Dietary resveratrol increases the expression of hepatic 7α-hydroxylase and ameliorates hypercholesterolemia in high-fat fed C57BL/6J mice

Lipids in Health and Disease

Pei Zhai¹  Liping Ma¹  Ermao Wang¹  Qiong Chen¹ 

[1] Department of food science, Guangdong Food and Drug Vocational College, Guangzhou, 510635, China

关键词: Mice;    Bile acid pool size;    LXRα;    High-fat diet;    Resveratrol;   

Others  :  1160307
DOI  :  10.1186/1476-511X-11-56

 received in 2012-04-04, accepted in 2012-05-02,  发布年份 2012

【 摘 要 】

Background

Resveratrol (RSV), a naturally occurring polyphenolic stilbenoid, is known to possess potent anti-atherogenic properties; however, the effect of RSV on hypercholesterolemia is not fully understood. We hypothesized that RSV decreases blood cholesterol levels through the activation of cholesterol 7α-hydroxylase (CYP7A1)-mediated bile acid synthetic pathway pathways in vitro and in vivo.

Methods

In this study, we evaluated body weight, serum lipid concentrations, hepatic lipid content and the size of the bile acid pool in high-fat diet (HFD)-fed C57BL/6 J mice that were treated with RSV. In addition, we characterized the underlying mechanism of the effects of RSV in HepG2 hepatocytes by Western blot analysis.

Results

RSV (200 mg/kg per day) reduced body weight and liver weight gains, improved serum lipid parameters, reduced hepatic cholesterol accumulation and increased the bile acid pool size in mice fed an HFD for 8 wks. RSV significantly increased liver expression of CYP7A1 mRNA and protein and CYP7A1 enzyme activity. Furthermore, RSV treatment upregulated CYP7A1 expression and induced liver X receptor alpha (LXRα) activation in a time- and dose-dependent manner in HepG2 cells. In addition, the specific liver X receptor alpha (LXRα) inhibitor geranylgeranyl pyrophosphate (GGPP) inhibited the RSV-induced expression of CYP7A1 in HepG2 hepatocytes.

Conclusion

The beneficial effects of RSV on HFD-induced hypercholesterolemia are mediated through LXRα signaling pathways, suggesting a potential target for the prevention of dyslipidemia.

【 授权许可】

   
2012 Chen et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Breslow JL: Cardiovascular disease burden increases, NIH funding decreases. Nat Med 1997, 3:600-601.
• [2]Goldstein JL, Kita T, Brown MS: Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med 1983, 309:288-296.
• [3]de Sauvage Nolting PR, Defesche JC, Buirma RJ, Hutten BA, Lansberg PJ, Kastelein JJ: Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia. J Intern Med 2003, 253:161-168.
• [4]Florentin M, Liberopoulos EN, Mikhailidis DP, Elisaf MS: Emerging options in the treatment of dyslipidemias: a bright future? Expert Opin Emerg Drugs 2011, 16:247-270.
• [5]Gilardi F, Mitro N, Godio C, Scotti E, Caruso D, Crestani M, De Fabiani E: The pharmacological exploitation of cholesterol 7alpha-hydroxylase, the key enzyme in bile acid synthesis: from binding resins to chromatin remodelling to reduce plasma cholesterol. Pharmacol Ther 2007, 116:449-472.
• [6]Luoma PV: Cytochrome P450 and gene activation–from pharmacology to cholesterol elimination and regression of atherosclerosis. Eur J Clin Pharmacol 2008, 64:841-850.
• [7]Pullinger CR, Eng C, Salen G, Shefer S, Batta AK, Erickson SK, Verhagen A, Rivera CR, Mulvihill SJ, Malloy MJ, Kane JP: Human cholesterol 7alpha- hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 2002, 110:109-117.
• [8]Baur JA, Sinclair DA: Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006, 5:493-506.
• [9]Gupta SC, Kannappan R, Reuter S, Kim JH, Aggarwal BB: Chemosensitization of tumors by resveratrol. Ann N Y Acad Sci 2011, 1215:150-160.
• [10]Petrovski G, Gurusamy N, Das DK: Resveratrol in cardiovascular health and disease. Ann N Y Acad Sci 2011, 1215:22-33.
• [11]Xia M, Hou M, Zhu H, Ma J, Tang Z, Wang Q, Li Y, Chi D, Yu X, Zhao T, Han P, Xia X, Ling W: Anthocyanins induce cholesterol efflux from mouse peritoneal macrophages: the role of the peroxisome proliferator-activated receptor {gamma}-liver X receptor {alpha}-ABCA1 pathway. J Biol Chem 2005, 280:36792-36801.
• [12]Renaud S, de Lorgeril M: Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992, 339:1523-1526.
• [13]Chu LM, Lassaletta AD, Robich MP, Sellke FW: Resveratrol in the prevention and treatment of coronary artery disease. Curr Atheroscler Rep 2011, 13:439-446.
• [14]Hao HD, He LR: Mechanisms of cardiovascular protection by resveratrol. J Med Food 2004, 7:290-298.
• [15]Wu JM, Hsieh TC, Wang Z: Cardioprotection by resveratrol: a review of effects/targets in cultured cells and animal tissues. Am J Cardiovasc Dis 2011, 1:38-47.
• [16]Roberts A, Thompson JS: Genetic factors in the development of atheroma and on serum total cholesterol levels in inbred mice and their hybrids. Prog Biochem Pharmacol 1977, 13:298-305.
• [17]Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P: Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 1985, 57:65-73.
• [18]Nijstad N, Gautier T, Briand F, Rader DJ, Tietge UJ: Biliary sterol secretion is required for functional in vivo reverse cholesterol transport in mice. Gastroenterology 2011, 140:1043-1051.
• [19]Wiersma H, Gatti A, Nijstad N, Kuipers F, Tietge UJ: Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice. J Lipid Res 2009, 50:1571-1580.
• [20]Post SM, Groenendijk M, van der Hoogt CC, Fievet C, Luc G, Hoekstra M, Princen HM, Staels B, Rensen PC: Cholesterol 7alpha-hydroxylase deficiency in mice on an APOE*3-Leiden background increases hepatic ABCA1 mRNA expression and HDL-cholesterol. Arterioscler Thromb Vasc Biol 2006, 26:2724-2730.
• [21]Cooper AD: Bile salt biosynthesis: an alternate synthetic pathway joins the mainstream. Gastroenterology 1997, 113:2005-2008.
• [22]Agellon LB, Drover VA, Cheema SK, Gbaguidi GF, Walsh A: Dietary cholesterol fails to stimulate the human cholesterol 7alpha-hydroxylase gene (CYP7A1) in transgenic mice. J Biol Chem 2002, 277:20131-20134.
• [23]Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ: Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 1998, 93:693-704.
• [24]Gupta S, Pandak WM, Hylemon PB: LXR alpha is the dominant regulator of CYP7A1 transcription. Biochem Biophys Res Commun 2002, 293:338-343.
• [25]Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM: Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 1997, 272:3137-3140.
• [26]Folch J, Lees M, Sloane Stanley GH: A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957, 226:497-509.
• [27]Gamble W, Vaughan M, Kruth HS, Avigan J: Procedure for determination of free cholesterol in micro- or nanogram amounts suitable for studies with cultured cells. J Lipid Res 1978, 19:1068-1070.
• [28]Tiemann M, Han Z, Soccio R, Bollineni J, Shefer S, Sehayek E, Breslow JL: Cholesterol feeding of mice expressing cholesterol 7alpha-hydroxylase increases bile acid pool size despite decreased enzyme activity. Proc Natl Acad Sci USA 2004, 101:1846-1851.
• [29]Ando H, Tsuruoka S, Yamamoto H, Takamura T, Kaneko S, Fujimura A: Regulation of cholesterol 7alpha-hydroxylase mRNA expression in C57BL/6 mice fed an atherogenic diet. Atherosclerosis 2005, 178:265-269.
• [30]Burke KT, Horn PS, Tso P, Heubi JE, Woollett LA: Hepatic bile acid metabolism in the neonatal hamster: expansion of the bile acid pool parallels increased Cyp7a1 expression levels. Am J Physiol Gastrointest Liver Physiol 2009, 297:G144-G151.
• [31]Wang N, Ranalletta M, Matsuura F, Peng F, Tall AR: LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL. Arterioscler Thromb Vasc Biol 2006, 26:1310-1316.