代谢功能障碍相关脂肪变性肝病和肝细胞癌的雄性小鼠模型-动脉网

A male mouse model for metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma

Nature 等信源发布 2024-08-02 12:30

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AbstractThe lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Here, we develop a mouse model (Streptozotocin with high-fat diet, STZ + HFD) that gradually develops fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction.

摘要缺乏适当的代谢功能障碍相关脂肪变性肝病（MASLD）临床前模型来概括整个疾病谱，阻碍了疾病病理生理学的探索和有效治疗策略的发展。在这里，我们开发了一种小鼠模型（高脂饮食链脲佐菌素，STZ+ HFD），该模型在代谢功能障碍的情况下逐渐发展为脂肪肝，代谢功能障碍相关脂肪性肝炎（MASH），肝纤维化和肝细胞癌（HCC）。

The hepatic transcriptomic features of STZ + HFD mice closely reflect those of patients with obesity accompanying type 2 diabetes mellitus, MASH, and MASLD-related HCC. Dietary changes and tirzepatide administration alleviate MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ + HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients is successfully established..

STZ+ HFD小鼠的肝脏转录组学特征密切反映了伴有2型糖尿病，MASH和MASLD相关HCC的肥胖患者的肝脏转录组学特征。饮食改变和tirzepatide给药减轻STZ+ HFD小鼠的MASH，肝纤维化和肝肿瘤发生。总之，成功建立了一种小鼠模型，该模型概括了在MASLD患者中观察到的主要组织病理学，转录组学和代谢改变。。

IntroductionMetabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a range of disorders characterized by excessive accumulation of triglyceride (TG) in hepatocytes, replacing the previous term non-alcoholic fatty liver disease (NAFLD), which relies on exclusionary confounder terms1.

引言代谢功能障碍相关脂肪变性肝病（MASLD）包括一系列以肝细胞中甘油三酯（TG）过度积累为特征的疾病，取代了以前的非酒精性脂肪肝病（NAFLD），后者依赖于排除性混杂因素1。

MASLD progresses from TG accumulation (metabolic dysfunction-associated steatotic liver, MASL) to inflammation and hepatocellular injury (metabolic dysfunction-associated steatohepatitis, MASH), hepatic fibrosis, and, ultimately, cirrhosis and/or hepatocellular carcinoma (HCC)2. MASLD is a rapidly growing health concern3 that has made an increasing contribution to end-stage liver disease in recent years, thus imposing a substantial socioeconomic burden4,5,6.

MASLD从TG积累（代谢功能障碍相关的脂肪肝，MASL）发展为炎症和肝细胞损伤（代谢功能障碍相关的脂肪性肝炎，MASH），肝纤维化，最终是肝硬化和/或肝细胞癌（HCC）2。MASLD是一个快速增长的健康问题3，近年来对终末期肝病的贡献越来越大，因此带来了巨大的社会经济负担4,5,6。

Owing to the lack of suitable MASLD animal models, limited studies have focused on the exploration of the underlying mechanisms and treatment strategies7. Therefore, establishment of an animal model that adequately reflects the entire spectrum of MASLD remains a crucial unmet need.Patients with metabolic disorders, such as type 2 diabetes mellitus (T2DM) and obesity, have a higher prevalence of MASLD and exacerbated risk of developing MASH, advanced fibrosis (defined as fibrosis stage ≥3), and HCC8,9,10.

由于缺乏合适的MASLD动物模型，有限的研究集中在探索潜在的机制和治疗策略7。因此，建立一个充分反映MASLD整个范围的动物模型仍然是一个关键的未满足需求。患有代谢紊乱的患者，如2型糖尿病（T2DM）和肥胖症，MASLD的患病率较高，并加剧了发生MASH，晚期纤维化（定义为纤维化阶段≥3）和HCC8,9,10的风险。

In a recent study on T2DM patients who had undergone liver biopsies, MASH and advanced fibrosis were detected in 58% and 38% cases, respectively11. Another study reported a higher incidence of MASLD and advanced fibrosis in T2DM patients with obesity compared to those without12. However, the mechanism underlying the rapid progression of MASLD in individuals with T2DM and obesity is not well understood.From the therapeutic aspect, pharmacological interventions based on lifestyle may be effective in blocking pathologi.

在最近一项关于接受肝活检的T2DM患者的研究中，分别有58%和38%的病例检测到MASH和晚期纤维化11。另一项研究报道，与没有肥胖的T2DM患者相比，肥胖T2DM患者的MASLD和晚期纤维化发生率更高12。。从治疗方面来看，基于生活方式的药物干预可能有效阻断病理学。

Data availability

数据可用性

The RNA-seq and ATAC-seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under the accession code GSE246223. Expression dataset of NAFLD patients with obesity, NAFLD patients with HCC, and HCC patients with other etiologies were downloaded from GEO database (GSE163211, GSE164760, GSE63898.

本研究中产生的RNA-seq和ATAC-seq数据已以登录号GSE246223保存在Gene Expression Omnibus（GEO）数据库中。从GEO数据库（GSE163211，GSE164760，GSE63898）下载肥胖NAFLD患者，HCC NAFLD患者和其他病因HCC患者的表达数据集。

The RNA-seq data of diethylnitrosamine-treated HFD-fed mice was downloaded from the Genome Sequence Archive [https://ngdc.cncb.ac.cn/gsa/browse/CRA000931]. Molecular signature gene sets of HCCs were obtained from three publicly available data ([https://doi.org/10.1002/hep.21467], [https://doi.org/10.1158/0008-5472.CAN-09-1089], [https://doi.org/10.1002/hep.29254]). Source data are provided with this paper..

从基因组序列档案中下载了经二乙基亚硝胺处理的HFD喂养小鼠的RNA-seq数据[https://ngdc.cncb.ac.cn/gsa/browse/CRA000931]。HCC的分子特征基因组是从三个公开可用的数据中获得的([https://doi.org/10.1002/hep.21467][https://doi.org/10.1158/0008-5472.CAN-09-1089][https://doi.org/10.1002/hep.29254])。本文提供了源数据。。

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and W.H.L.), a Medical Scientist Training Program from the Ministry of Science & ICT of Korea, and grants of National Research Foundation of Korea (2021R1I1A1A01043936 to W-I.C.; 2021M3E5D1A02015181 to W.C.; 2021R1A2C1012480 to Y.A.M; 2020M3A9E4039184 to J.Y.P.; and 2021R1A2C3005108, 2020M3A9E4038695 to H.K.).

和W.H.L.），韩国科学与信息技术部的医学科学家培训计划，以及韩国国家研究基金会的资助（2021R1I1A1A01043936授予W-I.C.；2021M3E5D1A02015181授予W.C.；2021R1A2C1012480授予Y.a.M.；2020M3A9E4039184授予J.Y.P.；2021R1A2C30051082020M3A9E4038695授予H.K.）。

We thank Won Gun Choi and Inseon Hwang for their helpful discussions and technical support. We also thank Hyeon Kyu Lee, Jungsun Park, Jung Eun Nam, Hee-Saeng Jung, Ju Eun Kim, and Hwajin Kim for their technical assistance in experiments.Author informationAuthor notesThese authors contributed equally: Byung-Kwan Jeong, Won-Il Choi, Wonsuk Choi.Authors and AffiliationsGraduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, KoreaByung-Kwan Jeong, Won-Il Choi, Jieun Moon, Won Hee Lee, Young Seok Ju, Pilhan Kim & Hail KimBiomedical Research Center, KAIST, Daejeon, KoreaByung-Kwan Jeong, Won-Il Choi, Jieun Moon, Won Hee Lee, Young Seok Ju, Pilhan Kim & Hail KimDepartment of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, KoreaWonsuk ChoiDepartment of Pathology, Chonnam National University Medical School, Hwasun, KoreaChan ChoiHanmi Research Center, Hanmi Pharmaceutical Co.

我们感谢Won Gun Choi和Inseon Hwang的有益讨论和技术支持。我们还要感谢李显圭、朴正善、郑恩南、Hee Saeng-Jung-Jun Kim和Hwajin Kim在实验中提供的技术援助。作者信息作者注意到这些作者做出了同样的贡献：Byung Kwan Jeong，Won Il Choi，Wonsuk Choi。作者和所属机构大田KAIST医学科学与工程研究生院，34141，KoreaByung Kwan Jeong，Won Il Choi，Jiun Moon，Won Hee Lee，Young Seok Ju，Pilhan Kim＆Hail Kim生物医学研究中心，KAIST，大田，KoreaByung Kwan Jeong，Won Il Choi，Jiun Moon，Won Hee Lee，Young Seok Ju，Pilhan Kim＆Hail Kim Chonnam国立大学医院内科，Chonnam国立大学医学院，Hwasun，KoreaWonsuk Choi韩密制药公司KoreaChan ChoiHanmi研究中心。

Ltd, Hwaseong, KoreaIn Young Choi, Sang-Hyun Lee & Jung Kuk KimDepartment of Mo.

有限公司，华盛，韩国杨崔，李相贤和金正国Mo部门。

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PubMed Google ScholarContributionsB-K.J., W-I.C., W.C., J.Y.P., and H.K. were responsible for the study concept and design. B-K.J., W-I.C., W.C., J.M., W.H.L., C.C., I.Y.C, S-H.L, J.K.K, P.K., Y.S.J., J.Y.P. and H.K. were responsible for the acquisition of data, technical and material support.

PubMed Google ScholarContributionsB-K.J.，W-I.C.，W.C.，J.Y.P。和H.K.负责研究概念和设计。。

B-K.J., W-I.C., W.C., W.H.L., Y.A.M. and H.K. were responsible for analysis and interpretation of data. B-K.J., W-I.C., W.C., Y.A.M, J.Y.P., and H.K. were responsible for the drafting of the manuscript. Y.S.J and J.Y.P. were responsible for critical revision of the manuscript for important intellectual content.

B-K.J.，W-I.C.，W.C.，W.H.L.，Y.A.M.和H.K.负责数据的分析和解释。B-K.J.，W-I.C.，W.C.，Y.A.M，J.Y.P。和H.K.负责起草手稿。Y、 S.J和J.Y.P.负责对重要知识内容的手稿进行严格修订。

All authors have critically reviewed the paper and approved the final version.Corresponding authorsCorrespondence to.

所有作者都对论文进行了批判性审查，并批准了最终版本。通讯作者通讯。

Wonsuk Choi, Jun Yong Park or Hail Kim.Ethics declarations

崔元寿、朴俊勇或金浩。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

。

Ethics

伦理学

All animal experiments complied with the relevant ethical regulations. Experimental protocols for this study were approved by the Institutional Animal Care and Use Committee of Korea Advanced Institute of Science and Technology (KAIST). The criteria for terminating the animal experiment were set as follows: if the size of the hepatic tumor measured externally in the mice exceeded a maximum diameter of 20 mm, or if the weight loss was more than 20%.

所有动物实验均符合相关道德规范。这项研究的实验方案得到了韩国高级科学技术研究所（KAIST）机构动物护理和使用委员会的批准。终止动物实验的标准设定如下：如果在小鼠外部测量的肝肿瘤大小超过最大直径20毫米，或者如果体重减轻超过20%。

Only one mouse had a tumor size that exceeded the maximum diameter, measuring 21 mm, which was within the margin of human error. Each week, the surface skin of the mouse liver was visually inspected and palpated to assess tumorigenesis, and the weight was measured to ensure compliance with these criteria.

只有一只小鼠的肿瘤大小超过了最大直径，尺寸为21毫米，这在人为错误的范围内。每周，目视检查和触诊小鼠肝脏的表面皮肤以评估肿瘤发生，并测量体重以确保符合这些标准。

Experiments using human specimens were performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and written informed consent was obtained from each participant. There was no compensation provided to research subjects for their participation. The study protocol was approved by the Severance Hospital Institutional Review Board (IRB No.

使用人体标本的实验是根据1975年赫尔辛基宣言的道德准则进行的，并获得了每个参与者的书面知情同意。没有为研究对象的参与提供任何补偿。该研究方案得到了遣散医院机构审查委员会（IRB No。

4-2018-0537, Seoul, Korea)..

4-2018-0537，韩国首尔）。。

Peer review

同行评审

Peer review information

同行评审信息

Nature Communications thanks Hidekazu Tsukamoto, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Nature Communications感谢Hidekazu Tsukamoto和另一位匿名审稿人对这项工作的同行评审做出的贡献。可以获得同行评审文件。

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Nat Commun 15, 6506 (2024). https://doi.org/10.1038/s41467-024-50660-yDownload citationReceived: 28 October 2023Accepted: 16 July 2024Published: 02 August 2024DOI: https://doi.org/10.1038/s41467-024-50660-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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