Docosahexanoic acid modifies low-density lipoprotein receptor abundance in HepG2 cells via suppression of the LXRα‑Idol pathway

Zhou,Ying; Guo,Yue; Zhuang,Xiaodong; Du,Zhimin

doi:10.3892/mmr.2014.2940

Docosahexanoic acid modifies low-density lipoprotein receptor abundance in HepG2 cells via suppression of the LXRα‑Idol pathway

Authors:
- Ying Zhou
- Yue Guo
- Xiaodong Zhuang
- Zhimin Du
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Affiliations: Department of Cardiology, Key Laboratory on Assisted Circulation, First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: November 13, 2014 https://doi.org/10.3892/mmr.2014.2940
Pages: 2329-2333

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Abstract

As a daily supplement, omega‑3 fatty acid is confirmed to be of benefit in hypertriglyceridemia. However, the effect of omega‑3 fatty acids on the low‑density lipoprotein cholesterol (LDL‑C) metabolism remains a controversial issue. In this study, we focused on the regulatory effect of docosahexanoic acid (DHA), one type of omega‑3 fatty acid, exerted on the LDL receptor (LDLR), a determinant regulator of the LDL‑C metabolism, and explored the potential mechanism. We observed that DHA increased hepatic LDLR protein in the presence of 25‑hydroxycholesterol in HepG2 cells but did not alter the mRNA level. Previous studies have identified inducible degrader of the LDLR (Idol) as a novel negative post‑translational modulator of LDLR and a direct transcriptional target of liver X receptor α (LXRα). Since DHA had no effect on the transcriptional level of LDLR, we speculated that the post‑transcriptional pathway LXRα‑Idol participated in this regulation. The results reveal that DHA downregulated the expression of LXRα and Idol in coordination with the upregulation of LDLR expression. Multiple mechanisms are involved in the regulation of LDLR by DHA, and the suppression of the LXRα‑Idol pathway is one of these mechanisms.

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1	Stone NJ, Robinson JG, Lichtenstein AH, et al: 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 63:2889–2934. 2014. View Article : Google Scholar
2	Amarenco P, Labreuche J, Lavallée P and Touboul PJ: Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 35:2902–2909. 2004. View Article : Google Scholar : PubMed/NCBI
3	ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, et al: Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 362:1563–1574. 2010. View Article : Google Scholar : PubMed/NCBI
4	Ingelsson E, Schaefer EJ, Contois JH, et al: Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 298:776–785. 2007. View Article : Google Scholar : PubMed/NCBI
5	Pedersen TR, Faergeman O, Kastelein JJ, et al: High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 294:2437–2445. 2005. View Article : Google Scholar : PubMed/NCBI
6	Yamamoto T, Davis CG, Brown MS, et al: The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 39:27–38. 1984. View Article : Google Scholar : PubMed/NCBI
7	Hua X, Yokoyama C, Wu J, et al: SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc Natl Acad Sci USA. 90:11603–11607. 1993. View Article : Google Scholar : PubMed/NCBI
8	Kawabe Y, Suzuki T, Hayashi M, Hamakubo T, Sato R and Kodama T: The physiological role of sterol regulatory element-binding protein-2 in cultured human cells. Biochim Biophys Acta. 1436:307–318. 1999. View Article : Google Scholar : PubMed/NCBI
9	Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D and Park SW: Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res. 49:399–409. 2008. View Article : Google Scholar
10	Fisher TS, Lo Surdo P, Pandit S, et al: Effects of pH and low density lipoprotein (LDL) on PCSK9-dependent LDL receptor regulation. J Biol Chem. 282:20502–20512. 2007. View Article : Google Scholar : PubMed/NCBI
11	Zelcer N, Hong C, Boyadjian R and Tontonoz P: LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science. 325:100–104. 2009. View Article : Google Scholar : PubMed/NCBI
12	Zelcer N and Tontonoz P: Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest. 116:607–614. 2006. View Article : Google Scholar : PubMed/NCBI
13	Pawar A, Botolin D, Mangelsdorf DJ and Jump DB: The role of liver X receptor-alpha in the fatty acid regulation of hepatic gene expression. J Biol Chem. 278:40736–40743. 2003. View Article : Google Scholar : PubMed/NCBI
14	Vanden Heuvel JP: Cardiovascular disease-related genes and regulation by diet. Curr Atheroscler Rep. 11:448–455. 2009. View Article : Google Scholar : PubMed/NCBI
15	Mustad VA, Ellsworth JL, Cooper AD, Kris-Etherton PM and Etherton TD: Dietary linoleic acid increases and palmitic acid decreases hepatic LDL receptor protein and mRNA abundance in young pigs. J Lipid Res. 37:2310–2323. 1996.PubMed/NCBI
16	Yu-Poth S, Yin D, Kris-Etherton PM, Zhao G and Etherton TD: Long-chain polyunsaturated fatty acids upregulate LDL receptor protein expression in fibroblasts and HepG2 cells. J Nutr. 135:2541–2545. 2005.PubMed/NCBI
17	Sorrentino V, Scheer L, Santos A, Reits E, Bleijlevens B and Zelcer N: Distinct functional domains contribute to degradation of the low density lipoprotein receptor (LDLR) by the E3 ubiquitin ligase inducible Degrader of the LDLR (IDOL). J Biol Chem. 286:30190–30199. 2011. View Article : Google Scholar : PubMed/NCBI
18	Janowski BA, Willy PJ, Devi TR, Falck JR and Mangelsdorf DJ: An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 383:728–731. 1996. View Article : Google Scholar : PubMed/NCBI
19	Field FJ, Born E and Mathur SN: Fatty acid flux suppresses fatty acid synthesis in hamster intestine independently of SREBP-1 expression. J Lipid Res. 44:1199–1208. 2003. View Article : Google Scholar : PubMed/NCBI
20	Xu J, Nakamura MT, Cho HP and Clarke SD: Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem. 274:23577–23583. 1999. View Article : Google Scholar : PubMed/NCBI
21	Xu J, Teran-Garcia M, Park JH, Nakamura MT and Clarke SD: Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay. J Biol Chem. 276:9800–9807. 2001. View Article : Google Scholar : PubMed/NCBI
22	Chen J, Jiang Y, Liang Y, et al: DPA n−3, DPA n−6 and DHA improve lipoprotein profiles and aortic function in hamsters fed a high cholesterol diet. Atherosclerosis. 221:397–404. 2012. View Article : Google Scholar : PubMed/NCBI