Abstract
Objective
To examine the effect of squalene on liver X receptors (LXRs) that regulate target genes associated with reverse cholesterol transport and thus control whole-body cholesterol homeostasis.
Results
To examine the effect of squalene on liver X receptors (LXRs) that regulate target genes associated with reverse cholesterol transport and thus control whole-body cholesterol homeostasis. Squalene significantly stimulated the transactivation of liver X receptor modulator LXRα and LXRβ. The mRNA expression of LXRs and their target genes, including ABCA1, ABCG1 and ApoE, was significantly induced in macrophages stimulated with squalene, resulting in removal of cholesterol from the cells. Notably, squalene did not induce higher hepatic triacylglycerol levels nor did it alter expression of sterol regulatory element-binding protein 1c (SREBP-1c) and FAS in hepatocyte cells, primarily because of its upregulation of Insig-2a, which delays nuclear translocation of SREBP-1c, a key hepatic lipogenic transcription factor.
Conclusion
Squalene has hypocholesterolemic effect through the activation of LXRα and β without inducing hepatic lipogenesis.
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References
Albers M, Blume B, Schlueter T, Wright MB, Kober I, Kremoser C, Deuschle U, Koegl MA (2006) A novel principle for partial agonism of liver X receptor ligands. Competitive recruitment of activators and repressors. J Biol Chem 281:4920–4930
Brown AJ, Sun L, Feramisco JD, Brown MS, Goldstein JL (2002) Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol Cell 10:237–245
Chan P, Tomlinson B, Lee CB, Lee YS (1996) Effectiveness and safety of low-dose pravastatin and squalene, alone and in combination, in elderly patients with hypercholesterolemia. J Clin Pharmacol 36:422–427
Dang HX, Liu Y, Pang W, Li CH, Wang NP, Shyy JYJ, Zhu Y (2009) Suppression of 2,3-oxidosqualene cyclase by high fat diet contributes to liver X receptor-α-mediated improvement of hepatic lipid profile. J Chem Biol 284:6218–6226
Geyeregger R, Zeyda M, Stulnig TM (2006) Liver X receptors in cardiovascular and metabolic disease. Cell Mol Life Sci 63:524–539
Hoang MH, Jia Y, Jun HJ, Lee JH, Lee BY, Lee SJ (2012) Fucosterol is a selective liver X receptor modulator that regulates the expression of key genes in cholesterol homeostasis in macrophages, hepatocytes, and intestinal cells. J Agric Food Chem 60:11567–11575
Hoang MH, Ha NC, Thom LT, Tam LT, Anh HT, Thu NT, Hong DD (2014) Extraction of squalene as value-added product from the residual biomass of Schizochytrium mangrovei PQ6 during biodiesel producing process. J Biosci Bioeng 118:632–639
Levin N, Bischoff ED, Daige CL, Thomas D, Vu CT, Heyman RA, Tangirala RK, Schulman IG (2005) Macrophage liver X receptor is required for antiatherogenic activity of LXR agonists. Arterioscl Thromb Vasc 25:135–142
Liu Y, Xu X, Bi D, Wang X, Zhang X, Dai H (2009) Influence of squalene feeding on plasma leptin, testosterone and blood pressure in rats. Indian J Med Res 129:150–153
Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ (2002) Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem 277:18793–18800
Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B (2000) Role of LXRs in control of lipogenesis. Genes Dev 14:2831–2838
Spanova M, Daum G (2011) Squalene – biochemistry, molecular biology, process biotechnology, and applications. Eur J Lipid Sci Technol 113:1299–1320
Svensson S, Ostberg T, Jacobsson M, Norstrom C, Stefansson K, Hallen D, Johansson IC, Zachrisson K, Ogg D, Jendeberg L (2003) Crystal structure of the heterodimeric complex of LXRα and RXRβ ligand-binding domains in a fully agonistic conformation. EMBO J 22:4625–4633
Wouters K, Shiri-Sverdlov R, van Gorp PJ, van Bilsen M, Hofker MH (2005) Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice. Clin Chem Lab Med 43:470–479
Yabe D, Brown MS, Goldstein JL (2002) Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci USA 99:12753–12758
Acknowledgements
This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under Grant number 106-YS.06-2013.23. We would like to send our appreciation to all of supports from National Key Laboratory, Institute of Biotechnology, VAST. The LXRα, β and LXRE plasmids were a generous gift of Prof. Dr. Sung-Joon Lee, Korea University, Seoul, Korea.
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Supplementary Table 1—Primers used for qRT-PCR.
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Hien, H.T.M., Ha, N.C., Thom, L.T. et al. Squalene promotes cholesterol homeostasis in macrophage and hepatocyte cells via activation of liver X receptor (LXR) α and β. Biotechnol Lett 39, 1101–1107 (2017). https://doi.org/10.1007/s10529-017-2345-y
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DOI: https://doi.org/10.1007/s10529-017-2345-y