COX-2在MCD饮食诱导的脂肪性肝纤维化中的作用及与PPARα的关系

doi:10.3969/j.issn.1000-1565.2008.04.018

摘要/Abstract

摘要： 探讨了COX-2在胆碱蛋氨酸缺乏(MCD)诱导的脂肪性肝纤维化模型中的表达变化以及与过氧化物酶体增殖物激活受体α(PPARα)的相互作用.雄性野生型小鼠(C57BL/6N)或PPARα-/-分别给予MCD饮食,MCD对照饮食8或9周.第1治疗组给予MCD饮食51 d后加用选择性PPARα激动剂匹立尼酸(Wy-14,643)5 d或12 d.第2治疗组给予MCD饮食7周后加用选择性COX-2抑制剂(塞来昔布)1或2周.COX-2在MCD饮食诱导的脂肪性肝纤维化模型中被大量诱导表达,选择性PPARα激动剂(Wy-14,643)的短期治疗显著降低COX-2表达和炎症因子TNF-α和IL-6以及重要致纤维化细胞因子TGF-β1 mRNA表达量.选择性COX-2抑制剂塞来昔布的短期治疗可明显减少脂肪性肝纤维化野生型小鼠的脂肪病变和炎症反应,降低血清ALT水平,但是塞来昔布对PPARα-/-小鼠无效.因此,COX-2在脂肪性肝纤维化病理进程中有十分重要的作用.选择性激动剂PPARα显著下调COX-2表达,而选择性COX-2抑制剂通过对PPARα激活而改善脂肪性肝纤维化病变.

关键词: 环氧化酶, 过氧化物酶体增殖物激活受体α, 脂肪性肝纤维化, 胆碱蛋氨酸缺乏饮食, 塞来昔布

中图分类号:

Q786

王世研,高向东,李宝琴,贾彦红. COX-2在MCD饮食诱导的脂肪性肝纤维化中的作用及与PPARα的关系[J]. 河北大学学报(自然科学版), 2008, 28(4): 414-422.

WANG Shi-yan,GAO Xiang-dong,LI Bao-qin,JIA Yan-hong. Role of COX-2 in MCD Diet Induced Fibrosis and Its Corelation with PPARα[J]. Journal of Hebei University (Natural Science Edition), 2008, 28(4): 414-422.

参考文献

[1] Day, CP, James, OF. Steatohepatitis: a tale of two hits? (editorial) [J]. Gastroenterology 1998, 4(4).
[2] FARRELL G C, LARTER C Z. Nonalcoholic fatty liver disease:from steatosis to cirrhosis [J]. Hepatology 2006, 43(z1).
[3] HOTAMISLIGIL G S. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes [J]. Diabetes 2005, 54(z2).
[4] Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw Boris A, Poli G, Olefsky J, Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. [J]. Nature medicine 2005, 2(2).
[5] Ramadori G, Christ B. Cytokines and the hepatic acute-phase response. [J]. Seminars in liver disease 1999, 2(2).
[6] YU J, IP E, DELA PE(N)A A. COX-2 induction in mice with experimental nutritional steatohepatitis:Role as pro-inflammatory mediator [J]. Hepatology 2006, 43(04).
[7] CHENG A S, CHAN H L, LEUNG W K. Expression of HBx and COX-2 in chronic hepatitis B, cirrhosis and hepatocellular carcinoma:implication of HBx in upregulation of COX-2 [J]. Modern Pathology 2004, 17(10).
[8] Chi Man Tang T, Tung Ping Poon R, Fan ST. The significance of cyclooxygenase-2 expression in human hepatocellular carcinoma. [J]. Biomedicine & pharmacotherapy =: Biomedecine & pharmacotherapie 2005, Suppl.2(Suppl.2).
[9] NANJI A A, ZAKIM D, RAHEMTULLA A. Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat [J]. Hepatology 1997, 26(06).
[10] YAMAMOTO H, KONDO M, NAKAMORI S. JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis [J]. Gastroenterology 2003, 125(02).
[11] Planaguma, A, Claria, J, Miquel, R, Lopez-Parra, M, Titos, E, Masferrer, JL, Arroyo, V, Rodes, J. The selective cyclooxygenase-2 inhibitor SC-236 reduces liver fibrosis by mechanisms involving non-parenchymal cell apoptosis and PPAR gamma activation [J]. The FASEB Journal 2005, 7(7).
[12] SHINOZUKA H, LOMBARDI B, SELL S, IAMARINO RM. Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline-deficient diet [J]. Cancer Research 1978, 38(04).
[13] Ahmed W, Ziouzenkova O, Brown J, Devchand P, Francis S, Kadakia M, Kanda T, Orasanu G, Sharlach M, Zandbergen F, Plutzky J. PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? [J]. Journal of Internal Medicine 2007, 2(2).
[14] Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). [J]. The Journal of biological chemistry 1998, 10(10).
[15] Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. [J]. Hepatology 2003, 1(1).
[16] IP E, FARRELL G, HALL P. Administration of the potent PPARalpha agonist, Wy-14, 643, reverses nutritional fibrosis and steatohepatitis in mice [J]. Hepatology 2004, 39(05).
[17] McMahon RF. Distribution of constitutive (COX-1) and inducible (COX-2) cyclooxygenase in postviral human liver cirrhosis: a possible role for COX-2 in the pathogenesis of liver cirrhosis. [J]. Journal of Clinical Pathology 2004, 4(4).
[18] NANJI A A, MIAO L, THOMAS P. Enhanced cyclooxygenase-2 gene expression in alcoholic liver disease in the rat [J]. GASTROENTEROLOGY 1997, 112(03).
[19] DINCHUK J E, CAR B D, FOCHT R J. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase Ⅱ [J]. Nature 1995, 378(6555).
[20] YU J, HUI A Y, CHU E S. Expression of a cyclo-oxygenase-2 transgene in murine liver causes hepatitis [J]. Gut 2007, 56(07).
[21] Miller C, Zhang M, He Y, Zhao J, Pelletier JP, Martel-Pelletier J, Di-Battista JA. Transcriptional induction of cyclooxygenase-2 gene by okadaic acid inhibition of phosphatase activity in human chondrocytes: co-stimulation of AP-1 and CRE nuclear binding proteins. [J]. Journal of Cellular Biochemistry 1998, 4(4).
[22] Delerive P, De Bosscher-K, Besnard S, Vanden Berghe-W, Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, Staels B. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. [J]. The Journal of biological chemistry 1999, 45(45).
[23] Grau R, Punzon C, Fresno M, Iniguez MA. Peroxisome-proliferator-activated receptor ot agonists inhibit cyclo-oxygenase 2 and vascular endothelial growth factor transcriptional activation in human colorectal carcinoma cells via inhibition of activator protein-1 [J]. The Biochemical Journal 2006, 1(1).
[24] Suleyman H, Demircan B, Karagoz Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. [J]. Pharmacological reports: PR 2007, 3(3).
[25] Lehmann JM., Oliver BB., Ringold GM., Kliewer SA., Lenhard JM.. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS ALPHA AND GAMMA ARE ACTIVATED BY INDOMETHACIN AND OTHER NON-STEROIDAL ANTI-INFLAMMATORY DRUGS [J]. The Journal of biological chemistry 1997, 6(6).
[26] Sheldrick EL, Derecka K, Marshall E, Chin EC, Hodges L, Wathes DC, Abayasekara DR, Flint AP. Peroxisome-proliferator-activated receptors and the control of levels of prostaglandin-endoperoxide synthase 2 by arachidonic acid in the bovine uterus. [J]. The Biochemical Journal 2007, 1(1).