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Characterizing disease progression of nonalcoholic steatohepatitis in Leptin-deficient rats by integrated transcriptome analysis
2021-03
发表期刊EXPERIMENTAL BIOLOGY AND MEDICINE (IF:2.8[JCR-2023],3.5[5-Year])
ISSN1535-3702
EISSN1535-3699
卷号246期号:6页码:678-687
发表状态已发表
DOI10.1177/1535370220976530
摘要

Nonalcoholic steatohepatitis (NASH) is an aggressive liver disease threatening human health, yet no medicine is developed to treat this disease. In this study, we first discovered that Leptin mutant rats (Lep(Delta I14/Delta I14)) exhibit characteristic NASH phenotypes including steatosis, lymphocyte infiltration, and ballooning after postnatal week 16. We then examined NASH progression by performing an integrated analysis of hepatic transcriptome in Leptin-deficient rats from postnatal 4 to 48 weeks. Initially, simple steatosis in Lep(Delta I14/Delta I14) rats were observed with increased expression of the genes encoding for rate-limiting enzymes in lipid metabolism such as acetyl-CoA carboxylase and fatty acid synthase. When NASH phenotypes became well developed at postnatal week 16, we found gene expression changes in insulin resistance, inflammation, reactive oxygen species and endoplasmic reticulum stress. As NASH phenotypes further progressed with age, we observed elevated expression of cytokines and chemokines including C-C motif chemokine ligand 2, tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta together with activation of the c-Jun N-terminal kinase and nuclear factor-kappa B pathways. Histologically, livers in Lep(Delta I14/Delta I14) rats exhibited increased cell infiltration of MPO+ neutrophils, CD8(+) T cells, CD68(+) hepatic macrophages, and CCR2(+) inflammatory monocyte-derived macrophages associated with macrophage polarization from M2 to M1. Subsequent cross-species comparison of transcriptomes in human, rat, and mouse NASH models indicated that Leptin-deficient rats bear more similarities to human NASH patients than previously established mouse NASH models. Taken together, our study suggests that Lep(Delta I14/Delta I14) rats are a valuable pre-clinical rodent model to evaluate NASH drug safety and efficacy.

关键词Nonalcoholic steatohepatitis transcriptome hepatic inflammation animal model
收录类别SCI ; SCIE
语种英语
WOS研究方向Medicine, Research & Experimental
WOS类目Research & Experimental Medicine
WOS记录号WOS:000628236400005
出版者SAGE PUBLICATIONS LTD
原始文献类型Article
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126103
专题免疫化学研究所
免疫化学研究所_公共科研平台_生物医学大数据平台
免疫化学研究所_特聘教授组_范国平组
通讯作者Fan, Guoping; Zhu, Xianmin
作者单位
1.Tongji Univ, Sch Med, Tongji Stem Cell Res Ctr, Shanghai 200092, Peoples R China;
2.Tongji Univ, Translat Ctr Stem Cell Res, Tongji Hosp, Dept Regenerat Med,Sch Med, Shanghai 200065, Peoples R China;
3.Tongji Univ, Shanghai Key Lab Signaling & Dis Res, Sch Life Sci & Technol, Inst Translat Res,Tongji Hosp, Shanghai 200092, Peoples R China;
4.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China;
5.Tongji Univ, Sch Med, Shanghai Pulm Hosp, Shanghai 200433, Peoples R China;
6.Guangdong Inst Appl Biol Resources, Guangdong Publ Lab Wild Anim Conservat & Utilizat, Guangdong Key Lab Anim Conservat & Resource Utili, Guangzhou 510260, Peoples R China;
7.Tongji Univ, Tsingtao Adv Res Inst, Res Ctr Stem Cells & Ageing, Tsingdao 266071, Peoples R China;
8.Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
通讯作者单位免疫化学研究所
推荐引用方式
GB/T 7714
Lu, Ping,Yang, Guang,Jiang, Lichun,et al. Characterizing disease progression of nonalcoholic steatohepatitis in Leptin-deficient rats by integrated transcriptome analysis[J]. EXPERIMENTAL BIOLOGY AND MEDICINE,2021,246(6):678-687.
APA Lu, Ping.,Yang, Guang.,Jiang, Lichun.,He, Wen.,Wu, Wanwan.,...&Zhu, Xianmin.(2021).Characterizing disease progression of nonalcoholic steatohepatitis in Leptin-deficient rats by integrated transcriptome analysis.EXPERIMENTAL BIOLOGY AND MEDICINE,246(6),678-687.
MLA Lu, Ping,et al."Characterizing disease progression of nonalcoholic steatohepatitis in Leptin-deficient rats by integrated transcriptome analysis".EXPERIMENTAL BIOLOGY AND MEDICINE 246.6(2021):678-687.
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