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Full Length Article | Open Access

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

Wenchao Wanga,b,c,d,1, Junjie Qiana,b,c,d, Mingge Shanga,b,c,d, Yiting Qiaoa,b,c,d, Jiacheng Huanga,b,c,d, Xinxin Gaoa,b,c,d, Zhou Yea,b,c,d, Xinyu Tonga,b,c,d, Kangdi Xua,b,c,d, Xiang Lia,b,c,d, Zhengtao Liue,f,1( ), Lin Zhoua,b,c,d( ), Shusen Zhenga,b,c,d,f( )
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 Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang 310003, China
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

1 These authors contributed equally to this work.

Peer review under responsibility of Chongqing Medical University.

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Abstract

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 multi-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 transcriptomic 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 hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes. In senescent 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-regulated, and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor. 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 expression due to aging may be used to treat liver aging-related diseases.

Keywords

Antioxidant capabilityFGF21Liver agingLiver regenerationMultiomics analysis

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Genes & Diseases
Volume 11 Issue 5,
September 2024
Article number: 101161
DOI: 10.1016/j.gendis.2023.101161
Cite this article:
Wang W, Qian J, Shang M, et al. Integrative analysis of the transcriptome and metabolome reveals the importance of hepatokine FGF21 in liver aging. Genes & Diseases, 2024, 11(5): 101161. https://doi.org/10.1016/j.gendis.2023.101161

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Received: 18 July 2023
Revised: 03 October 2023
Accepted: 16 October 2023
Published: 07 November 2023
© 2023 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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