非酒精性脂肪性肝病动物实验模型研究进展

黄海燕; 辛永宁; 姜曼; 金文文; 姜相君; 宣世英

doi:10.3969/j.issn.1001-5256.2014.09.028

非酒精性脂肪性肝病动物实验模型研究进展

DOI: 10.3969/j.issn.1001-5256.2014.09.028

1. 泰山医学院
2. 青岛市市立医院消化内二科
3. 青岛市消化疾病重点实验室

基金项目:

国家自然科学基金(81170337/H0304)；

详细信息

中图分类号: R575.5
计量
- 文章访问数: 2862
- HTML全文浏览量: 24
- PDF下载量: 572
- 被引次数: 0
出版历程
- 收稿日期: 2014-02-13
- 出版日期: 2014-09-20

Research advances in animal models of nonalcoholic fatty liver disease

Taishan Medical University

Research funding:

摘要

摘要: 近年来随着肥胖、2型糖尿病、高脂血症等发生率的升高,非酒精性脂肪性肝病(NAFLD)的发病率也逐渐升高,成为常见的慢性肝脏疾病之一,而在我国是仅次于慢性病毒性肝炎的第二大肝病。但其发病机制仍未阐明,因NAFLD的发生和演进病程长,且从人体获取肝组织进行研究或药物试验等受伦理限制,因此NAFLD动物模型在本病研究中起了重要作用。综述了具备与NAFLD患者组织病理学表现相似的动物模型,并比较其建模原理及优缺点。为深入研究NAFLD发病机制,筛选防治药物等提供了有利工具。
- 脂肪肝 /
- 疾病模型,动物 /
- 小鼠 /
- 综述
Abstract: In recent years, the incidence of nonalcoholic fatty liver disease ( NAFLD) has increased gradually along with the rising prevalence of obesity, type 2 diabetes, and hyperlipidemia, and NAFLD has become one of the most common chronic liver diseases in the world and the second major liver disease after chronic viral hepatitis in China. However, its pathogenesis has not yet been clarified. Animal models are playing an important role in researches on NAFLD due to the facts that the development and progression of NAFLD require a long period of time, and ethical limitations exist in conducting drug trials in patients or collecting liver tissues from patients. The animal models with histopathology similar to that of NAFLD patients are reviewed, and their modeling principle, as well as the advantages and disadvantages, are compared. Animal models provide a powerful tool for further studies of NAFLD pathogenesis and drug screening for prevention and treatment of NAFLD.
- fatty liver /
- disease models, animal /
- mice /
- review

HTML全文

参考文献(48)

[1] PAPPACHAN JM, ANTONIO FA, EDAVALATH M, et al.Non-alcoholic fatty liver disease:a diabetologist's perspective[J].Endocrine, 2014, 45 (3) :344-353.

[2] GOH VJ, SILVER DL.The lipid droplet as a potential therapeutic target in NAFLD[J].Semin Liver Dis, 2013, 33 (4) :312-320.

[3] MIKOLASEVIC I, RACKI S, ZAPUTOVIC L, et al.Nonalcoholic fatty liver disease (NAFLD) :a new risk factor for adverse cardiovascular events in dialysis patients[J].Med Hypotheses, 2014, 82 (2) :205-208.

[4]HEBBARD L, GEORGE J.Animal models of nonalcoholic fatty liver disease[J].Nat Rev Gastroenterol Hepatol, 2011, 8 (1) :35-44.

[5]REDDY SK, ZHAN M, ALEXANDER HR, et al.Nonalcoholic fatty liver disease is associated with benign gastrointestinal disorders[J].World J Gastroenterol, 2013, 19 (45) :8301-8311.

[6]IMAJO K, YONEDA M, KESSOKU T, et al.Rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J].Int J Mol Sci, 2013, 14 (11) :21833-21857.

[7]KANURI G, BERGHEIM I.In vitro and in vivo models of non-alcoholic fatty liver disease (NAFLD) [J].Int J Mol Sci, 2013, 14 (6) :11963-11980.

[8]GUEBRE-XABIER M, YANG S, LIN HZ, et al.Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers:potential mechanism for sensitization to liver damage[J].Hepatology, 2000, 31 (3) :633-640.

[9]LECLERCQ IA, FARRELL GC, FIELD J, et al.CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis[J].J Clin Invest, 2000, 105 (8) :1067-1075.

[10] KAPLAN LM.Leptin, obesity, and liver disease[J].Gastroenterology, 1998, 115 (4) :997-1001.

[11]SAHAI A, MALLADI P, PAN X, et al.Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis:role of short-form leptin receptors and osteopontin[J].Am J Physiol Gastrointest Liver Physiol, 2004, 287 (5) :g1035-g1043.

[12]ZHANG DD, JIANG M, XIN YN, et al.Construction of lentivirus vectors containing PNPLA3 gene and overexpression of PNPLA3 in Huh-7 cells[J].Chin J Hepatol, 2013, 21 (3) :236-238. (in Chinese) 张丁丁, 姜曼, 辛永宁, 等.PNPLA3基因慢病毒载体及其过表达Huh-7细胞系的构建[J].中华肝脏病杂志, 2013, 21 (3) :236-238.

[13]ROTMAN Y, KOH C, ZMUDA JM, et al.The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease[J].Hepatology, 2010, 52 (3) :894-903.

[14] LI JZ, HUANG Y, KARAMAN R, et al.Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis[J].J Clin Invest, 2012, 122 (11) :4130-4144.

[15]HAO Q, HANSEN JB, PETERSEN RK, et al.ADD1/SREBP1c activates the PGC1-alpha promoter in brown adipocytes[J].Biochim Biophys Acta, 2010, 1801 (4) :421-429.

[16]ESPENSHADE PJ.SREBPs:sterol-regulated transcription factors[J].J Cell Sci, 2006, 119 (Pt 6) :973-976.

[17] NAKAYAMA H, OTABE S, UENO T, et al.Transgenic mice expressing nuclear sterol regulatory element-binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis[J].Metabolism, 2007, 56 (4) :470-475.

[18]SHIMOMURA I, HAMMER RE, RICHARDSON JA, et al.Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue:model for congenital generalized lipodystrophy[J].Genes Dev, 1998, 12 (20) :3182-3194.

[19]SCHATTENBERG JM, GALLE PR.Animal models of non-alcoholic steatohepatitis:of mice and man[J].Dig Dis, 2010, 28 (1) :247-254.

[20]MASAKI T, CHIBA S, TATSUKAWA H, et al.Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KKAy obese mice[J].Hepatology, 2004, 40 (1) :177-184.

[21]MYERS MP, STOLAROV JP, ENG C, et al.P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase[J].Proc Natl Acad Sci U S A, 1997, 94 (17) :9052-9057.

[22] HE L, HOU X, KANEL G, et al.The critical role of AKT2 in hepatic steatosis induced by PTEN loss[J].Am J Pathol, 2010, 176 (5) :2302-2308.

[23] SVEGLIATI-BARONI G, CANDELARESI C, SACCOMANNO S, et al.A model of insulin resistance and nonalcoholic steatohepatitis in rats:role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury[J].Am J Pathol, 2006, 169 (3) :846-860.

[24]KERSTEN S, SEYDOUX J, PETERS JM, et al.Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting[J].J Clin Invest, 1999, 103 (11) :1489-1498.

[25]REDDY JK.Nonalcoholic steatosis and steatohepatitis.Ⅲ.Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis[J].Am J Physiol Gastrointest Liver Physiol, 2001, 281 (6) :g1333-g1339.

[26] LONDON RM, GEORGE J.Pathogenesis of NASH:animal models[J].Clin Liver Dis, 2007, 11 (1) :55-74.

[27]LU SC, ALVAREZ L, HUANG ZZ, et al.Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation[J].Proc Natl Acad Sci U S A, 2001, 98 (10) :5560-5565.

[28] COOK WS, JAIN S, JIA Y, et al.Peroxisome proliferator-activated receptor alpha-responsive genes induced in the newborn but not prenatal liver of peroxisomal fatty acyl-CoA oxidase null mice[J].Exp Cell Res, 2001, 268 (1) :70-76.

[29]COBURN CT, KNAPP FJ, FEBBRAIO M, et al.Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice[J].J Biol Chem, 2000, 275 (42) :32523-32529.

[30]MA KL, RUAN XZ, POWIS SH, et al.Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice[J].Hepatology, 2008, 48 (3) :770-781.

[31]TAKAHASHI Y, SOEJIMA Y, FUKUSATO T.Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J].World J Gastroenterol, 2012, 18 (19) :2300-2308.

[32]DENG QG, SHE H, CHENG JH, et al.Steatohepatitis induced by intragastric overfeeding in mice[J].Hepatology, 2005, 42 (4) :905-914.

[33]ITO M, SUZUKI J, TSUJIOKA S, et al.Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to highfat diet[J].Hepatol Res, 2007, 37 (1) :50-57.

[34] de ALWIS NM, DAY CP.Non-alcoholic fatty liver disease:the mist gradually clears[J].J Hepatol, 2008, 48 (Suppl 1) :s104-s112.

[35] ANSTEE QM, GOLDIN RD.Mouse models in non-alcoholic fatty liver disease and steatohepatitis research[J].Int J Exp Pathol, 2006, 87 (1) :1-16.

[36] DELA PA, LECLERCQ I, FIELD J, et al.NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis[J].Gastroenterology, 2005, 129 (5) :1663-1674.

[37]LECLERCQ IA, FARRELL GC, FIELD J, et al.CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis[J].J Clin Invest, 2000, 105 (8) :1067-1075.

[38]IP E, FARRELL G, HALL P, et al.Administration of the potent PPARalpha agonist, Wy-14, 643, reverses nutritional fibrosis and steatohepatitis in mice[J].Hepatology, 2004, 39 (5) :1286-1296.

[39] LARTER CZ, YEH MM.Animal models of NASH:getting both pathology and metabolic context right[J].J Gastroenterol Hepatol, 2008, 23 (11) :1635-1648.

[40] KIRSCH R, CLARKSON V, SHEPHARD EG, et al.Rodent nutritional model of non-alcoholic steatohepatitis:species, strain and sex difference studies[J].J Gastroenterol Hepatol, 2003, 18 (11) :1272-1282.

[41] ACKERMAN Z, ORON-HERMAN M, GROZOVSKI M, et al.Fructose-induced fatty liver disease:hepatic effects of blood pressure and plasma triglyceride reduction[J].Hypertension, 2005, 45 (5) :1012-1018.

[42] ARMUTCU F, COSKUN O, GUREL A, et al.Thymosin alpha 1attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats[J].Clin Biochem, 2005, 38 (6) :540-547.

[43]KOHLI R, KIRBY M, XANTHAKOS SA, et al.High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis[J].Hepatology, 2010, 52 (3) :934-944.

[44]XING LX, HE YW.Experiment study on nonalcoholic fatty liver model induced by injection of oxytetracycline intraperitoneally in rats[J].J Clin Hepatol, 2007, 23 (1) :29-31. (in Chinese) 邢凌翔, 贺永文.氧四环素腹腔注射制备大鼠非酒精性脂肪肝模型的实验研究[J].临床肝胆病杂志, 2007, 23 (1) :29-31.

[45]WANG L, LYU JH, RAO WY, et al.Effect of baogan tablets on hepatic fibrosis induced by carbon tetrachloride complex factors in rats[J].Chin J Exp Med Formul, 2013, 19 (7) :234-236. (in Chinese) 王丽, 吕纪华, 饶伟源, 等.保肝片对大鼠肝纤维化模型的影响[J].中国实验方剂学杂志, 2013, 19 (7) :234-236.

[46] SINHA-HIKIM I, SINHA-HIKIM AP, SHEN R, et al.A novel cystine based antioxidant attenuates oxidative stress and hepatic steatosis in diet-induced obese mice[J].Exp Mol Pathol, 2011, 91 (1) :419-428.

[47] KASHIREDDY PV, RAO MS.Lack of peroxisome proliferator-activated receptor alpha in mice enhances methionine and choline deficient diet-induced steatohepatitis[J].Hepatol Res, 2004, 30 (2) :104-110.

[48]JU DH, ZHAO HY, LIU MJ.Advances in animal models of nonalcoholic fatty liver disease that combine disease and syndromes[J].World Chin J Dig, 2010, 18 (14) :1452-1455. (in Chinese) 鞠大宏, 赵宏艳, 刘梅洁.非酒精性脂肪性肝病病证结合动物模型的研究进展[J].世界华人消化杂志, 2010, 18 (14) :1452-1455.引证本文:HUANG HY, XIN YN, JIANG M, et al.Research advances in animal models of nonalcoholic fatty liver disease[J].J Clin Hepatol, 2014, 30 (9) :948-953. (in Chinese) 黄海燕, 辛永宁, 姜曼, 等.非酒精性脂肪性肝病动物实验模型研究进展[J].临床肝胆病杂志, 2014, 30 (9) :948-953.

施引文献

资源附件(0)

访问统计