Baicalin promotes cholesterol efflux by regulating the expression of SR‑BI in macrophages

Yu,Renchao; Lv,Yuexia; Wang,Juanling; Pan,Nana; Zhang,Rui; Wang,Xiaxia; Yu,Haichu; Tan,Lijuan; Zhao,Yunhe; Li,Bo

doi:10.3892/etm.2016.3884

Baicalin promotes cholesterol efflux by regulating the expression of SR‑BI in macrophages

Authors:
- Renchao Yu
- Yuexia Lv
- Juanling Wang
- Nana Pan
- Rui Zhang
- Xiaxia Wang
- Haichu Yu
- Lijuan Tan
- Yunhe Zhao
- Bo Li
View Affiliations

Affiliations: Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266555, P.R. China, Clinical Skill Training Center, People's Hospital of Weifang, Weifang, Shandong 261041, P.R. China, Department of Cardiology, Central Hospital of Zibo, Zibo, Shandong 255036, P.R. China
Published online on: November 8, 2016 https://doi.org/10.3892/etm.2016.3884
Pages: 4113-4120

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Intake of a high dosage of baicalin has previously been shown to attenuate hyperlipidemia induced by a high-fat diet. Baicalin functions as an activator of peroxisome proliferator‑activated receptor‑γ (PPAR‑γ), which is the key regulator of reverse cholesterol transport (RCT). The present study aimed to test the hypothesis that baicalin could promote cholesterol efflux in macrophages through activating PPAR‑γ. Phorbol 12‑myristate 13‑acetate‑stimulated THP‑1 cells were treated with oxidized low‑density lipoprotein and (3H)‑cholesterol for 24 h, and the effects of baicalin on cholesterol efflux were evaluated in the presence of apolipoprotein A‑1 (ApoA‑1), or high‑density lipoprotein subfraction 2 (HDL2) or subfraction 3 (HDL3). The expression levels of scavenger receptor class B type I (SR‑BI), PPAR‑γ and liver X receptor‑α (LXRα) were detected and specific inhibitors or activators of SR‑BI, PPAR‑γ and LXRα were applied to investigate the mechanism. Treatment of THP‑1 macrophages with baicalin significantly accelerated HDL‑mediated, but not ApoA‑1‑mediated cholesterol efflux. However, baicalin treatment increased the expression of SR‑BI at the mRNA and protein levels in a dose‑ and time‑dependent manner, and pre‑treatment with the SR‑BI inhibitor BLT‑1 and SR‑BI small interfering RNA significantly inhibited baicalin‑induced cholesterol efflux. Furthermore, baicalin increased the expression of PPAR‑γ and LXRα, and the application of specific agonists and inhibitors of PPAR‑γ and LXRα changed the expression of SR‑BI, as well as cholesterol efflux. It may be concluded that baicalin induced cholesterol efflux from THP‑1 macrophages via the PPAR‑γ/LXRα/SR‑BI pathway.

View Figures

View References

1	Cooper RA: Influence of increased membrane cholesterol on membrane fluidity and cell function in human red blood cells. J Supramol Struct. 8:413–430. 1978. View Article : Google Scholar : PubMed/NCBI
2	Needham D and Nunn RS: Elastic deformation and failure of lipid bilayer membranes containing cholesterol. Biophys J. 58:997–10094. 1990. View Article : Google Scholar : PubMed/NCBI
3	Hu J, Zhang Z, Shen WJ and Azhar S: Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab (Lond). 7:472010. View Article : Google Scholar : PubMed/NCBI
4	Gupta A and Smith DA: The 2013 American college of cardiology/American heart association guidelines on treating blood cholesterol and assessing cardiovascular risk: A busy practitioner's guide. Endocrinol Metab Clin North Am. 43:869–892. 2014. View Article : Google Scholar : PubMed/NCBI
5	Seo HS and Choi MH: Cholesterol homeostasis in cardiovascular disease and recent advances in measuring cholesterol signatures. J Steroid Biochem Mol Biol. 153:72–79. 2015. View Article : Google Scholar : PubMed/NCBI
6	Hovingh GK, Van Wijland MJ, Brownlie A, Bisoendial RJ, Hayden MR, Kastelein JJ and Groen AK: The role of the ABCA1 transporter and cholesterol efflux in familial hypoalphalipoproteinemia. J Lipid Res. 44:1251–1255. 2003. View Article : Google Scholar : PubMed/NCBI
7	Ohashi R, Mu H, Wang X, Yao Q and Chen C: Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM. 98:845–856. 2005. View Article : Google Scholar : PubMed/NCBI
8	Thuahnai ST, Lund-Katz S, Dhanasekaran P, de la Llera-Moya M, Connelly MA, Williams DL, Rothblat GH and Phillips MC: Scavenger receptor class B type I-mediated cholesteryl ester-selective uptake and efflux of unesterified cholesterol. Influence of high density lipoprotein size and structure. J Biol Chem. 279:12448–12455. 2004. View Article : Google Scholar : PubMed/NCBI
9	Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, et al: A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 7:161–171. 2001. View Article : Google Scholar : PubMed/NCBI
10	Tontonoz P, Nagy L, Alvarez JG, Thomazy VA and Evans RM: PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 93:241–252. 1998. View Article : Google Scholar : PubMed/NCBI
11	Zhao R, Feng J and He G: miR-613 regulates cholesterol efflux by targeting LXRα and ABCA1 in PPARγ activated THP-1 macrophages. Biochem Biophys Res Commun. 448:329–334. 2014. View Article : Google Scholar : PubMed/NCBI
12	Krakauer T, Li BQ and Young HA: The flavonoid baicalin inhibits superantigen-induced inflammatory cytokines and chemokines. FEBS Lett. 500:52–55. 2001. View Article : Google Scholar : PubMed/NCBI
13	Zhao Y, Li H, Gao Z and Xu H: Effects of dietary baicalin supplementation on iron overload-induced mouse liver oxidative injury. Eur J Pharmacol. 509:195–200. 2005. View Article : Google Scholar : PubMed/NCBI
14	Li BQ, Fu T, Dongyan Y, Mikovits JA, Ruscetti FW and Wang JM: Flavonoid baicalin inhibits HIV-1 infection at the level of viral entry. Biochem Biophys Res Commun. 276:534–538. 2000. View Article : Google Scholar : PubMed/NCBI
15	Chiu YW, Lin TH, Huang WS, Teng CY, Liou YS, Kuo WH, Lin WL, Huang HI, Tung JN, Huang CY, et al: Baicalein inhibits the migration and invasive properties of human hepatoma cells. Toxicol Appl Pharmacol. 255:316–326. 2011. View Article : Google Scholar : PubMed/NCBI
16	Abbasi P, Shamsasenjan K, Akbari AA Movassaghpour, Akbarzadehlaleh P, Dehdilani N and Ejtehadifar M: The effect of Baicalin as A PPAR activator on erythroid differentiation of CD133 (+)hematopoietic stem cells in umbilical cord blood. Cell J. 17:15–26. 2015.PubMed/NCBI
17	Yue J, Li B, Jing Q and Guan Q: Salvianolic acid B accelerated ABCA1-dependent cholesterol efflux by targeting PPAR-γ and LXRα. Biochem Biophys Res Commun. 462:233–238. 2015. View Article : Google Scholar : PubMed/NCBI
18	Zheng Y, Liu Y, Jin H, Pan S, Qian Y, Huang C, Zeng Y, Luo Q, Zeng M and Zhang Z: Scavenger receptor B1 is a potential biomarker of human nasopharyngeal carcinoma and its growth is inhibited by HDL-mimetic nanoparticles. Theranostics. 3:477–486. 2013. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Yancey PG, Bortnick AE, Kellner-Weibel G, de la Llera-Moya M, Phillips MC and Rothblat GH: Importance of different pathways of cellular cholesterol efflux. Arterioscler Thromb Vasc Biol. 23:712–719. 2003. View Article : Google Scholar : PubMed/NCBI
21	Chinetti G, Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapman J, Fruchart JC, Tedgui A, Najib-Fruchart J, et al: CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation. 101:2411–2417. 2000. View Article : Google Scholar : PubMed/NCBI
22	Nakaya K, Ayaori M, Hisada T, Sawada S, Tanaka N, Iwamoto N, Ogura M, Yakushiji E, Kusuhara M, Nakamura H and Ohsuzu F: Telmisartan enhances cholesterol efflux from THP-1 macrophages by activating PPARgamma. J Atheroscler Thromb. 14:133–141. 2007. View Article : Google Scholar : PubMed/NCBI
23	Voloshyna I, Hai O, Littlefield MJ, Carsons S and Reiss AB: Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPARγ and adenosine. Eur J Pharmacol. 698:299–309. 2013. View Article : Google Scholar : PubMed/NCBI
24	Xi Y, Wu M, Li H, Dong S, Luo E, Gu M, Shen X, Jiang Y, Liu Y and Liu H: Baicalin attenuates high fat diet-induced obesity and liver dysfunction: Dose-response and potential role of CaMKKβ/AMPK/ACC pathway. Cell Physiol Biochem. 35:2349–2359. 2015. View Article : Google Scholar : PubMed/NCBI
25	Liao P, Liu L, Wang B, Li W, Fang X and Guan S: Baicalin and geniposide attenuate atherosclerosis involving lipids regulation and immunoregulation in ApoE^−/- mice. Eur J Pharmacol. 740:488–495. 2014. View Article : Google Scholar : PubMed/NCBI
26	Rosenson RS, Brewer HB Jr, Davidson WS, Fayad ZA, Fuster V, Goldstein J, Hellerstein M, Jiang XC, Phillips MC, Rader DJ, et al: Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport. Circulation. 125:1905–1919. 2012. View Article : Google Scholar : PubMed/NCBI
27	Trigatti B, Covey S and Rizvi A: Scavenger receptor class B type I in high-density lipoprotein metabolism, atherosclerosis and heart disease: Lessons from gene-targeted mice. Biochem Soc Trans. 32:116–120. 2004. View Article : Google Scholar : PubMed/NCBI
28	Gu X, Kozarsky K and Krieger M: Scavenger receptor class B, type I-mediated [3H]cholesterol efflux to high and low density lipoproteins is dependent on lipoprotein binding to the receptor. J Biol Chem. 275:29993–30001. 2000. View Article : Google Scholar : PubMed/NCBI
29	Jian B, de la Llera-Moya M, Ji Y, Wang N, Phillips MC, Swaney JB, Tall AR and Rothblat GH: Scavenger receptor class B type I as a mediator of cellular cholesterol efflux to lipoproteins and phospholipid acceptors. J Biol Chem. 273:5599–5606. 1998. View Article : Google Scholar : PubMed/NCBI
30	Liadaki KN, Liu T, Xu S, Ishida BY, Duchateaux PN, Krieger JP, Kane J, Krieger M and Zannis VI: Binding of high density lipoprotein (HDL) and discoidal reconstituted HDL to the HDL receptor scavenger receptor class B type I. Effect of lipid association and APOA-I mutations on receptor binding. J Biol Chem. 275:21262–21471. 2000. View Article : Google Scholar : PubMed/NCBI
31	Majdalawieh A and Ro HS: PPARgamma1 and LXRalpha face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1. Nucl Recept Signal. 8:e0042010. View Article : Google Scholar : PubMed/NCBI
32	Tang SL, Chen WJ, Yin K, Zhao GJ, Mo ZC, Lv YC, Ouyang XP, Yu XH, Kuang HJ, Jiang ZS, et al: PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXRα through the IGF-I-mediated signaling pathway. Atherosclerosis. 222:344–354. 2012. View Article : Google Scholar : PubMed/NCBI
33	Ma AZ, Song ZY and Zhang Q: Cholesterol efflux is LXRalpha isoform-dependent in human macrophages. BMC Cardiovasc Disord. 14:802014. View Article : Google Scholar : PubMed/NCBI
34	Kämmerer I, Ringseis R, Biemann R, Wen G and Eder K: 13-hydroxy linoleic acid increases expression of the cholesterol transporters ABCA1, ABCG1 and SR-BI and stimulates apoA-I-dependent cholesterol efflux in RAW264. 7 macrophages. Lipids Health Dis. 10:2222011. View Article : Google Scholar : PubMed/NCBI