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Transcriptomic Landscape Analysis Reveals a Persistent DNA Damage Response in Metabolic Dysfunction-associated Steatohepatitis Post-dietary Intervention

文献类型：期刊论文

作者Zou, Zi-Yuan6,7; Ren, Tian-Yi7; Jiao, Ting-Ying4,6; Wang, Meng-Yu7; Huang, Lei-Jie3; Lin, Shuang-Zhe7; Wang, Yuan-Yang6; Guo, Xiao-Zhen6; Song, Ye-Yu6,7; Yang, Rui-Xu7
刊名JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY
出版日期2024-08-02
页码15
关键词Apoptosis DNA Damage Metabolic dysfunction-associated stea- totic liver disease RNA-Seq Tumor suppressor protein P53 Western Diets
ISSN号2225-0719
DOI10.14218/JCTH.2024.00111
通讯作者Xie, Cen(xiecen@simm.ac.cn) ; Fan, Jian-Gao(fanjiangao@xinhuamed.com.cn)
英文摘要Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis, have emerged as the most prevalent liver diseases worldwide. Currently, lifestyle modification is the foremost guidelinerecommended management strategy for MASLD. However, it remains unclear which detrimental signals persist in MASLD even after disease remission. Thus, we aimed to examine the persistent changes in liver transcriptomic profiles following this reversal. Methods: Male C57BL/6J mice were divided into three groups: Western diet (WD) feeding, chow diet (CD) feeding, or diet reversal from WD to CD. After 16 weeks of feeding, RNA sequencing was performed on the mice's livers to identify persistent alterations characteristic of MASLD. Additionally, RNA sequencing databases containing high-fat diet-fed P53-knockout mice and human MASLD samples were utilized. Results: WD-induced MASLD triggered persistent activation of the DNA damage response (DDR) and its primary transcription factor, P53, long after the resolution of the hepatic phenotype through dietary reversal. Elevated levels of P53 might promote apoptosis, thereby exacerbating metabolic dysfunction-associated steatohepatitis, as they strongly correlated with hepatocyte ballooning, an indicator of apoptosis activation. Moreover, P53 knockout in mice led to downregulated expression of apoptosis signaling in the liver. Mechanistically, P53 may regulate apoptosis by transcriptionally activating the expression of apoptosis-enhancing nuclease (AEN). Consistently, P53, AEN, and the apoptosis process all exhibited persistently elevated expression and showed a strong inter-correlation in the liver following dietary reversal. Conclusions: The liver demonstrated upregulation of DDR signaling and the P53-AEN-apoptosis axis both during and after exposure to WD. Our findings provide new insights into the mechanisms of MASLD relapse, highlighting DDR signaling as a promising target to prevent MASLD recurrence.
WOS关键词FATTY LIVER-DISEASE ; NONALCOHOLIC STEATOHEPATITIS ; HEPATIC STEATOSIS ; CELL-DEATH ; NASH
资助项目Strategic Priority Re- search Program of the Chinese Academy of Sciences[XDB39020600] ; National Natural Science Foundation of China[81900507] ; National Natural Science Foundation of China[82100606] ; National Natural Science Foundation of China[82170593] ; National Natural Science Foundation of China[82222071] ; National Natural Science Foundation of China[91957116] ; Shanghai Municipal Science and Tech- nology Major Project
WOS研究方向Gastroenterology & Hepatology
语种英语
WOS记录号WOS:001283381200001
出版者XIA & HE PUBLISHING INC
源URL[http://119.78.100.183/handle/2S10ELR8/312574]  
专题新药研究国家重点实验室
通讯作者Xie, Cen; Fan, Jian-Gao
作者单位1.Shanghai Jiao Tong Univ, Dept Gastroenterol, Shanghai Key Lab Pediat Gastroenterol & Nutr, Xinhua Hosp,Sch Med, Shanghai 200092, Peoples R China
2.Shanghai Key Lab Pediat Gastroenterol & Nutr, Shanghai 200092, Peoples R China
3.Ningbo 2 Hosp, Dept Gastroenterol, Ningbo, Zhejiang, Peoples R China
4.Fudan Univ, Human Phenome Inst, Sch Life Sci, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Beijing, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Shanghai Jiao Tong Univ, Xinhua Hosp, Ctr Fatty Liver, Dept Gastroenterol,Sch Med, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zou, Zi-Yuan,Ren, Tian-Yi,Jiao, Ting-Ying,et al. Transcriptomic Landscape Analysis Reveals a Persistent DNA Damage Response in Metabolic Dysfunction-associated Steatohepatitis Post-dietary Intervention[J]. JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY,2024:15.
APA Zou, Zi-Yuan.,Ren, Tian-Yi.,Jiao, Ting-Ying.,Wang, Meng-Yu.,Huang, Lei-Jie.,...&Fan, Jian-Gao.(2024).Transcriptomic Landscape Analysis Reveals a Persistent DNA Damage Response in Metabolic Dysfunction-associated Steatohepatitis Post-dietary Intervention.JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY,15.
MLA Zou, Zi-Yuan,et al."Transcriptomic Landscape Analysis Reveals a Persistent DNA Damage Response in Metabolic Dysfunction-associated Steatohepatitis Post-dietary Intervention".JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY (2024):15.

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来源：上海药物研究所

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