Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

MicroRNA-mediated Regulation of LDL Receptor: Biological and Pharmacological Implications

Author(s): Reyhaneh Keshavarz, Željko Reiner, Gokhan Zengin, Ali H. Eid and Amirhossein Sahebkar*

Volume 31, Issue 14, 2024

Published on: 12 May, 2023

Page: [1830 - 1838] Pages: 9

DOI: 10.2174/0929867330666230407091652

Price: $65

Abstract

One of the main causes of atherosclerosis is a disruption in cellular cholesterol hemostasis. The low-density lipoprotein receptor (LDLR) is an important factor in maintaining cholesterol homeostasis by the receptor-mediated endocytosis of LDL particles. Defective hepatic LDLR activity and uptake of LDL particles lead to elevated blood levels of low-density lipoprotein cholesterol (LDL-C), which is associated with a higher risk of atherosclerotic cardiovascular disease. LDLR expression can be affected by microRNAs (miRNAs). Some miRNAs, like miR-148a, miR-185, miR-224, miR-520, miR-128-1, miR-27a/b, miR-130b, and miR-301 seem to be important post-transcriptional regulators of LDLR related genes. These findings indicate the critical role of miRNAs in regulating LDL metabolism. The aim of this review was to provide insight into the miRNAs involved in LDLR activity and their potential roles in the treatment of cardiovascular disease.

Keywords: MicroRNA, low-density lipoprotein receptor, atherosclerosis, cellular cholesterol hemostasis, receptormediated endocytosis, low-density lipoprotein cholesterol.

[1]
Macchi, C.; Greco, M.F.; Favero, C.; Dioni, L.; Cantone, L.; Hoxha, M.; Vigna, L.; Solazzo, G.; Corsini, A.; Banach, M.; Pesatori, A.C.; Bollati, V.; Ruscica, M. Associations among PCSK9 levels, atherosclerosis-derived extracellular vesicles, and their miRNA content in adults with obesity. Front. Cardiovasc. Med., 2022, 8, 785250.
[http://dx.doi.org/10.3389/fcvm.2021.785250] [PMID: 35071356]
[2]
Alvarez, M.L.; Khosroheidari, M.; Eddy, E.; Done, S.C. MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis. Atherosclerosis, 2015, 242(2), 595-604.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.08.023] [PMID: 26318398]
[3]
Aryal, B.; Singh, A.K.; Rotllan, N.; Price, N.; Fernández-Hernando, C. MicroRNAs and lipid metabolism. Curr. Opin. Lipidol., 2017, 28(3), 273-280.
[http://dx.doi.org/10.1097/MOL.0000000000000420] [PMID: 28333713]
[4]
Goedeke, L.; Wagschal, A.; Fernández-Hernando, C.; Näär, A.M. miRNA regulation of LDL-cholesterol metabolism. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 2016, 1861(12)(12 Pt B), 2047-2052.
[http://dx.doi.org/10.1016/j.bbalip.2016.03.007] [PMID: 26968099]
[5]
Bahrami, A.; Parsamanesh, N.; Atkin, S.L.; Banach, M.; Sahebkar, A. Effect of statins on toll-like receptors: A new insight to pleiotropic effects. Pharmacol. Res., 2018, 135, 230-238.
[http://dx.doi.org/10.1016/j.phrs.2018.08.014] [PMID: 30120976]
[6]
Ferretti, G.; Bacchetti, T.; Sahebkar, A. Effect of statin therapy on paraoxonase-1 status: A systematic review and meta-analysis of 25 clinical trials. Prog. Lipid Res., 2015, 60, 50-73.
[http://dx.doi.org/10.1016/j.plipres.2015.08.003] [PMID: 26416579]
[7]
Parizadeh, S.M.R.; Azarpazhooh, M.R.; Moohebati, M.; Nematy, M.; Ghayour-Mobarhan, M.; Tavallaie, S.; Rahsepar, A.A.; Amini, M.; Sahebkar, A.; Mohammadi, M.; Ferns, G.A.A. Simvastatin therapy reduces prooxidant-antioxidant balance: Results of a placebo-controlled cross-over trial. Lipids, 2011, 46(4), 333-340.
[http://dx.doi.org/10.1007/s11745-010-3517-x] [PMID: 21207250]
[8]
Sahebkar, A.; Kotani, K.; Serban, C.; Ursoniu, S.; Mikhailidis, D.P.; Jones, S.R.; Ray, K.K.; Blaha, M.J.; Rysz, J.; Toth, P.P.; Muntner, P.; Lip, G.Y.H.; Banach, M. Statin therapy reduces plasma endothelin-1 concentrations: A meta-analysis of 15 randomized controlled trials. Atherosclerosis, 2015, 241(2), 433-442.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.05.022] [PMID: 26074317]
[9]
Sahebkar, A.; Serban, C.; Mikhailidis, D.P.; Undas, A.; Lip, G.Y.H.; Muntner, P.; Bittner, V.; Ray, K.K.; Watts, G.F.; Hovingh, G.K.; Rysz, J.; Kastelein, J.J.; Banach, M. Association between statin use and plasma D-dimer levels. A systematic review and meta-analysis of randomised controlled trials. Thromb. Haemost., 2015, 114(3), 546-557.
[PMID: 26017749]
[10]
Sahebkar, A.; Serban, C.; Ursoniu, S.; Mikhailidis, D.P.; Undas, A.; Lip, G.Y.H.; Bittner, V.; Ray, K.K.; Watts, G.F.; Hovingh, G.K.; Rysz, J.; Kastelein, J.J.P.; Banach, M. The impact of statin therapy on plasma levels of von Willebrand factor antigen. Thromb. Haemost., 2016, 115(3), 520-532.
[http://dx.doi.org/10.1160/th15-08-0620] [PMID: 26632869]
[11]
Koushki, K.; Shahbaz, S.K.; Mashayekhi, K.; Sadeghi, M.; Zayeri, Z.D.; Yousefi, M.T.; Banach, M.; Al- Rasadi, K.; Johnston, T.P.; Sahebkar A. Anti-inflammatory action of statins in cardiovascular disease: The role of inflammasome and toll-Like receptor pathways. Clin. Rev. Allergy. Immunol., 2021, 60(2), 175-199.
[http://dx.doi.org/10.1007/s12016-020-08791-9]
[12]
Sohrevardi, S.; Nasab, F.; Mirjalili, M.; Bagherniya, M.; Tafti, A.; Jarrahzadeh, M.; Azarpazhooh, M.; Saeidmanesh, M.; Banach, M.; Jamialahmadi, T.; Sahebkar, A. Effect of atorvastatin on delirium status of patients in the intensive care unit: A randomized controlled trial. Arch. Med. Sci., 2019, 17(5), 1423-1428.
[http://dx.doi.org/10.5114/aoms.2019.89330] [PMID: 34522273]
[13]
Bahrami, A.; Bo, S.; Jamialahmadi, T.; Sahebkar, A. Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on ageing: Molecular mechanisms. Ageing Res. Rev., 2020, 58, 101024.
[http://dx.doi.org/10.1016/j.arr.2020.101024] [PMID: 32006687]
[14]
Vallejo-Vaz, A.J.; De Marco, M.; Stevens, C.A.T.; Akram, A.; Freiberger, T.; Hovingh, G.K.; Kastelein, J.J.P.; Mata, P.; Raal, F.J.; Santos, R.D.; Soran, H.; Watts, G.F.; Abifadel, M.; Aguilar-Salinas, C.A.; Al-khnifsawi, M.; AlKindi, F.A.; Alnouri, F.; Alonso, R.; Al-Rasadi, K.; Al-Sarraf, A.; Ashavaid, T.F.; Binder, C.J.; Bogsrud, M.P.; Bourbon, M.; Bruckert, E.; Chlebus, K.; Corral, P.; Descamps, O.; Durst, R.; Ezhov, M.; Fras, Z.; Genest, J.; Groselj, U.; Harada-Shiba, M.; Kayikcioglu, M.; Lalic, K.; Lam, C.S.P.; Latkovskis, G.; Laufs, U.; Liberopoulos, E.; Lin, J.; Maher, V.; Majano, N.; Marais, A.D.; März, W.; Mirrakhimov, E.; Miserez, A.R.; Mitchenko, O.; Nawawi, H.M.; Nordestgaard, B.G.; Paragh, G.; Petrulioniene, Z.; Pojskic, B.; Postadzhiyan, A.; Reda, A.; Reiner, Ž.; Sadoh, W.E.; Sahebkar, A.; Shehab, A.; Shek, A.B.; Stoll, M.; Su, T.C.; Subramaniam, T.; Susekov, A.V.; Symeonides, P.; Tilney, M.; Tomlinson, B.; Truong, T.H.; Tselepis, A.D.; Tybjærg-Hansen, A.; Vázquez-Cárdenas, A.; Viigimaa, M.; Vohnout, B.; Widén, E.; Yamashita, S.; Banach, M.; Gaita, D.; Jiang, L.; Nilsson, L.; Santos, L.E.; Schunkert, H.; Tokgözoğlu, L.; Car, J.; Catapano, A.L.; Ray, K.K. Overview of the current status of familial hypercholesterolaemia care in over 60 countries-the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Atherosclerosis, 2018, 277, 234-255.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.08.051] [PMID: 30270054]
[15]
Banach, M.; Serban, C.; Ursoniu, S.; Rysz, J.; Muntner, P.; Toth, P.P.; Jones, S.R.; Rizzo, M.; Glasser, S.P.; Watts, G.F.; Blumenthal, R.S.; Lip, G.Y.H.; Mikhailidis, D.P.; Sahebkar, A. Statin therapy and plasma coenzyme Q10 concentrations-A systematic review and meta-analysis of placebo-controlled trials. Pharmacol. Res., 2015, 99, 329-336.
[http://dx.doi.org/10.1016/j.phrs.2015.07.008] [PMID: 26192349]
[16]
Bytyçi, I.; Penson, P.E.; Mikhailidis, D.P.; Wong, N.D.; Hernandez, A.V.; Sahebkar, A.; Thompson, P.D.; Mazidi, M.; Rysz, J.; Pella, D.; Reiner, Ž.; Toth, P.P.; Banach, M. Prevalence of statin intolerance: A meta-analysis. Eur. Heart J., 2022, 43(34), 3213-3223.
[http://dx.doi.org/10.1093/eurheartj/ehac015] [PMID: 35169843]
[17]
Treiber, T.; Treiber, N.; Meister, G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat. Rev. Mol. Cell Biol., 2019, 20(1), 5-20.
[http://dx.doi.org/10.1038/s41580-018-0059-1] [PMID: 30228348]
[18]
Yang, S.C.; Alalaiwe, A.; Lin, Z.C.; Lin, Y.C.; Aljuffali, I.A.; Fang, J.Y. Anti-inflammatory microRNAs for treating inflammatory skin dseases. Biomolecules, 2022, 12(8), 1072.
[http://dx.doi.org/10.3390/biom12081072] [PMID: 36008966]
[19]
Medley, J.C.; Panzade, G.; Zinovyeva, A.Y. microRNA strand selection: Unwinding the rules. Wiley Interdiscip. Rev. RNA, 2021, 12(3), e1627.
[http://dx.doi.org/10.1002/wrna.1627] [PMID: 32954644]
[20]
Goedeke, L.; Aranda, J.F.; Fernández-Hernando, C. microRNA regulation of lipoprotein metabolism. Curr. Opin. Lipidol., 2014, 25(4), 282-288.
[http://dx.doi.org/10.1097/MOL.0000000000000094] [PMID: 24978143]
[21]
Ramírez, C.M.; Goedeke, L.; Fernández-Hernando, C. “Micromanaging” metabolic syndrome. Cell Cycle, 2011, 10(19), 3249-3252.
[http://dx.doi.org/10.4161/cc.10.19.17558] [PMID: 21946517]
[22]
Goedeke, L.; Rotllan, N.; Ramírez, C.M.; Aranda, J.F.; Canfrán-Duque, A.; Araldi, E.; Fernández-Hernando, A.; Langhi, C.; de Cabo, R.; Baldán, Á.; Suárez, Y.; Fernández-Hernando, C. miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice. Atherosclerosis, 2015, 243(2), 499-509.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.09.033] [PMID: 26520906]
[23]
Chen, W.J.; Yin, K.; Zhao, G.J.; Fu, Y.C.; Tang, C.K. The magic and mystery of MicroRNA-27 in atherosclerosis. Atherosclerosis, 2012, 222(2), 314-323.
[http://dx.doi.org/10.1016/j.atherosclerosis.2012.01.020] [PMID: 22307089]
[24]
Wagschal, A.; Najafi-Shoushtari, S.H.; Wang, L.; Goedeke, L.; Sinha, S.; deLemos, A.S.; Black, J.C.; Ramírez, C.M.; Li, Y.; Tewhey, R.; Hatoum, I.; Shah, N.; Lu, Y.; Kristo, F.; Psychogios, N.; Vrbanac, V.; Lu, Y.C.; Hla, T.; de Cabo, R.; Tsang, J.S.; Schadt, E.; Sabeti, P.C.; Kathiresan, S.; Cohen, D.E.; Whetstine, J.; Chung, R.T.; Fernández-Hernando, C.; Kaplan, L.M.; Bernards, A.; Gerszten, R.E.; Näär, A.M. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat. Med., 2015, 21(11), 1290-1297.
[http://dx.doi.org/10.1038/nm.3980] [PMID: 26501192]
[25]
Salerno, A.G.; van Solingen, C.; Scotti, E.; Wanschel, A.C.B.A.; Afonso, M.S.; Oldebeken, S.R.; Spiro, W.; Tontonoz, P.; Rayner, K.J.; Moore, K.J. LDL receptor pathway regulation by miR-224 and miR-520d. Front. Cardiovasc. Med., 2020, 7, 81.
[http://dx.doi.org/10.3389/fcvm.2020.00081] [PMID: 32528976]
[26]
Jiang, H.; Zhang, J.; Du, Y.; Jia, X.; Yang, F.; Si, S.; Wang, L.; Hong, B. microRNA-185 modulates low density lipoprotein receptor expression as a key posttranscriptional regulator. Atherosclerosis, 2015, 243(2), 523-532.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.10.026] [PMID: 26523989]
[27]
Yang, M.; Liu, W.; Pellicane, C.; Sahyoun, C.; Joseph, B.K.; Gallo-Ebert, C.; Donigan, M.; Pandya, D.; Giordano, C.; Bata, A.; Nickels, J.T., Jr Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake. J. Lipid Res., 2014, 55(2), 226-238.
[http://dx.doi.org/10.1194/jlr.M041335] [PMID: 24296663]
[28]
Xu, Y.; Gao, J.; Gong, Y.; Chen, M.; Chen, J.; Zhao, W.; Tan, S. Hsa-miR-140-5p down-regulates LDL receptor and attenuates LDL-C uptake in human hepatocytes. Atherosclerosis, 2020, 297, 111-119.
[http://dx.doi.org/10.1016/j.atherosclerosis.2020.02.004] [PMID: 32109664]
[29]
van Solingen, C.; Oldebeken, S.R.; Salerno, A.G.; Wanschel, A.C.B.A.; Moore, K.J. High-throughput screening identifies MicroRNAs regulating human PCSK9 and hepatic low-density lipoprotein receptor expression. Front. Cardiovasc. Med., 2021, 8, 667298.
[http://dx.doi.org/10.3389/fcvm.2021.667298] [PMID: 34322524]
[30]
Ma, N.; Fan, L.; Dong, Y.; Xu, X.; Yu, C.; Chen, J.; Ren, J. New PCSK9 inhibitor miR-552-3p reduces LDL-C via enhancing LDLR in high fat diet-fed mice. Pharmacol. Res., 2021, 167, 105562.
[http://dx.doi.org/10.1016/j.phrs.2021.105562] [PMID: 33737240]
[31]
Wang, N.; He, L.; Lin, H.; Tan, L.; Sun, Y.; Zhang, X.; Danser, A.H.J.; Lu, H.S.; He, Y.; Lu, X. MicroRNA-148a regulates low-density lipoprotein metabolism by repressing the (pro)renin receptor. PLoS One, 2020, 15(5), e0225356.
[http://dx.doi.org/10.1371/journal.pone.0225356] [PMID: 32437440]
[32]
Liu, A.; Frostegård, J. PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque. J. Intern. Med., 2018, 284(2), 193-210.
[http://dx.doi.org/10.1111/joim.12758] [PMID: 29617044]
[33]
Rotllan, N.; Fernández-Hernando, C. MicroRNA regulation of cholesterol metabolism. Cholesterol, 2012, 2012, 1-8.
[http://dx.doi.org/10.1155/2012/847849] [PMID: 22919472]
[34]
Lambert, G.; Sjouke, B.; Choque, B.; Kastelein, J.J.P.; Hovingh, G.K. The PCSK9 decade. J. Lipid Res., 2012, 53(12), 2515-2524.
[http://dx.doi.org/10.1194/jlr.R026658] [PMID: 22811413]
[35]
Reiner, Ž. PCSK9 inhibitors in clinical practice: Expectations and reality. Atherosclerosis, 2018, 270, 187-188.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.01.001] [PMID: 29366497]
[36]
Dong, J.; He, M.; Li, J.; Pessentheiner, A.; Wang, C.; Zhang, J.; Sun, Y.; Wang, W.T.; Zhang, Y.; Liu, J.; Wang, S.C.; Huang, P.H.; Gordts, P.L.S.M.; Yuan, Z.Y.; Tsimikas, S.; Shyy, J.Y.J. microRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production. JCI Insight, 2020, 5(23), e143812.
[http://dx.doi.org/10.1172/jci.insight.143812] [PMID: 33119548]
[37]
Momtazi, A.A.; Banach, M.; Pirro, M.; Stein, E.A.; Sahebkar, A. MicroRNAs: New therapeutic targets for familial hypercholesterolemia? Clin. Rev. Allergy Immunol., 2018, 54(2), 224-233.
[http://dx.doi.org/10.1007/s12016-017-8611-x] [PMID: 28534160]
[38]
Šimić, I.; Reiner, Z. Adverse effects of statins-myths and reality. Curr. Pharm. Des., 2015, 21(9), 1220-1226.
[http://dx.doi.org/10.2174/1381612820666141013134447] [PMID: 25312733]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy