar : PubMed/NCBI
13	Kolovou V, Marvaki A, Boutsikou M, Vasilopoulos G, Degiannis D, Marvaki C and Kolovou G: Effect of ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms on plasma lipid variables and common demographic parameters in Greek nurses. Open Cardiovasc Med J. 10:233–239. 2016. View Article : Google Scholar : PubMed/NCBI
14	Wang S and Smith JD: ABCA1 and nascent HDL biogenesis. Biofactors. 40:547–554. 2014. View Article : Google Scholar : PubMed/NCBI
15	Vaughan AM and Oram JF: ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins. J Biol Chem. 280:30150–30157. 2005. View Article : Google Scholar : PubMed/NCBI
16	Oosterveer MH, Grefhorst A, Groen AK and Kuipers F: The liver X receptor: Control of cellular lipid homeostasis and beyond Implications for drug design. Prog Lipid Res. 49:343–352. 2010. View Article : Google Scholar : PubMed/NCBI
17	Ikhlef S, Berrougui H, Kamtchueng SO and Khalil A: Paraoxonase 1-treated oxLDL promotes cholesterol efflux from macrophages by stimulating the PPARγ-LXRα-ABCA1 pathway. FEBS Lett. 590:1614–1629. 2016. View Article : Google Scholar : PubMed/NCBI
18	Sharma K and Baliga RR: Genetics of dyslipidemia and ischemic heart disease. Curr Cardiol Rep. 19:462017. View Article : Google Scholar : PubMed/NCBI
19	Soutar AK: Unexpected roles for PCSK9 in lipid metabolism. Curr Opin Lipidol. 22:192–196. 2011. View Article : Google Scholar : PubMed/NCBI
20	Liu M, Wu G, Baysarowich J, Kavana M, Addona GH, Bierilo KK, Mudgett JS, Pavlovic G, Sitlani A, Renger JJ, et al: PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain. J Lipid Res. 51:2611–2618. 2010. View Article : Google Scholar : PubMed/NCBI
21	Romanov VS, Pospelov VA and Pospelova TV: Cyclin-dependent kinase inhibitor p21(Waf1): Contemporary view on its role in senescence and oncogenesis. Biochemistry (Mosc). 77:575–584. 2012. View Article : Google Scholar : PubMed/NCBI
22	Shih CT, Chang YF, Chen YT, Ma CP, Chen HW, Yang CC, Lu JC, Tsai YS, Chen HC and Tan BC: The PPARγ-SETD8 axis constitutes an epigenetic, p53-independent checkpoint on p21-mediated cellular senescence. Aging Cell. 16:797–813. 2017. View Article : Google Scholar : PubMed/NCBI
23	Zhang M, Xie Z, Gao W, Pu L, Wei J and Guo C: Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats. Nutr Res. 36:271–279. 2016. View Article : Google Scholar : PubMed/NCBI
24	Mehrbani M, Choopani R, Fekri A and Mehrabani M, Mosaddegh M and Mehrabani M: The efficacy of whey associated with dodder seed extract on moderate-to-severe atopic dermatitis in adults: A randomized, double-blind, placebo-controlled clinical trial. J Ethnopharmacol. 172:325–332. 2015. View Article : Google Scholar : PubMed/NCBI
25	Sun X, Yamasaki M, Katsube T and Shiwaku K: Effects of quercetin derivatives from mulberry leaves: Improved gene expression related hepatic lipid and glucose metabolism in short-term high-fat fed mice. Nutr Res Pract. 9:137–143. 2015. View Article : Google Scholar : PubMed/NCBI
26	Bhaskar S, Sudhakaran PR and Helen A: Quercetin attenuates atherosclerotic inflammation and adhesion molecule expression by modulating TLR-NF-κB signaling pathway. Cell Immunol. 310:131–140. 2016. View Article : Google Scholar : PubMed/NCBI
27	Sun L, Li E, Wang F, Wang T, Qin Z, Niu S and Qiu C: Quercetin increases macrophage cholesterol efflux to inhibit foam cell formation through activating PPARγ-ABCA1 pathway. Int J Clin Exp Pathol. 8:10854–10860. 2015.PubMed/NCBI
28	Guo S, Tian H, Dong R, Yang N, Zhang Y, Yao S, Li Y, Zhou Y, Si Y and Qin S: Exogenous supplement of N-acetylneuraminic acid ameliorates atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis. 251:183–191. 2016. View Article : Google Scholar : PubMed/NCBI
29	Byun EB, Yang MS, Choi HG, Sung NY, Song DS, Sin SJ and Byun EH: Quercetin negatively regulates TLR4 signaling induced by lipopolysaccharide through Tollip expression. Biochem Biophys Res Commun. 431:698–705. 2013. View Article : Google Scholar : PubMed/NCBI
30	Chang YC, Lee TS and Chiang AN: Quercetin enhances ABCA1 expression and cholesterol efflux through a p38-dependent pathway in macrophages. J Lipid Res. 53:1840–1850. 2012. View Article : Google Scholar : PubMed/NCBI
31	Lu Y and Jia YP: Quercetin upregulates ABCA1 expression through liver X receptor alpha signaling pathway in THP-1 macrophages. Eur Rev Med Pharmacol Sci. 20:3945–3952. 2016.PubMed/NCBI
32	Gong C, Yang Z, Zhang L, Wang Y, Gong W and Liu Y: Quercetin suppresses DNA double-strand break repair and enhances the radiosensitivity of human ovarian cancer cells via p53-dependent endoplasmic reticulum stress pathway. Onco Targets Ther. 11:17–27. 2017. View Article : Google Scholar : PubMed/NCBI
33	Shen DZ, Xing SL, Chen C, et al: Effect of shouqian granule on atherosclerosis in ApoE^−/− mice based on expression of TLR4, MCP-1 and ICAM-1 in mice. Chin Med Emerg. 2:192–194+232. 2017.
34	Shen DZ, Chen C, Chen JL and Xing S: Effect of shoushen granules on level of blood lipids and inflammatory cytokines when treating carotid artherosclerosis. Chin Arch Tradit Chin Med. 1:22–24. 2014.
35	Shen DZ, Xing SL, Chen C, Shen R and Lou DF: Effect of Shoushen granule on arterial elasticity in patients with carotid atherosclerosis: a clinical randomized controlled trial. J Tradit Chin Med. 4:389–395. 2015.