Integrative analysis of the transcriptome and metabolome reveals the importance of hepatokine FGF21 in liver aging

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外文摘要：Aging is a contributor to liver disease.Hence,the concept of liver aging has become prominent and has attracted considerable interest,but its underlying mechanism remains poorly understood.In our study,the internal mechanism of liver aging was explored via mul-ti-omics analysis and molecular experiments to support future targeted therapy.An aged rat liver model was established with D-galactose,and two other senescent hepatocyte models were established by treating HepG2 cells with D-galactose and H2O2.We then performed tran-scriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models.In livers,genes related to peroxisomes,fatty acid elongation,and fatty acid degradation exhibited down-regulated expression with aging,and the hepato-kine Fgf21 expression was positively correlated with the down-regulation of these genes.In se-nescent hepatocytes,similar to the results found in aged livers,FGF21 expression was also decreased.Moreover,the expressions of cell cycle-related genes were significantly down-regu-lated,and the down-regulated gene E2F8 was the key cell cycle-regulating transcription fac-tor.We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver.We successfully validated the results from cellular and animal experiments using human liver and blood samples.Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expres-sion due to aging may be used to treat liver aging-related diseases.

外文关键词：

Antioxidant capabilityFGF21Liver agingLiver regenerationMultiomics analysis

作者：

Wenchao Wang、Junjie Qian、Mingge Shang、Yiting Qiao、Jiacheng Huang、Xinxin Gao、Zhou Ye、Xinyu Tong、Kangdi Xu、Xiang Li、Zhengtao Liu、Lin Zhou、Shusen Zheng

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作者单位：

Division of Hepatobiliary and Pancreatic Surgery,Department of Surgery,First Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou,Zhejiang 310003,China

NHC Key Laboratory of Combined Multi-organ Transplantation,Hangzhou,Zhejiang 310003,China

Key Laboratory of the Diagnosis and Treatment of Organ Transplantation,Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer,Chinese Academy of Medical Sciences(2019RU019),Hangzhou,Zhejiang 310003,China

Key Laborat

Shulan International Medical College,Zhejiang Shuren University,Hangzhou,Zhejiang 310015,China

Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College,Hangzhou,Zhejiang 310000,China

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基金：

Research Unit Project of the Chinese Academy of Medical SciencesResearch Project of Jinan Microecological Biomedicine Shandong Laboratory(China)Fundamental Research Funds for the Central Universities(China)

项目编号：

2019-I2M-5-030JNL-2022002A226-2023-00107

出版年：

2024

DOI：

10.1016/j.gendis.2023.101161

基因与疾病(英文)

ISSN：

年,卷(期)：2024.11(5)