药学学报, 2013, 48(12): 1778-1784
引用本文:
朱升龙, 张振宇, 任桂萍, 叶贤龙, 马蕾, 于丹, 韩苗苗, 赵景壮, 张天援, 李德山. FGF21对MSG胰岛素抵抗小鼠的非酒精性脂肪肝的治疗作用及其机制研究[J]. 药学学报, 2013, 48(12): 1778-1784.
ZHU Sheng-long, ZHANG Zhen-yu, REN Gui-ping, YE Xian-long, MA Lei, YU Dan, HAN Miao-miao, ZHAO Jing-zhuang, ZHANG Tian-yuan, LI De-shan. Therapeutic effect of fibroblast growth factor 21 on NAFLD in MSG-IR mice and its mechanism[J]. Acta Pharmaceutica Sinica, 2013, 48(12): 1778-1784.

FGF21对MSG胰岛素抵抗小鼠的非酒精性脂肪肝的治疗作用及其机制研究
朱升龙1, 张振宇1, 任桂萍1, 叶贤龙1, 马蕾1, 于丹1, 韩苗苗1, 赵景壮2, 张天援1, 李德山1
1. 东北农业大学生命科学学院, 黑龙江 哈尔滨 150030;
2. 中国水产科学院黑龙江水产研究所, 黑龙江 哈尔滨 150070
摘要:
研究成纤维细胞生长因子21(fibroblast growth factor 21,FGF21)对谷氨酸钠(MSG)肥胖小鼠非酒精性脂肪肝(non-alcoholic fatty liver disease,NAFLD)的治疗作用及其作用机制。实验分为正常对照组、模型对照组、高剂量FGF21治疗组和低剂量FGF21治疗组。给药5周,给药期间每周监测小鼠体重,给药结束时测定血脂和血清胰岛素及转氨酶含量。Real-time PCR方法检测肝脏和脂肪组织内能量代谢调节关键基因表达。结果显示,治疗5周后,不同剂量FGF21均明显降低 MSG模型体重(P<0.01),纠正其血脂紊乱(P<0.01),减轻模型小鼠的肝内脂肪变性,恢复其肝脏细胞正常形态结构,并且可显著改善MSG模型鼠胰岛素抵抗状态。因此,FGF21能显著减轻MSG肥胖小鼠体重、改善胰岛素抵抗、逆转模型小鼠的肝内脂肪变性,这一发现为临床应用FGF21治疗非酒精性脂肪肝奠定了理论基础。
关键词:    成纤维细胞生长因子21      胰岛素抵抗      非酒精性脂肪肝      谷氨酸钠     
Therapeutic effect of fibroblast growth factor 21 on NAFLD in MSG-IR mice and its mechanism
ZHU Sheng-long1, ZHANG Zhen-yu1, REN Gui-ping1, YE Xian-long1, MA Lei1, YU Dan1, HAN Miao-miao1, ZHAO Jing-zhuang2, ZHANG Tian-yuan1, LI De-shan1
1. College of Life Science, Northeast Agricultural University, Harbin 150030, China;
2. Heilongjiang River Fishery Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China
Abstract:
This study is to evaluate the therapeutic effect of fibroblast growth factor 21 (FGF21) on NAFLD in MSG-IR mice and to provide mechanism insights into its therapeutic effect. The MSG-IR mice with insulin resistance were treated with high dose (0.1 μmol·kg-1·d-1) and low dose (0.025 μmol·kg-1·d-1) of FGF21 once a day for 5 weeks. Body weight was measured weekly. At the end of the experiment, serum lipids, insulin and aminotransferases were measured. Hepatic steatosis was observed. The expression of key genes regulating energy metabolism were detected by real-time PCR. The results showed that after 5 weeks treatment, both doses of FGF21 reduced body weight (P<0.01), corrected dyslipidemia (P<0.01), reversed steatosis and restored the liver morphology in the MSG model mice and significantly ameliorated insulin resistance. Additionally, real-time PCR showed that FGF21 significantly reduced transcription levels of fat synthetic genes, decreased fat synthesis and promoted lipolysis and energy metabolism by up-regulating key genes of lipolysis, thereby liver fat accumulation was reduced and liver function was restored to normal levels. In conclusion, FGF21 significantly reduces body weight of the MSG-IR mice, ameliorates insulin resistance, reverses hepatic steatosis. These findings provide a theoretical support for clinical application of FGF21 as a novel therapeutics for treatment of NAFLD.
Key words:    fibroblast growth factor 21    insulin-resistance    non-alcoholic fatty liver disease    MSG   
收稿日期: 2013-07-10
基金项目: 黑龙江省发改委项目(黑发改项目[2011] 1570号);黑龙江省教育厅科学技术研究项目(12521z004).
通讯作者: 李德山
Email: deshanli@163.com
相关功能
PDF(2989KB) Free
打印本文
0
作者相关文章
朱升龙  在本刊中的所有文章
张振宇  在本刊中的所有文章
任桂萍  在本刊中的所有文章
叶贤龙  在本刊中的所有文章
马蕾  在本刊中的所有文章
于丹  在本刊中的所有文章
韩苗苗  在本刊中的所有文章
赵景壮  在本刊中的所有文章
张天援  在本刊中的所有文章
李德山  在本刊中的所有文章

参考文献:
[1] Kallwitz ER, McLachlan A, Cotler SJ. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease[J]. World J Gastroenterol, 2008, 14: 22-28.
[2] Neuschwander-Tetri BA. Nonalcoholic steatohepatitis and the metabolic syndrome[J]. Am J Med Sci, 2005, 330: 326-335.
[3] Zhang DY, Liu ZY, Choi CS, et al. Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance[J]. Proc Natl Acad Sci USA, 2007, 104: 17075-17080.
[4] Nishimura T, Nakatake Y, Konishi M, et al. Identification of a novel FGF, FGF-21, preferentially expressed in the liver[J]. Biochim Biophys Acta, 2000, 1492: 203-206.
[5] Kharitonenkov A, Wroblewski VJ, Koester A, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21[J]. Endocrinology, 2007, 148: 774-781.
[6] Kharitonenkov A, Shiyanova TL, Koester A, et al. FGF-21 as a novel metabolic regulator[J]. Clin Invest, 2005, 115: 1627-1635.
[7] Inagaki T, Dutchak P, Zhao GX, et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21[J]. Cell Metab, 2007, 5: 415-425.
[8] Watanabe M, Shimada T, Iiduka S, et al. Preventive effects of Salacia reticulata on non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) in monosodium glutamate treated mice[J]. J Tradit Med, 2011, 28: 73-82.
[9] Sun GP, Ye XL, Ren GP, et al. Fibroblast growth factor-21 mediates hepatic glucose metabolism of type 1 diabetes model and its mechanism[J]. Prog Biochem Biophys, 2011, 38: 953-960.
[10] Sun SJ, Shen ZF, Chen YT, et al. Effects of conjugated linoleic acid on obese MSG mice with insulin resistance[J]. Acta Pharm Sin (药学学报), 2003, 38: 904-907.
[11] Liu SN, Liu Q, Shen ZF. A preliminary study on the mechanism of impaired beta cell function in monosodium glutamate obese rat with insulin resistance[J]. Acta Pharm Sin (药学学报), 2008, 43: 1106-1111.
[12] Xu XZ, Zhao CX, Wang LY, et al. Increased CYP2J3 expression reduces insulin resistance in fructose-treated rats and db/db mice[J]. Diabetes, 2010, 59: 997-1005.
[13] Bedogni G, Miglioli L, Masutti F, et al. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study[J]. Hepatology, 2005, 42: 44-52.
[14] Duvnjak M, Lerotić I, Barsić N, et al. Pathogenesis and management issues for non-alcoholic fatty liver disease[J]. World J Gastroenterol, 2007, 13: 4539-4550.
[15] Sobhonslidsuk A, Jongjirasiri S, Thakkinstian A, et al. Visceral fat and insulin resistance as predictors of non-alcoholic steatohepatitis[J]. World J Gastroenterol, 2007, 13: 3614-3618.
[16] Xu J, Lloyd DJ, Hale C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice[J]. Diabetes, 2009, 58: 250-259.
相关文献:
1.朱升龙, 任桂萍, 张振宇, 王文飞, 叶贤龙, 韩苗苗, 赵景壮, 徐彤宇, 刘铭瑶, 李德山.成纤维细胞生长因子21对胰岛素抵抗所致高血压的治疗作用[J]. 药学学报, 2013,48(9): 1409-1414