姜黄素衍生物L6H4对2型糖尿病大鼠肝组织的保护作用

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摘要目的：探讨姜黄素衍生物L6H4对2型糖尿病及高脂大鼠肝组织的保护作用及其机制。方法：40只雄性SD大鼠随机均分为5组：正常对照组、高脂组、高脂治疗组、糖尿病组及糖尿病治疗组。高脂高糖喂养诱导高脂模型，高脂高糖喂养加腹腔注射链脲佐菌素（STZ）诱导2型糖尿病模型。高脂治疗组和糖尿病治疗组用0.2 mg·kg-1·d-1 L6H4灌胃8周。生化法检测大鼠血糖、血脂水平以及血谷丙转氨酶（ALT）、谷草转氨酶（AST）、血浆白蛋白（ALB）等肝功能指标；放射免疫法测定血胰岛素（FINs）水平并计算胰岛素抵抗指数（HOMA-IR）；光镜及透射电镜下观察大鼠肝组织形态改变；免疫组织化学法检测大鼠肝脏转化生长因子β1（TGF-β1）、基质金属蛋白酶抑制剂2（TIMP-2）、基质金属蛋白酶2（MMP-2）的蛋白表达水平。结果：高脂组、糖尿病组血糖，血脂及血清ALT、AST水平显著升高，ALB水平显著下降，经L6H4干预后，高脂治疗组及糖尿病治疗组的血糖，血脂及血清ALT、AST均明显下降，ALB明显增高。高脂组肝细胞脂肪变性，有少量胶原纤维形成；糖尿病组正常肝索结构破坏，肝细胞脂肪变性更为显著，局灶可见坏死，纤维增生明显，纤维间隔增厚，汇管区可见粗大胶原纤维；L6H4治疗后上述形态学改变明显改善。高脂组及糖尿病组肝脏TGF-β1、TIMP-2蛋白表达升高，MMP-2蛋白表达下降，L6H4治疗后，TGF-β1、TIMP-2蛋白表达明显降低，MMP-2蛋白表达明显升高。结论：姜黄素衍生物L6H4可改善2型糖尿病大鼠的糖脂代谢及胰岛素抵抗，对2型糖尿病及高脂大鼠肝组织具有保护作用，抑制肝脏TGF-β1及TIMP-2表达，上调MMP-2表达为其可能机制。

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	董细丹
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	蔡国平

关键词 ：糖尿病；姜黄素衍生物L6H4；肝纤维化；转化生长因子&beta, 1；基质金属蛋白酶抑制剂2；基质金属蛋白酶2；大鼠

Abstract：Objective: To investigate the protective effect and its mechanism of curcumin derivative L6H4 on hepatic tissue from type 2 diabetic and hyperlipidemic rats. Methods: Forty male Sprague-Dawley (SD) rats were randomly divided into five groups evenly, normal control group, high fat group, high fat+L6H4 treated group, diabetes mellitus group and diabetes mellitus+L6H4 treated group. The rats were fed with high fat and high sugar diet to induce hyperlipidemic model, and then injected with streptozotocin intraperitoneally to induce type 2 diabetic models. Rats in high fat+L6H4 treated group and diabetes mellitus+L6H4 treated group were given a gavage of curcumin derivative L6H4 at a dosage of 0.2 mg•kg-1•d-1 for 8 weeks. After the treatment, blood glucose and lipid levels as well as serum liver function indexes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) were measured by automatic biochemical analyzer, free blood insulin (FIN) was tested by radioimmunoassay and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. The morphology of liver was observed under light microscope and transmission electron microscope. The expression of transforming growth factor β1 (TGF-β1), tissue inhibitor metalloprotemase 2 (TIMP-2) and matrix metalloproteinase 2 (MMP-2) were measured by immunohistochemical method. Results: Compared with normal control group, blood glucose and lipid levels, ALT as well as AST were significantly increased while ALB was significantly decreased in high fat and diabetes mellitus groups. After the treatment of L6H4, blood glucose and lipid levels as well as serum liver function indexes (ALT, AST) were markedly decreased while ALB was increased in high fat+L6H4 treated group and diabetes mellitus+L6H4 treated groups. Fatty degeneration and mild proliferation of fibrous tissue could be observed in high fat group, and the diabetes mellitus group showed further damage with focal necrosis, more pronounced fatty degeneration, and destruction of the hepatic cord, proliferation of fibrous tissue was remarkable, resulting in the thicker septa and the well observed deposition of collagen fiber in portal area, and were relived by the treatment of L6H4. The expression of TGF-β1, TIMP-2 and MMP-2 were markedly increased in high fat group and diabetes mellitus group, after the appliance of L6H4, TGF-β1 and TIMP-2 were decreased while MMP-2 was increased. Conclusion: Curcumin derivative L6H4 shows an effect in attenuating insulin resistance and regulating glucolipid metabolism, and exerts protective effect on the hepatic tissue from type 2 diabetic rats, down-regulation of the expression of TGF-β1, TIMP-2 and up-regulation of MMP-2 maybe involved in it.

Key words： diabetes mellitus curcumin derivative L6H4 hepatic fibrosis transforming growth factor β1 tissue inhibitor metalloprotemase 2 matrix metalloproteinase 2 rats

收稿日期: 2017-07-05

PACS:

基金资助:浙江省公益性技术应用研究计划项目（2011C23123）；温州市高层次人才创新技术项目。

通讯作者: 蔡国平，硕士生导师，Email：15005876737@163.com。

作者简介: 董细丹（1991-），女，浙江温州人，硕士生。

链接本文:

https://xb.wmu.edu.cn/CN/ 或 https://xb.wmu.edu.cn/CN/Y2017/V47/I12/888

[1] BRIL F, CUSI K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: A call to action[J]. Diabetes Care, 2017, 40(3): 419-430.
[2] TANG Y. Curcumin targets multiple pathways to halt hepatic stellate cell activation: Updated mechanisms in vitro and in vivo[J]. Dig Dis Sci, 2015, 60(6): 1554-1564.
[3] 应丽丽, 倪瑾瑶, 李慧敏, 等. 姜黄素类似物L6H4对2型糖尿病大鼠心肌的保护作用[J]. 中国病理生理杂志, 2016, 32(1): 27-32.
[4] 刘曦, 马骏, 胡茂通, 等. 姜黄素类似物L6H4对2型糖尿病大鼠肾脏的保护作用[J]. 中国应用生理学杂志, 2017, 33 (1): 11-15.
[5] SUMIDA Y, SEKO Y, YONEDA M. Novel antidiabetic medications for non-alcoholic fatty liver disease with type 2 diabetes mellitus[J]. Hepatol Res, 2017, 47(4): 266-280.
[6] CHITURI S, ABEYGUNASEKERA S, FARRELL G C, et al.
Nash and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome[J]. Hepatology, 2002, 35(2): 373-379.
[7] CHIANG D J, PRITCHARD M T, NAGY L E. Obesity, diabetes mellitus, and liver fibrosis[J]. Am J Physiol Gastrointest Liver Physiol, 2011, 300(5): G697-702.
[8] GRESSNER A M, WEISKIRCHEN R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and tgf-beta as major players and therapeutic targets[J]. J Cell Mol Med, 2006, 10(1): 76-99.
[9] 党双锁, 李亚萍. Tgf-β1在肝纤维化研究中的新进展[J]. 世界华人消化杂志, 2010, 18(16): 1631-1636.
[10] XU F, LIU C, Zhou D, et al. Tgf-beta/smad pathway and its regulation in hepatic fibrosis[J]. J Histochem Cytochem, 2016, 64(3): 157-167.
[11] LIU X, HU H, YIN J Q. Therapeutic strategies against tgf-beta signaling pathway in hepatic fibrosis[J]. Liver Int, 2006, 26(1): 8-22.
[12] HEMMANN S, GRAF J, RODERFELD M, et al. Expression of mmps and timps in liver fibrosis: a systematic review with special emphasis on anti-fibrotic strategies[J]. J Hepatol, 2007, 46(5): 955-975.
[13] ARPINO V, BROCK M, GILL S E. The role of timps in regulation of extracellular matrix proteolysis[J]. Matrix Biol, 2015, 44-46: 247-254.
[14] NIE Q H, ZHU C L, ZHANG Y F, et al. Inhibitory effect of antisense oligonucleotide targeting timp-2 on immune-induced liver fibrosis[J]. Dig Dis Sci, 2010, 55(5): 1286-1295.
[15] HU Y B, LI D G, LU H M. Modified synthetic sirna targeting tissue inhibitor of metalloproteinase-2 inhibits hepatic fibrogenesis in rats[J]. J Gene Med, 2007, 9(3): 217-229.
[16] 黄月红, 郭杞兰, 陈治新, 等. 四氯化碳诱导肝纤维化早期大鼠肝窦内皮细胞及基底膜形态改变的动态研究[J]. 中国病理生理杂志, 2014, 30(8): 1501-1505.
[17] CHENG Y, PING J, XU L M. Effects of curcumin on peroxisome proliferator-activated receptor gamma expression and nuclear translocation/redistribution in culture-activated rat hepatic stellate cells[J]. Chin Med J (Engl), 2007, 120(9): 794-801.
[18] HUSSAIN Z, THU H E, AMJAD M W, et al. Exploring recent developments to improve antioxidant, anti-inflammatory and antimicrobial efficacy of curcumin: A review of new trends and future perspectives[J]. Mater Sci Eng C Mater Biol Appl, 2017, 77: 1316-1326.
[19] PANASHI Y, AHMADI Y, TEYMOURI M, et al. Curcumin as a potential candidate for treating hyperlipidemia: A review of cellular and metabolic mechanisms[J]. J Cell Physiol, 2018, 233(1): 141-152.
[20] 王玲, 徐梦菲, 刘曦, 等. 姜黄素衍生物b06对2型糖尿病大鼠肝脏的保护作用[J]. 中国病理生理杂志, 2014, 30(2): 328-332.