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Article(id=1211269161217560854, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269157790806494, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.04.16, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1595779200000, receivedDateStr=2020-07-27, revisedDate=1614268800000, revisedDateStr=2021-02-26, acceptedDate=null, acceptedDateStr=null, onlineDate=1766718672326, onlineDateStr=2025-12-26, pubDate=1619539200000, pubDateStr=2021-04-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766718672326, onlineIssueDateStr=2025-12-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766718672326, creator=13701087609, updateTime=1766718672326, updator=13701087609, issue=Issue{id=1211269157790806494, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='4', pageStart='319', pageEnd='424', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766718671510, creator=13701087609, updateTime=1766718756000, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1211269512217882745, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269157790806494, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1211269512217882746, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269157790806494, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=414, endPage=419, ext={EN=ArticleExt(id=1211269162496823585, articleId=1211269161217560854, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress in mouse models of non-alcoholic fatty liver disease associated hepatocellular carcinoma, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Non-alcoholic fatty liver disease (NAFLD) has gradually become an important factor causing hepatocellular carcinoma (HCC), and the clinical treatment effects of NAFLD-HCC and general liver cancer are significantly different, and there are many differences in drug sensitivity. At present, the pathogenesis of NAFLD-HCC is not yet clear. Therefore, it is particularly important to construct pre-clinical animal models of NAFLD-HCC. There are various induction methods for animal models of NAFLD-HCC, including dietary induction, chemical induction, genetic induction, dietary combined with chemical induction, genetic combined with dietary and other induction methods. More and more studies have found that there are certain differences in the histopathological types of animal models of NAFLD-HCC induced by different methods. Therefore, according to the research problem, choosing the most suitable animal model is of great significance for studying the causes of NAFLD-HCC and subsequent development of new drugs. The mouse models established for preclinical studies of the progression of NAFLD-HCC were summarized in this paper to reveal the pathogenesis of NAFLD-HCC, and to explore possible new targets for prevention or treatment of NAFLD-HCC.

, correspAuthors=Li-Ping An, authorNote=null, correspAuthorsNote=
*E-mail:
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非酒精性脂肪性肝病(NAFLD)已经逐渐成为引发肝细胞癌(HCC)的重要因素，且NAFLD-HCC与一般肝癌的临床治疗效果存在明显差异，对药物的敏感性有诸多不同。目前NAFLD-HCC的发病机制尚未明确，因此构建临床前的NAFLD-HCC动物模型尤为重要。NAFLD-HCC动物模型的诱导方法多种多样，包括饮食诱导、化学诱导、遗传诱导、饮食结合化学诱导、遗传结合饮食诱导等。越来越多的研究发现，不同方法诱导的NAFLD-HCC动物模型的组织病理学存在一定差异。因此，根据研究目的选择最合适的动物模型，对探讨NAFLD-HCC的发病原因以及后续的新药研发具有重要意义。该文总结已构建的用于NAFLD-HCC临床前研究的鼠模型，以揭示NAFLD-HCC的发生机制，探讨NAFLD-HCC预防或治疗可能的新靶标。

, correspAuthors=安丽平, authorNote=null, correspAuthorsNote=
安丽平，E-mail：
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耿海波，硕士研究生，副教授，主要从事药物分析和微生物应用方面的研究

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Oncotarget, 2017, 8(56): 95586-95595., articleTitle=Collagen I promotes hepatocellular carcinoma cell proliferation by regulating integrin beta1/FAK signaling pathway in nonalcoholic fatty liver, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1211269163121774926, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269161217560854, xref=1, ext=[AuthorCompanyExt(id=1211269163138552144, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269161217560854, companyId=1211269163121774926, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Food and Drug Engineering, Shijiazhuang University of Applied Technology, Shijiazhuang 050081, China), AuthorCompanyExt(id=1211269163155329363, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269161217560854, companyId=1211269163121774926, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1石家庄职业技术学院食品与药品工程系，石家庄 050081)]), AuthorCompany(id=1211269163285352798, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269161217560854, xref=2, ext=[AuthorCompanyExt(id=1211269163297935711, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269161217560854, companyId=1211269163285352798, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Basic Medical College, Hebei University of Chinese Medicine, Shijiazhuang 050200, China), AuthorCompanyExt(id=1211269163310518624, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269161217560854, companyId=1211269163285352798, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2河北中医学院基础医学院，石家庄 050200)])], figs=[ArticleFig(id=1211269165290230267, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269161217560854, language=EN, label=Tab.1, caption=

Modeling methods for non-alcoholic fatty liver disease associated hepatocellular carcinoma model

, figureFileSmall=null, figureFileBig=null, tableContent=
动物模型名称作者年份造模方法特征优缺点
饮食诱导NAFLD-HCC模型Wolf等[5]2014年CD+HFD肝脏脂肪变性；代谢综合征；肝脏损害肿瘤发生率仅为25%
De Minicis等[6]2014年CDAA肝纤维化；胰岛素抵抗；肝脏脂肪变性9个月时发生HCC
Ikawa-Yoshida等[7]2017年CDAHFD肝纤维化；小梁、假腺和实体生长36周时出现肝纤维化并向HCC进展，无体重减轻或其他器官致癌
Ganz等[8]2015年高脂高胆固醇高糖饮食脂肪变性；脂肪性肝炎；肝纤维化49周时NASH逐渐发展为纤维化，与肿瘤进展有关
Tucker等[9]2020年75%脂肪CDE饮食AST、ALT水平升高18周时35%的小鼠患有增生性结节或癌症
Asgharpour等[10]2016年B6/129小鼠饲喂高脂高碳水化合物饮食脂肪变性；NASH52周时发生HCC，这可能是NASH-HCC的理想临床前模型
化学和饮食相结合诱导NAFLD-HCC模型Van Campenhout等[11]
Iida等[12]
Xie等[13]		2020年
2019年
2017年		HFD+STZ脂肪变性；小叶炎症；纤维化；体重增加，空腹血糖升高，血清ALT水平升高20周时出现肿瘤突出，整个过程在相对较短的时间内即可完成。另外该模型提供了有关代谢异常、NASH和HCC关联机制的见解
Liang等[14]2018年HFHC+DENHFHC喂养的小鼠中40%的HCC存在肺转移HCC多样性和大小显著增加
Tian等[15]2019年DEN结合高脂高碳水化合物饮食和富含高果糖玉米糖浆的饮用水脂质(包括TG、FFA和胆固醇)浓度增加28周时出现肿瘤
Eugénio等[16]2020年STZ+高脂高糖饮食轻度肝损伤；微弱的炎症和纤维化；早期形成更多的肝肿瘤；活化的辅助细胞和细胞毒性T细胞渗透肝脏肿瘤出现较早
Fang等[17]2020年HFD+2-芴基乙酰胺大鼠癌变组织和血清同时发现CD44表达水平升高18周时发现癌变，研究提示CD44表达增加与NAFLD中肝细胞的恶性转化有关
化学、饮食及低氧诱导NAFLD-HCC模型Chen等[20]2019年STAM小鼠HFD、STZ及模拟缺氧缺氧条件下表现出更快的肿瘤进展低氧诱导的肿瘤数量更多，HIF-2α可作为生物标志物，并可用于NAFLD-HCC治疗靶标的开发
高拷贝转座子全基因组随机诱变结合基因操作诱导NAFLD-HCC模型Kodama等[22]2018年PTEN KO小鼠结合SB诱变筛选PTEN KO/SB小鼠肿瘤发生率明显更高，在遗传干扰的NAFLD模型中，SB诱变促进了肝肿瘤的发展5个月时开始出现肝肿瘤，所有雄性和雌性小鼠分别在7个月和8个月时出现肝肿瘤
高拷贝转座子全基因组随机诱变结合HFD诱导NAFLD-HCC模型Kodama等[22]2018年HFD/SB脂质沉积；每只动物的最大肿瘤体积随时间延长而增大；基于饮食的NAFLD模型中，SB诱变显著加速了肝肿瘤的形成肿瘤发生率在1岁时为54%，但在1.3岁时达到100%
基因操作诱变NAFLD-HCC模型Kitade等[23]2017年Sav1/PTEN双敲除小鼠双敲除小鼠肝脏中TG和胆固醇水平显著升高所有小鼠均在垂死时发展为多发性肝肿瘤
Liu等[25]2018年特异的SQLE转基因小鼠促进了胆固醇合成SQLE为NAFLD-HCC中的致癌基因，SQLE抑制剂可能是预防和治疗NAFLD-HCC潜在的有效药物
Gandhi等[27]2015年肝特异性的ALR-L-KO小鼠2周龄时引起脂肪变性；8周龄时发生纤维化/肝硬化；1岁时形成HCC抑制肝细胞中ALR的合成可能导致线粒体功能障碍和细胞死亡，从而导致连续的NASH和HCC发生
Khare等[28]2020年长链3-羟基酰基-CoA脱氢酶缺陷的小鼠模型明显的肝脂肪变性，没有任何纤维化或肝硬化的迹象3月龄时开始发展为明显的肝脂肪变性，13月龄时开始出现肝癌。该模型不仅有助于了解NASH的发病机制，而且有助于了解NASH向HCC的进展过程
基因操作和化学联合诱导NAFLD-HCC模型Jin等[29]2016年二乙基亚硝胺干预的db/db小鼠更高的体重、肝脏重量、肝脂肪变性、HCC发生率，并且肿瘤结节的数量更多、体积更大该小鼠模型表明，肥胖和NASH增加了HCC发生的易感性
Guri等[30]2017年TSC1和PTEN双基因敲除小鼠，同时给予CD高脂饮食和二乙基亚硝胺处理癌变发生速度快4周龄时出现肝脏体积增大；12周龄时显微镜下可观察到肝脏组织发生癌变
NAFLD-HCC原位移植瘤模型Zheng等[31]2017年HFD或MCD饮食HFD或MCD组肿瘤重量占肝脏重量百分比和转移性肿瘤的肝叶数目明显高于对照组HFD或MCD饮食12周，肝原位注射H22细胞2周后取材。造模时间短
), ArticleFig(id=1211269165462196742, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269161217560854, language=CN, label=表1, caption=

NAFLD-HCC造模方法

, figureFileSmall=null, figureFileBig=null, tableContent=
动物模型名称作者年份造模方法特征优缺点
饮食诱导NAFLD-HCC模型Wolf等[5]2014年CD+HFD肝脏脂肪变性；代谢综合征；肝脏损害肿瘤发生率仅为25%
De Minicis等[6]2014年CDAA肝纤维化；胰岛素抵抗；肝脏脂肪变性9个月时发生HCC
Ikawa-Yoshida等[7]2017年CDAHFD肝纤维化；小梁、假腺和实体生长36周时出现肝纤维化并向HCC进展，无体重减轻或其他器官致癌
Ganz等[8]2015年高脂高胆固醇高糖饮食脂肪变性；脂肪性肝炎；肝纤维化49周时NASH逐渐发展为纤维化，与肿瘤进展有关
Tucker等[9]2020年75%脂肪CDE饮食AST、ALT水平升高18周时35%的小鼠患有增生性结节或癌症
Asgharpour等[10]2016年B6/129小鼠饲喂高脂高碳水化合物饮食脂肪变性；NASH52周时发生HCC，这可能是NASH-HCC的理想临床前模型
化学和饮食相结合诱导NAFLD-HCC模型Van Campenhout等[11]
Iida等[12]
Xie等[13]		2020年
2019年
2017年		HFD+STZ脂肪变性；小叶炎症；纤维化；体重增加，空腹血糖升高，血清ALT水平升高20周时出现肿瘤突出，整个过程在相对较短的时间内即可完成。另外该模型提供了有关代谢异常、NASH和HCC关联机制的见解
Liang等[14]2018年HFHC+DENHFHC喂养的小鼠中40%的HCC存在肺转移HCC多样性和大小显著增加
Tian等[15]2019年DEN结合高脂高碳水化合物饮食和富含高果糖玉米糖浆的饮用水脂质(包括TG、FFA和胆固醇)浓度增加28周时出现肿瘤
Eugénio等[16]2020年STZ+高脂高糖饮食轻度肝损伤；微弱的炎症和纤维化；早期形成更多的肝肿瘤；活化的辅助细胞和细胞毒性T细胞渗透肝脏肿瘤出现较早
Fang等[17]2020年HFD+2-芴基乙酰胺大鼠癌变组织和血清同时发现CD44表达水平升高18周时发现癌变，研究提示CD44表达增加与NAFLD中肝细胞的恶性转化有关
化学、饮食及低氧诱导NAFLD-HCC模型Chen等[20]2019年STAM小鼠HFD、STZ及模拟缺氧缺氧条件下表现出更快的肿瘤进展低氧诱导的肿瘤数量更多，HIF-2α可作为生物标志物，并可用于NAFLD-HCC治疗靶标的开发
高拷贝转座子全基因组随机诱变结合基因操作诱导NAFLD-HCC模型Kodama等[22]2018年PTEN KO小鼠结合SB诱变筛选PTEN KO/SB小鼠肿瘤发生率明显更高，在遗传干扰的NAFLD模型中，SB诱变促进了肝肿瘤的发展5个月时开始出现肝肿瘤，所有雄性和雌性小鼠分别在7个月和8个月时出现肝肿瘤
高拷贝转座子全基因组随机诱变结合HFD诱导NAFLD-HCC模型Kodama等[22]2018年HFD/SB脂质沉积；每只动物的最大肿瘤体积随时间延长而增大；基于饮食的NAFLD模型中，SB诱变显著加速了肝肿瘤的形成肿瘤发生率在1岁时为54%，但在1.3岁时达到100%
基因操作诱变NAFLD-HCC模型Kitade等[23]2017年Sav1/PTEN双敲除小鼠双敲除小鼠肝脏中TG和胆固醇水平显著升高所有小鼠均在垂死时发展为多发性肝肿瘤
Liu等[25]2018年特异的SQLE转基因小鼠促进了胆固醇合成SQLE为NAFLD-HCC中的致癌基因，SQLE抑制剂可能是预防和治疗NAFLD-HCC潜在的有效药物
Gandhi等[27]2015年肝特异性的ALR-L-KO小鼠2周龄时引起脂肪变性；8周龄时发生纤维化/肝硬化；1岁时形成HCC抑制肝细胞中ALR的合成可能导致线粒体功能障碍和细胞死亡，从而导致连续的NASH和HCC发生
Khare等[28]2020年长链3-羟基酰基-CoA脱氢酶缺陷的小鼠模型明显的肝脂肪变性，没有任何纤维化或肝硬化的迹象3月龄时开始发展为明显的肝脂肪变性，13月龄时开始出现肝癌。该模型不仅有助于了解NASH的发病机制，而且有助于了解NASH向HCC的进展过程
基因操作和化学联合诱导NAFLD-HCC模型Jin等[29]2016年二乙基亚硝胺干预的db/db小鼠更高的体重、肝脏重量、肝脂肪变性、HCC发生率，并且肿瘤结节的数量更多、体积更大该小鼠模型表明，肥胖和NASH增加了HCC发生的易感性
Guri等[30]2017年TSC1和PTEN双基因敲除小鼠，同时给予CD高脂饮食和二乙基亚硝胺处理癌变发生速度快4周龄时出现肝脏体积增大；12周龄时显微镜下可观察到肝脏组织发生癌变
NAFLD-HCC原位移植瘤模型Zheng等[31]2017年HFD或MCD饮食HFD或MCD组肿瘤重量占肝脏重量百分比和转移性肿瘤的肝叶数目明显高于对照组HFD或MCD饮食12周，肝原位注射H22细胞2周后取材。造模时间短
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非酒精性脂肪性肝病相关肝癌鼠模型的研究进展
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耿海波 1, 2 , 安丽平 2, *
解放军医学杂志 | 综述 2021,46(4): 414-419
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解放军医学杂志 | 综述 2021, 46(4): 414-419
非酒精性脂肪性肝病相关肝癌鼠模型的研究进展
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耿海波1, 2, 安丽平2, *
作者信息
  • 1石家庄职业技术学院食品与药品工程系，石家庄 050081
  • 2河北中医学院基础医学院，石家庄 050200

    • 耿海波，硕士研究生，副教授，主要从事药物分析和微生物应用方面的研究

通讯作者:

安丽平，E-mail：
Research progress in mouse models of non-alcoholic fatty liver disease associated hepatocellular carcinoma
Hai-Bo Geng1, 2, Li-Ping An2, *
Affiliations
  • 1Department of Food and Drug Engineering, Shijiazhuang University of Applied Technology, Shijiazhuang 050081, China
  • 2Basic Medical College, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
出版时间: 2021-04-28 doi: 10.11855/j.issn.0577-7402.2021.04.16
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非酒精性脂肪性肝病(NAFLD)已经逐渐成为引发肝细胞癌(HCC)的重要因素，且NAFLD-HCC与一般肝癌的临床治疗效果存在明显差异，对药物的敏感性有诸多不同。目前NAFLD-HCC的发病机制尚未明确，因此构建临床前的NAFLD-HCC动物模型尤为重要。NAFLD-HCC动物模型的诱导方法多种多样，包括饮食诱导、化学诱导、遗传诱导、饮食结合化学诱导、遗传结合饮食诱导等。越来越多的研究发现，不同方法诱导的NAFLD-HCC动物模型的组织病理学存在一定差异。因此，根据研究目的选择最合适的动物模型，对探讨NAFLD-HCC的发病原因以及后续的新药研发具有重要意义。该文总结已构建的用于NAFLD-HCC临床前研究的鼠模型，以揭示NAFLD-HCC的发生机制，探讨NAFLD-HCC预防或治疗可能的新靶标。

非酒精性脂肪性肝病相关肝癌  /  饮食诱导  /  化学诱导  /  遗传诱导  /  动物模型  /  应用评价

Non-alcoholic fatty liver disease (NAFLD) has gradually become an important factor causing hepatocellular carcinoma (HCC), and the clinical treatment effects of NAFLD-HCC and general liver cancer are significantly different, and there are many differences in drug sensitivity. At present, the pathogenesis of NAFLD-HCC is not yet clear. Therefore, it is particularly important to construct pre-clinical animal models of NAFLD-HCC. There are various induction methods for animal models of NAFLD-HCC, including dietary induction, chemical induction, genetic induction, dietary combined with chemical induction, genetic combined with dietary and other induction methods. More and more studies have found that there are certain differences in the histopathological types of animal models of NAFLD-HCC induced by different methods. Therefore, according to the research problem, choosing the most suitable animal model is of great significance for studying the causes of NAFLD-HCC and subsequent development of new drugs. The mouse models established for preclinical studies of the progression of NAFLD-HCC were summarized in this paper to reveal the pathogenesis of NAFLD-HCC, and to explore possible new targets for prevention or treatment of NAFLD-HCC.

non-alcoholic fatty liver disease associated hepatocellular carcinoma  /  dietary induction  /  chemical induction  /  genetic induction  /  animal model  /  application evaluation
耿海波, 安丽平. 非酒精性脂肪性肝病相关肝癌鼠模型的研究进展. 解放军医学杂志, 2021 , 46 (4) : 414 -419 . DOI: 10.11855/j.issn.0577-7402.2021.04.16
Hai-Bo Geng, Li-Ping An. Research progress in mouse models of non-alcoholic fatty liver disease associated hepatocellular carcinoma[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (4) : 414 -419 . DOI: 10.11855/j.issn.0577-7402.2021.04.16
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肝癌是癌症死亡的重要病因[1]，其中肝细胞癌(hepatocellular carcinoma，HCC)是原发性肝癌的主要组织学亚型，占肝癌总数的70%~85%。与生活方式改变相关的非酒精性脂肪性肝病(nonalcoholic fatty liver disease，NAFLD)是最常见的慢性肝病，也是HCC相关的危险因素[2]。越来越多的流行病学证据表明，NAFLD已成为HCC的主要病因[3-4]，在临床实践中，NAFLD-HCC表现出不同的生物学特性，是最容易被忽视的类型。目前NAFLD-HCC进展的潜在机制尚未完全明确，这也阻碍了对NAFLD-HCC患者特定治疗措施的制定。因此，为了探讨预防或治疗HCC的有效疗法，全面了解NAFLD患者发生HCC的分子机制具有重要意义。本文总结已构建的用于NAFLD-HCC临床前研究的鼠模型，以揭示NAFLD-HCC的发生机制，探讨预防或治疗NAFLD-HCC可能的新靶标。
1 饮食诱导NAFLD-HCC模型
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研究发现，仅喂食一种饮食的模型具有明显的局限性。C57BL/6小鼠饲喂高脂饮食(high fat diet，HFD)未出现类似NAFLD的病理表现，而饲喂蛋氨酸和胆碱缺乏(methionine and choline-deficient，MCD)饮食后却表现出类似NAFLD的病理改变，但MCD饮食不能诱发代谢综合征或肥胖症的特征。2014年Wolf等[5]提出一种混合饮食模型，该模型结合了胆碱缺乏(choline-deficient，CD)饮食和HFD，建模成功后同时存在肝脏脂肪变性、代谢综合征和肝脏损害等特征，主要表现为血清谷丙转氨酶(ALT)和谷草转氨酶(AST)水平升高。HFD小鼠模型的肿瘤发生率为2.5%，CD-HFD小鼠模型则为25%。在另一种联合饮食模型中，C57BL/6小鼠饲喂胆碱缺乏L-氨基酸饮食(choline-deficient L-amino acid-defined diet，CDAA)后，表现出类似于非酒精性脂肪性肝炎(nonalcoholic steatohepatitis，NASH)所致肝癌的肝损伤。采用CDAA饲养小鼠可引起胰岛素抵抗、肝脂肪变性增加、肝损伤和纤维化，并在第9个月形成HCC模型[6]。既往研究显示，C57BL/6J小鼠给予胆碱缺乏L-氨基酸高脂饮食(choline-deficient L-amino acid-defined high fat diet，CDAHFD)喂养36周，NAFLD中发生的肝纤维化持续存在并开始向HCC进展；继续喂养至60周，HCC进一步发展，但未发现严重的体重减轻及其他器官癌变[7]。CDAHFD小鼠模型可能是研究NAFLD引发HCC的有效模型，且有助于更好地了解肝癌发生过程中的病理变化。
采用高脂高胆固醇高糖饮食[58%脂肪、10%胆固醇以及含有42 g/L糖类(55%果糖和45%蔗糖)的饮用水]喂养雄性C57BL/6小鼠，8周时发生脂肪变性，27周时脂肪性肝炎与纤维化共同出现，49周时NASH逐渐发展为纤维化，且与肝肿瘤的发展有关[8]。Tucker等[9]利用75%脂肪胆碱缺乏乙硫氨酸(choline-deficient ethionine，CDE)饮食饲养小鼠18周，发现35%的小鼠发生增生性结节或癌变。Asgharpour等[10]报道了一种饮食诱导的NAFLD动物模型，概括了人类与NASH相关HCC的关键特征：将C57BL/6J和129S1/SvlmK小鼠的子代之间重复交配超过4年，产生同基因小鼠B6/129，给予B6/129小鼠高脂高糖饮食，4~8周时发生脂肪变性，16~24周时发生NASH，52周时发生HCC，这可能是NASH相关HCC的理想临床前模型。
2 化学和饮食相结合诱导NAFLD-HCC模型
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喂食CDAA并接受小剂量腹腔注射四氯化碳(carbon tetrachloride，CCl4)的C57BL/6小鼠具有明显的NASH和HCC特征。与仅饲喂CDAA的小鼠相比，该模型小鼠具有更多的脂肪变性、小叶炎症和纤维形成。此外，仅35%的CDAA C57BL/6小鼠发展为HCC，但所有CDAA+CCl4小鼠均发展为HCC，且平均肿瘤直径更大[6]。因此，与单独CDAA饮食模型相比，CDAA+CCl4诱导模型更好地展现了NAFLD向HCC进展的过程。在另一种联合模型中，C57BL/6小鼠饲喂HFD并用链脲佐菌素(streptozotocin，STZ)处理，可观察到的组织学变化为脂肪变性、小叶炎症、纤维化等，且在第20周观察到肿瘤形成。Van Campenhout等[11]认为，STZ+HFD构建的NAFLD-HCC模型可观察到类似于人类NAFLD的特征，包括体重增加、空腹血糖升高和血清ALT水平升高，且整个过程在相对较短的时间内即可完成。Iida等[12]采用STZ+HFD处理小鼠，动态观察NASH至HCC的过程中血液游离氨基酸水平的变化，发现小鼠在16周时表现出纤维化和HCC。Xie等[13]使用STZ+HFD诱导的NASH-HCC小鼠模型研究微生物群与肝细胞癌变之间的机制联系以及性别差异，发现雄性小鼠的HCC发生率更高，其肝内疏水性胆汁酸(bile acid，BA)显著增多，且肝抑制性miRNA表达下降，提示代谢异常、NASH与HCC的发生机制相互关联。Liang等[14]发现，高脂高胆固醇(high-fat with high cholesterol，HFHC)饮食喂养的动物可表现出NASH的进展过程，而高脂无胆固醇(high-fat without cholesterol，HF)饮食喂养的动物仅发展为简单的脂肪变性。与暴露于二乙基亚硝胺(diethylnitrosamine，DEN)的HFD喂养小鼠相比，HFHC饮食喂养小鼠HCC的多样性和大小显著增加。此外，在HFHC饮食喂养的小鼠中，40%的HCC存在肺转移，而HFD喂养的小鼠未显示出肺转移。Tian等[15]以DEN分别结合高脂高糖饮食和富含高果糖玉米糖浆饮用水的方法造模，造模28周后处死小鼠，发现高脂高糖饮食诱导的NAFLD-HCC模型中脂质(包括三酰甘油、游离脂肪酸和胆固醇)水平明显增加。
Eugénio等[16]对STZ诱导的糖尿病雄性小鼠喂养HFHC饮食或高脂高糖饮食1~16周，发现高脂高糖饮食诱导的模型发生轻度肝损伤、微弱的炎症和纤维化，且这些病理变化与早期形成更多的肝肿瘤有关。但在HFHC饮食诱导模型的肝脏中，可同时观察到活化的细胞毒性T细胞及肿瘤结节数量减少，表明免疫系统的激活限制了肿瘤的发展。该研究展示了糖尿病小鼠中两种不同的HCC进展模型。Fang等[17]采用HFD饲养SD大鼠12周诱导NAFLD的形成，然后在HFD的基础上增加0.05% 2-芴基乙酰胺诱导HCC的发生，18周时发现癌变，且癌变组织和血清CD44表达水平升高，提示CD44表达增加可能与NAFLD中肝细胞的恶性转化有关。
3 化学、饮食及低氧诱导NAFLD-HCC模型
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低氧微环境常见于各种实体瘤中，为了抵抗缺氧介导的组织坏死和细胞死亡，肿瘤会改变其基因表达以适应这种环境。低氧环境也对实体瘤的发生发展有重要作用，缺氧诱导因子-2α(hypoxia-inducible factor 2α，HIF-2α)是缺氧诱导因子家族的成员，在缺氧条件下稳定并可易位至细胞核。在缺氧微环境中，HIF-2α上调并通过激活经由PI3K-Akt-mTOR途径的脂质合成来促进脂肪性肝癌的发展。STAM小鼠是一种与人类NAFLD-HCC进展相似的模型，暴露于缺氧条件下可表现出更快的肿瘤进展[18]。给出生5 d的幼鼠注射200 μg STZ，并饲喂脂肪含量为60%的饮食，为了模拟缺氧，小鼠6:00 am至2:00 pm于笼中进行60 s IH循环(吸入5% FiO2持续30 s，然后吸入21% FiO2持续30 s)[19]。暴露于低氧环境的STAM小鼠肝脏表面肿瘤数目为(2.9±1.9)个，而未行低氧干预的STAM小鼠为(0.8±1.0)个[20]。因此，HIF-2α可作为NAFLD-HCC治疗的潜在靶标。
4 高拷贝转座子全基因组随机诱变结合基因操作诱导NAFLD-HCC模型
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Watanabe等[21]对磷脂酶和张力蛋白同源物(phosphatase and tensin homolog，PTEN)基因敲除小鼠进行“睡美人”(sleeping beauty，SB)诱变筛选，这是一种遗传干扰的NAFLD-HCC模型。已知PTEN基因敲除小鼠可自发发展为脂肪性肝炎和肝纤维化，并可导致肝癌的形成，潜伏期为1年。具有SB转座诱变的PTEN基因敲除小鼠在5个月时开始出现肝肿瘤，所有雄性和雌性小鼠分别在7个月和8个月时出现肿瘤。与PTEN基因敲除小鼠相比，SB转座诱变的PTEN基因敲除小鼠的肿瘤发生率明显增高[22]。表明在遗传干扰的NAFLD模型中，SB诱变促进了肝肿瘤的发展。
5 高拷贝转座子全基因组随机诱变结合HFD诱导NAFLD-HCC模型
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使用SB转座子或piggyBac转座子进行插入诱变可用于识别多种癌症类型中的癌基因。无论SB转座子的状态如何，HFD喂养都会引起肝脏中脂质的沉积[23]。SB转座子结合HFD喂养小鼠(high fat diet-sleeping beauty，HFD/SB)的肿瘤发生率在1岁时为54%，但在1.3岁时达到100%。HFD喂养的小鼠在没有活性SB转运的情况下未发现肿瘤形成，而正常饮食喂养的小鼠即使存在活性SB转运也很少发生肿瘤。因此，与其他小鼠相比，HFD/SB小鼠的肿瘤发生率明显增高，最大肿瘤体积随时间延长而明显增大，表明在基于饮食的NAFLD模型中，SB诱变显著加速了肝肿瘤的形成[22]。
6 基因操作诱变NAFLD-HCC模型
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支架蛋白Sav1是Hippo信号传导途径的重要组成部分，在NAFLD-HCC中具有抑癌作用。肝脏特异性缺失Sav1可促进肝脂质蓄积、凋亡和纤维化，从而导致肝脏特异性PTEN突变小鼠肝癌的加速发生。具有肝特异性Sav1或PTEN缺失的小鼠存活可超过1年，但肝特异性Sav1/PTEN双敲除小鼠的存活期明显缩短，大约从3个月开始出现死亡，其寿命明显短于Sav1或PTEN单敲除小鼠或同窝对照小鼠。值得注意的是，所有小鼠均在死亡前发展为多发性肝肿瘤，表明Sav1在缺乏PTEN的NAFLD小鼠肝脏中具有较强的抑癌作用，Sav1缺失显著增加了PTEN缺陷小鼠肝脏脂质的蓄积。与其他小鼠相比，Sav1/PTEN双敲除小鼠肝脏中三酰甘油和胆固醇水平显著升高[23]。PTEN由于具有脂质磷酸酶活性而成为肿瘤抑制因子，且在多种肿瘤中发生突变[24]，对于预防肝脏肿瘤的发生非常重要，缺乏PTEN会导致肿瘤细胞增殖、抗凋亡和肿瘤的发生。肝细胞特异性PTEN缺陷小鼠的特征与人类NASH和NASH-HCC相似[21]。在40~44周，66%的雄性和30%的雌性PTEN缺陷小鼠发生肝脏肿瘤；在74~78周，83%的雄性和50%的雌性小鼠发生肝脏肿瘤。
NAFLD-HCC样品的RNA测序分析表明，角鲨烯环氧酶(squalene epoxidase，SQLE)是在NAFLD-HCC患者中过度表达的顶级异常代谢基因。小鼠肝细胞特异的SQLE过表达促进了HFHC饮食诱导的HCC的发展。SQLE通过其代谢产物如胆固醇酯和烟酰胺腺嘌呤二核苷酸磷酸等发挥致癌作用。SQLE表达增加促进了胆固醇酯的生物合成，从而诱导了NAFLD-HCC细胞的生长。SQLE在人类NAFLD-HCC和HCC中过表达，且其表达与患者预后不良相关。特比萘芬是美国食品和药物管理局(FDA)批准的针对SQLE的抗真菌药物，在异种移植模型和SQLE基因过表达小鼠中，可明显抑制SQLE诱导的NAFLD-HCC细胞生长，并减慢肿瘤的发展。特比萘芬抑制肿瘤生长与降低胆固醇酯浓度、恢复PTEN表达和抑制Akt-mTOR有关，SQLE抑制剂可能是预防和治疗NAFLD-HCC潜在的有效药物[25]。
黑色素皮质素4受体(melanocortin receptor-4，MC4R)是一种跨膜G蛋白偶联受体，参与体重调节。缺乏MC4R的小鼠饲喂HFD 20周和1年，分别会导致NASH和肝脏中多个高度分化的HCC形成[26]。肝再生因子(augmenter of liver regeneration，ALR)被称为广泛多效蛋白，对于维持线粒体功能、脂质稳态和细胞存活至关重要。Gandhi等[27]发现，肝特异性ALR缺失小鼠2周龄时发生肝脂肪变性、线粒体变性和肝细胞凋亡，8周龄时发生肝纤维化和肝硬化并在1岁时形成HCC(占60%)。因此，理论上认为，抑制肝细胞中ALR的合成可能引起线粒体功能障碍和细胞死亡，从而导致连续的NASH和HCC发生，但对其潜在机制了解甚少。Khare等[28]首次使用长链3-羟基酰基-CoA脱氢酶(long-chain 3-hydoxy acyl-CoA dehydrogenase，LCHAD)缺陷小鼠模型进行NAFLD-HCC的研究。LCHAD外显子15缺失对纯合子小鼠具有胚胎致死性，而杂合子(heterozygous mice，HT)3月龄时开始发展为明显的肝脂肪变性，13月龄时开始形成肝癌，但未发现任何纤维化或肝硬化的迹象。野生型(WT)小鼠均未出现脂肪变性和HCC(n=39)，而HT-LCHAD小鼠(n=41)则显示出脂肪变性，其中20%(8/41)出现了具有HCC组织学特征的肝脏肿块。因此，该模型有助于了解NASH的发病机制以及NASH向HCC的发展过程。
7 基因操作和化学联合诱导NAFLD-HCC模型
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db/db小鼠的遗传性肥胖是NASH-HCC发生的直接促进因素，与野生型瘦弱小鼠相比，致癌物二乙基亚硝胺干预的db/db小鼠体重、肝脏重量、肝脂肪变性和HCC发生率较高，且肿瘤结节的数量较多、体积较大，表明肥胖和NASH增加了HCC发生的易感性[29]。Guri等[30]应用TSC1和PTEN双基因敲除小鼠，给予CD高脂饮食和二乙基亚硝胺处理，4周龄时出现肝脏增大，12周龄时显微镜下可观察到癌变发生，证实mTORC2可通过脂质促进肿瘤的发生。
8 NAFLD-HCC原位移植瘤模型
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Zheng等[31]研究胶原蛋白Ⅰ通过调节整联蛋白β1/FAK信号通路发挥对肝癌细胞的促增殖作用，对实验组饲喂HFD或MCD来诱导NFALD小鼠模型，对照组喂食标准的小鼠饮食，12周后，将5×106个H22细胞(小鼠肝癌细胞系)注入小鼠肝脏，2周后处死小鼠，评估肝脏中肿瘤的生长情况，结果发现HFD或MCD组小鼠肿瘤重量占肝脏重量百分比和转移性肿瘤的肝叶数目明显多于对照组。
总之，为了深入了解NAFLD-HCC的发生机制，找到相应的预防和治疗方法，近年来科研工作者开发了大量NAFLD-HCC小鼠模型，汇总信息如表1所示。
9 总结与展望
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多年来科研工作者已经开发了大量NAFLD-HCC小鼠模型，其诱导方法包括饮食诱导、化学诱导、遗传诱导、饮食结合化学诱导、遗传结合饮食诱导等，对于了解该病的进展具有重要意义。单纯性脂肪变性被认为是一种相对良性的疾病，但NAFLD仍然会发展为HCC，虽然遗传和营养模型已被广泛应用于相关研究，但迄今为止，并非所有的模型都能复制完整的人类NAFLD-HCC组织学和系统代谢的类型。遗传模型已经被证实是有用的研究方法，但在研究表型的特定基因突变时，在大部分NAFLD-HCC患者中并未发现，同时需要注意的是，对于饮食诱导的模型，饮食的类型和组成具有广泛的异质性。此外，化学诱导的从NAFLD到HCC的进展是否与人类条件相关仍有待验证。
临床NAFLD患者的肝纤维化程度和肿瘤发生时间存在个体差异，已有的可用小鼠模型是否代表了真正的人类NAFLD-HCC启动和(或)进展仍有待验证，但可以确定的是，这些小鼠模型对于研究NAFLD-HCC的潜在机制至关重要。因此，未来的研究目标应侧重于通过使用这些小鼠模型获得更全面的NAFLD-HCC评估。在分子水平上，细胞和鼠模型显示出基因修饰、细胞应激和炎症在驱动HCC进程中的重要性，是否可以开发具有有限脱靶效应的药物来限制HCC的生长仍有待研究。
总之，当前可用的模型均有其特定的优点和缺点，仍需持续改进和标准化。为了满足科研工作和医学领域深入研究NAFLD-HCC的需求，研究人员期望选择合适的NAFLD小鼠模型以进一步探索特定机制和(或)治疗目标。NAFLD-HCC小鼠模型的研究最终将使科学家和临床医师了解人类NAFLD-HCC完整的发病机制并开发新的疗法，并在预防或治疗NAFLD-HCC方面取得新突破。
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2021年第46卷第4期
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doi: 10.11855/j.issn.0577-7402.2021.04.16
  • 接收时间：2020-07-27
  • 首发时间：2025-12-26
  • 出版时间：2021-04-28
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  • 收稿日期：2020-07-27
  • 修回日期：2021-02-26
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    1石家庄职业技术学院食品与药品工程系，石家庄 050081
    2河北中医学院基础医学院，石家庄 050200

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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