您的位置: 首页 > 2023年3月 第54卷 第3期 > 文字全文
2023年7月 第38卷 第7期11
目录

基因编辑在非酒精性脂肪性肝病动物模型构建中的应用及研究进展

Research progress of genome editing for constructing the animal models of nonalcoholic fatty liver disease

来源期刊: 广州医药 | 8-13 发布时间:2023-04-14 收稿时间:2025/11/13 18:36:21 阅读量:24
作者:
关键词:
非酒精性脂肪性肝病动物模型基因编辑
nonalcoholic fatty liver diseaseanimal modelgenome editing
DOI:
10.3969/j.issn.1000-8535.2023.03.002
收稿时间:
2022-12-10 
修订日期:
 
接收日期:
 
引用总数:
1  
非酒精性脂肪性肝病(NAFLD)是世界范围内慢性肝病的一个主要原因,约15%的NAFLD患者会发展为非酒精性脂肪性肝炎、肝纤维化、肝硬化甚至肝癌。目前其发病及进展机制尚未明确,也无有效治疗手段。因此,构建临床前NAFLD动物模型至关重要,有助于为NAFLD提供临床治疗的新方案。本文将系统分析目前已构建的NAFLD动物模型在临床前研究中的局限性,并重点总结和综述基于基因编辑在NAFLD动物模型构建中的应用及研究进展,这对于探讨NAFLD发病机制及新药研发具有重要的临床意义。
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, and about 15% of NAFLD patients will develop into nonalcoholic steatohepatitis, hepatic fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. However, the biological mechanism of the pathogenesis and progression of NAFLD is not fully understood, and there are still no effective or targeted therapies for NAFLD. Therefore, it is an urgent need to construct pre-clinical animal models of NAFLD, which will help to better understand and explore the potential therapeutic strategy in the treatment of NAFLD. Here, we summarize the recent advances and limitations of the established animal models of NAFLD and focus on the potential application and research progress of genome editing for constructing the animal models of NAFLD. There animal models will be very useful to reveal the pathologic mechanism of human NAFLD, and to screen new therapeutic drugs.
1、 ARSOV T, LARTER C Z, NOLAN C J, et al. Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice[J].Biochem Biophys Res Commun,2006,342(4):1152-1159. ARSOV T, LARTER C Z, NOLAN C J, et al. Adaptive failure to high-fat diet characterizes steatohepatitis in Alms1 mutant mice[J].Biochem Biophys Res Commun,2006,342(4):1152-1159.
2、 NAKAGAWA H, UMEMURA A, TANIGUCHI K, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development[J].Cancer Cell,2014,26(3):331-343. NAKAGAWA H, UMEMURA A, TANIGUCHI K, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development[J].Cancer Cell,2014,26(3):331-343.
3、 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. 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.
4、 EBERLé D, HEGARTY B, BOSSARD P, et al. SREBP transcription factors: master regulators of lipid homeostasis[J].Biochimie,2004,86(11):839-848. EBERLé D, HEGARTY B, BOSSARD P, et al. SREBP transcription factors: master regulators of lipid homeostasis[J].Biochimie,2004,86(11):839-848.
5、 JIANG S, MINTER L C, STRATTON S A, et al. TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice[J].J Hepatol,2015,62(2):371-379. JIANG S, MINTER L C, STRATTON S A, et al. TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice[J].J Hepatol,2015,62(2):371-379.
6、 GANDHI C R, CHAILLET J R, NALESNIK M A, et al. Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice[J].Gastroenterology,2015,148(2):379-391.e4. GANDHI C R, CHAILLET J R, NALESNIK M A, et al. Liver-specific deletion of augmenter of liver regeneration accelerates development of steatohepatitis and hepatocellular carcinoma in mice[J].Gastroenterology,2015,148(2):379-391.e4.
7、 HORIE Y, SUZUKI A, KATAOKA E, et al. Hepatocyte-specific PTEN deficiency results in steatohepatitis and hepatocellular carcinomas[J].J Clin Invest,2004, 113(12):1774-1783. HORIE Y, SUZUKI A, KATAOKA E, et al. Hepatocyte-specific PTEN deficiency results in steatohepatitis and hepatocellular carcinomas[J].J Clin Invest,2004, 113(12):1774-1783.
8、 CHEN C Y, CHEN J, HE L, et al. PTEN: Tumor Suppressor and Metabolic Regulator[J].Front Endocrinol (Lausanne),2018(9):338. CHEN C Y, CHEN J, HE L, et al. PTEN: Tumor Suppressor and Metabolic Regulator[J].Front Endocrinol (Lausanne),2018(9):338.
9、 HAINER V, ALDHOON HAINEROVá I, KUNE?OVá M, et al. Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R)[J].Physiol Res,2020,69(Suppl 2):S245-S254. HAINER V, ALDHOON HAINEROVá I, KUNE?OVá M, et al. Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R)[J].Physiol Res,2020,69(Suppl 2):S245-S254.
10、 ITOH M, SUGANAMI T, NAKAGAWA N, et al.Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis[J].Am J Pathol,2011, 179(5):2454-2463. ITOH M, SUGANAMI T, NAKAGAWA N, et al.Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis[J].Am J Pathol,2011, 179(5):2454-2463.
11、 VéNIANT M M, WITHYCOMBE S, YOUNG S G.Lipoprotein size and atherosclerosis susceptibility in Apoe(-/-) and Ldlr(-/-) mice[J].Arterioscler Thromb Vasc Biol, 2001,21(10):1567-1570. VéNIANT M M, WITHYCOMBE S, YOUNG S G.Lipoprotein size and atherosclerosis susceptibility in Apoe(-/-) and Ldlr(-/-) mice[J].Arterioscler Thromb Vasc Biol, 2001,21(10):1567-1570.
12、 HUEBBE P, RIMBACH G.Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors[J].Ageing Res Rev,2017(37):146-161. HUEBBE P, RIMBACH G.Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors[J].Ageing Res Rev,2017(37):146-161.
13、 SUBRAMANIAN S, GOODSPEED L, WANG S, et al. Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice[J].J Lipid Res,2011,52(9):1626-1635. SUBRAMANIAN S, GOODSPEED L, WANG S, et al. Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice[J].J Lipid Res,2011,52(9):1626-1635.
14、 GO G W, MANI A.Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis[J].Yale J Biol Med,2012,85(1):19-28. GO G W, MANI A.Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis[J].Yale J Biol Med,2012,85(1):19-28.
15、 ZHANG Y, CHUA S Jr.Leptin function and regulation[J].Compr Physiol,2017,8(1):351-369. ZHANG Y, CHUA S Jr.Leptin function and regulation[J].Compr Physiol,2017,8(1):351-369.
16、 MINAMI Y, YUAN Y, UEDA H R.High-throughput genetically modified animal experiments achieved by next-generation mammalian genetics[J].J Biol Rhythms,2022, 37(2):135-151. MINAMI Y, YUAN Y, UEDA H R.High-throughput genetically modified animal experiments achieved by next-generation mammalian genetics[J].J Biol Rhythms,2022, 37(2):135-151.
17、 LI X, WU Y, ZHAO J, et al. Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus[J].Theranostics, 2020,10(6):2675-2695. LI X, WU Y, ZHAO J, et al. Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus[J].Theranostics, 2020,10(6):2675-2695.
18、 FUJII M, SHIBAZAKI Y, WAKAMATSU K,et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma[J].Med Mol Morphol,2013,46(3):141-152. FUJII M, SHIBAZAKI Y, WAKAMATSU K,et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma[J].Med Mol Morphol,2013,46(3):141-152.
19、 WELTMAN M D, FARRELL G C, LIDDLE C.Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation[J].Gastroenterology, 1996,111(6):1645-1653. WELTMAN M D, FARRELL G C, LIDDLE C.Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation[J].Gastroenterology, 1996,111(6):1645-1653.
20、 RINELLA M E, ELIAS M S, SMOLAK R R, et al. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet[J].J Lipid Res,2008, 49(5):1068-1076. RINELLA M E, ELIAS M S, SMOLAK R R, et al. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet[J].J Lipid Res,2008, 49(5):1068-1076.
21、 FAN J G, CAO H X.Role of diet and nutritional management in non-alcoholic fatty liver disease[J].J Gastroenterol Hepatol,2013,28(Suppl 4):81-87. FAN J G, CAO H X.Role of diet and nutritional management in non-alcoholic fatty liver disease[J].J Gastroenterol Hepatol,2013,28(Suppl 4):81-87.
22、 SANTHEKADUR P K, KUMAR D P, SANYAL A J.Preclinical models of non-alcoholic fatty liver disease[J].J Hepatol,2018,68(2):230-237. SANTHEKADUR P K, KUMAR D P, SANYAL A J.Preclinical models of non-alcoholic fatty liver disease[J].J Hepatol,2018,68(2):230-237.
23、 COLE B K, FEAVER R E, WAMHOFF B R, et al. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery[J].Expert Opin Drug Discov,2018,13(2):193-205. COLE B K, FEAVER R E, WAMHOFF B R, et al. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery[J].Expert Opin Drug Discov,2018,13(2):193-205.
24、 ASGHARPOUR A, CAZANAVE S C, PACANA T, et al.A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer[J].J Hepatol,2016, 65(3):579-588. ASGHARPOUR A, CAZANAVE S C, PACANA T, et al.A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer[J].J Hepatol,2016, 65(3):579-588.
25、 TSUCHIDA T, LEE Y A, FUJIWARA N,et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer[J].J Hepatol,2018,69(2):385-395. TSUCHIDA T, LEE Y A, FUJIWARA N,et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer[J].J Hepatol,2018,69(2):385-395.
26、 TACKE F, WEISKIRCHEN R.Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention[J].Ann Transl Med,2021,9(8):729. TACKE F, WEISKIRCHEN R.Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention[J].Ann Transl Med,2021,9(8):729.
27、 LOOMBA R, FRIEDMAN S L, SHULMAN G I.Mechanisms and disease consequences of nonalcoholic fatty liver disease[J].Cell,2021,184(10):2537-2564. LOOMBA R, FRIEDMAN S L, SHULMAN G I.Mechanisms and disease consequences of nonalcoholic fatty liver disease[J].Cell,2021,184(10):2537-2564.
28、 TARGHER G, BYRNE C D, TILG H.NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications[J].Gut,2020,69(9):1691-1705. TARGHER G, BYRNE C D, TILG H.NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications[J].Gut,2020,69(9):1691-1705.
29、 ADAMS L A, ANSTEE Q M, TILG H, et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases[J].Gut, 2017,66(6):1138-1153. ADAMS L A, ANSTEE Q M, TILG H, et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases[J].Gut, 2017,66(6):1138-1153.
30、 ZHOU J, BAI L, ZHANG X J, et al. Nonalcoholic fatty liver disease and cardiac remodeling risk: Pathophysiological mechanisms and clinical implications[J].Hepatology,2021,74(5):2839-2847. ZHOU J, BAI L, ZHANG X J, et al. Nonalcoholic fatty liver disease and cardiac remodeling risk: Pathophysiological mechanisms and clinical implications[J].Hepatology,2021,74(5):2839-2847.
31、 TAN D J H, NG C H, LIN S Y, et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis[J].Lancet Oncol,2022, 23(4):521-530. TAN D J H, NG C H, LIN S Y, et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis[J].Lancet Oncol,2022, 23(4):521-530.
32、 COTTER T G, RINELLA M.Nonalcoholic Fatty Liver Disease 2020: The State of the Disease[J].Gastroenterology,2020,158(7):1851-1864. COTTER T G, RINELLA M.Nonalcoholic Fatty Liver Disease 2020: The State of the Disease[J].Gastroenterology,2020,158(7):1851-1864.
33、 FRIEDMAN S L, NEUSCHWANDER-TETRI B A, RINELLA M,et al. Mechanisms of NAFLD development and therapeutic strategies[J].Nat Med,2018,24(7):908-922. FRIEDMAN S L, NEUSCHWANDER-TETRI B A, RINELLA M,et al. Mechanisms of NAFLD development and therapeutic strategies[J].Nat Med,2018,24(7):908-922.
34、 SHEKA A C, ADEYI O, THOMPSON J,et al.Nonalcoholic steatohepatitis: A review[J].JAMA,2020,323(12):1175-1183. SHEKA A C, ADEYI O, THOMPSON J,et al.Nonalcoholic steatohepatitis: A review[J].JAMA,2020,323(12):1175-1183.
1、过源,安增梅,周营,等.高脂饮食对生命幼年营养不良大鼠脂糖代谢影响[J].中国医药科学,2024,14(15):24-28.DOI:10.20116/j.issn2095-0616.2024.15.06. 过源,安增梅,周营,等.高脂饮食对生命幼年营养不良大鼠脂糖代谢影响[J].中国医药科学,2024,14(15):24-28.DOI:10.20116/j.issn2095-0616.2024.15.06.
上一篇
下一篇
出版者信息








《广州医药》公众号
目录