Curcumin Up-Regulates LDL Receptor Expression via the Sterol Regulatory Element Pathway in HepG2 Cells

Abstract

Plasma low-density lipoprotein-cholesterol (LDL-C) is mainly taken up and cleared by the hepatocellular LDL receptor (LDL-R). LDL-R gene expression is regulated by the sterol regulatory element binding proteins (SREBPs). Previous studies have shown that curcumin reduces plasma LDL-C and has hypolipidemic and anti-atherosclerotic effects. Herein, we investigated the effect of curcumin on LDL-R expression and its molecular mechanism in HepG2 cells. Curcumin increased LDL-R expression (mRNA and protein) and the resultant uptake of DiI-LDL in a dose- and time-dependent manner. Using a GFP reporter system in a transfected HepG2/SRE-GFP cell line, we found that curcumin activated the sterol regulatory element of the LDL-R promoter. In HepG2/Insig2 cells, curcumin reversed the inhibition of LDL-R expression induced by Insig2 overexpression. These data demonstrate that curcumin increases LDL-R protein expression and uptake activity via the SREBPs pathway. These findings contribute to our further understanding of the cholesterol-lowering and anti-atherosclerotic effects of curcumin.

curcumin - Curcuma longa L. - Zingiberaceae - low-density lipoprotein receptor - SREBP - HepG2

References

• 1 Sharma R A, Steward W P, Gescher A J. Pharmacokinetics and pharmacodynamics of curcumin.  Adv Exp Med Biol. 2007;  595 453-70
• 2 Wo X D, Cui X Q, Tang L H. Effects of curcumin on the activities of plasma lipase and the concentrations of lipids in hyperlipidemic rats induced by high lipid diet.  Chin J Arterioscler. 2003;  11 223-6
• 3 Manjunatha H, Srinivasa K. Hypolipidemic and antioxidant effects of curcumin and capsaicin in high-fat-fed rats.  Can J Physiol Pharmacol. 2007;  85 588-96
• 4 Olszanecki R, Jawien J, Gajda M, Mateuszuk L, Gebska A, Korabiowska M. et al . Effect of curcumin on atherosclerosis in apoE/LDLR-double knockout mice.  J Physiol Pharmacol. 2005;  56 627-35
• 5 Dou X B, Fan C L, Hong X Q, Qian Y, Wo X D. Effect of curcumin on expression of LDLR in human lymphocytes.  J Chin Pharm. 2005;  40 980-2
• 6 Chunlei F, Xingde W, Xiaobing D, Li X, Ying Q, Yan L. et al . Regulation of LDL receptor expression by the effect of curcumin on sterol regulatory element pathway.  Pharmacol Rep. 2006;  58 577-81
• 7 Qian Y, Fan C L, Dou X B, Hu L F, Wo X D. Effect of curcumin on sterol regulatory report system in HEK-293.  Chin Pharmacol Bull. 2006;  22 257-60
• 8 Fan C L, Wo X D, Qian Y, Yan J, Gao L P. Effect of curcumin on the expression of LDL receptor in mouse macrophages.  J Ethnopharmacol. 2006;  105 251-4
• 9 Fan C L, Qian Y, Lu D Z, Wo X D, Gao L P, Yan J. Establishing sterol regulatory report system in xenopus oocytes and its application for screening of lipid-lowering drugs.  J Chin Pharm. 2006;  41 664-8
• 10 Soutar A K, Knight B L. Structure and regulation of the LDL-receptor and its gene.  Br Med Bull. 1990;  46 891-916
• 11 Brown M S, Goldstein J. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.  Cell. 1997;  89 331-40
• 12 Liu J, Zhang F, Li C, Lin M, Briggs M R. Synergistic activation of human LDL receptor expression by SCAP ligand and cytokine oncostatin M.  Arterioscler Thromb Vasc Biol. 2003;  23 90-6
• 13 Yu-Poth S, Yin D, Zhao G, Kris-Etherton P M, Etherton T D. Conjugated linoleic acid upregulates LDL receptor gene expression in HepG2 cells.  J Nutr. 2004;  134 68-71
• 14 Salleh M N, Runnie I, Roach P D, Mohamed S, Abeywardena M Y. Inhibition of low-density lipoprotein oxidation and up-regulation of low-density lipoprotein receptor in HepG2 cells by tropical plant extracts.  J Agric Food Chem. 2002;  50 3693-7
• 15 Peschel D, Koerting R, Nass N. Curcumin induces changes in expression of genes involved in cholesterol homeostasis.  J Nutr Biochem. 2007;  18 113-9
• 16 Brown M S, Goldstein J L. A receptor-mediated pathway for cholesterol homeostasis.  Science. 1986;  232 4-47
• 17 Briggs M R, Yokoyama C, Wang X, Brown M S, Goldstein J L. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter, I: identification of the protein and delineation of its target nucleotide sequence.  J Biol Chem. 1993;  268 14 490-6
• 18 Sun L P, Seemann J, Brown M S, Goldstein J L. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi:Insig renders sorting signal in SCAP inaccessible to COPII proteins.  Proc Natl Acad Sci. 2007;  104 6519-26
• 19 Yabe D, Brown M S, Goldstein J L. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins.  Proc Natl Acad Sci. 2002;  99 12 753-8
• 20 Yang T, Espenshade P J, Wright M E, Yabe D, Gong Y, Aebersold R. et al . Crucial step in cholesterol homeostasis:sterols promote binding of SCAP to Insig-1, a membrane protein that facilitates retention of SREBPs in ER.  Cell. 2002;  110 489-500
• 21 Higgins M E, Ioannou Y A. Apoptosis-induced release of mature sterol regulatory element-binding proteins activates sterol-responsive genes.  J Lipid Res. 2001;  42 939-46
• 22 Baum L, Cheung S K, Mok V C, Lam L C, Leung V P, Hui E. et al . Curcumin effects on blood lipid profile in a 6-month human study.  Pharmacol Res. 2007;  56 509-14