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The molecular mechanism of curcumin on the expression of liver cells in LDLR

Author: ZuoXiaoBing
Tutor: WoXingDe
School: Beijing University of Traditional Chinese Medicine
Course: Chinese and Western medicine combined with the basis
Keywords: Chinese Medicine Curcumin Low-density lipoprotein receptor SREBP pathway Cholesterol HepG2 cells Insig-2
CLC: R285.5
Type: PhD thesis
Year: 2007
Downloads: 336
Quote: 1
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Abstract


The elevation of serum cholesterol levels, especially LDL-C, is by far one of the mostrelative risk factors that cause atherosclerosis and CHD. Lowering LDL-C levels bymedication can reduce the mortality of CHD significantly. The majority of LDL-C are takenup and cleared by hepatic LDLR. LDLR is a trans-membrane receptor located on cell surface,the expression level of which is tightly regulated by sterols or non-sterols pathway both onthe transcription and post-transcription level. Up-regulation of hepatic LDLR is the mosteffective method to lower serum LDL-C levels. The most widely-used cholesterol-loweringdrug at present is statins. Statins can inhibit the enzymatic activity of HMG-CoA reductasecompetitively, and then inhibit the cellular cholesterol synthesis. In general, statins haveexcellent effect in hypercholesterolemia. However, a small part of patients can not toleratestatins because of adverse effects such as liver function damage. So, the efforts for screeningnew types of LDLR up-regulators have being done for a long time.Objective:Based on the traditional Chinese herbal medicine on the screen, we discovered HuoxueHuayu turmeric extract of curcumin could significantly reduce serum cholesterol, LDL-C andplayed the role of hypolipidemic and anti-atherosclerotic effect. In order to study themolecular mechanism of the curcumin effects on cholesterol-lowering, we designed a seriesof experiments. In the basis of previous research, from the level of gene expression and cellsignaling regulation, the issue is order to clarify the mechanism of curcumin on the LDLRexpression and search for the interaction between curcumin and the key protein moleculesand genes in the signal pathway.Methods:PartⅠis the effects of curcumin-induced expression of LDLR.Firstly, using human liver HepG2 cells as LDLR gene expression detection system, aftercurcumin treated, liver cells-derived LDLR protein expression and activity of endocytosis areanalysised by Western-Blot, Rt-PCR, Fluorescence microscopy, flow cytometry and othertechniques. Then the effects of curcumin on LDLR on the gene expression are identified, andthe role of cholesterol-reducing mechanism was clarified from the receptor protein levels.PartⅡis the mechanism of curcumin-induced expression of LDLR.①Green fluorescent protein (GFP) reporter gene is constructed in the downstream oflow-density lipoprotein receptor gene control components, SRE-1, and then is transductedinto HepG2 cells by liposome-mediated methods. Then LDLR gene expression regulationreporting system is conducted and the HepG2/SRE-GFP stable cell line is established. Aftercurcumin treated, the mechanism of curcumin on the promoter SRE-1 is explained from the level of gene expression regulation.②The CMV-Insig2 plasmid is also transducted into HepG2 cells by liposome-mediatedmethods and then constructs the stable cell lines, HepG2/Insig2. After curcumin treated, themechanism of curcumin on the Insig2 is revealed from the level of gene expression regulation.And the possible molecular or genetic target of curcumin in the role of cholesterol lowering isexplored.Results:PartⅠresults showed that,①curcumin can enhance HepG2 LDLR uptake of LDL,Obviously with the time-dependent and dose-dependent manner. And the 25μmol/L and the24-hour time LDLR have the strongest endocytosis activity.②Curcumin can significantlypromote the expression in HepG2 LDLR, with obvious time-dependent and dose-dependentmanner.③Curcumin can up-regulate the expression of LDLR mRNA to a significant extentin the human hepatoma cell line HepG2.PartⅡresults showed that,①Curcumin can activate the promoter element SRE-1 toincrease LDLR expression.②Certain concentration of curcumin can reverse and restore theSREBP pathway inhibited by the Insig2 and up-regulate the expression of LDLR.Conclusion:In summary, from the receptor level, gene expression levels and the signal regulationpathway level, we discussed the mechanism of the curcumin on the cholesterol-lowering by aseries of studies. All the evidence proved that curcumin, as a cholesterol-lowering drug, canpromote the LDLR expression by acting with some regulational molecular in the SREBPpathway. But which step the curcumin acts on remains to be further studied.

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