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

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

Genes and Diseases (Sep 2024)

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

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

Affiliations

Wenchao Wang: 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
Junjie Qian: 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
Mingge Shang: 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
Yiting Qiao: 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
Jiacheng Huang: 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
Xinxin Gao: 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
Zhou Ye: 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
Xinyu Tong: 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
Kangdi Xu: 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
Xiang Li: 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
Zhengtao Liu: 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; Corresponding author. Shulan International Medical College, Zhejiang Shuren University, Hangzhou, Zhejiang 310015, China.
Lin Zhou: 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; Corresponding author. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
Shusen Zheng: 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 (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310000, China; Corresponding author. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.

Journal volume & issue: Vol. 11, no. 5
p. 101161

Abstract

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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.

Published in Genes and Diseases

ISSN: 2352-3042 (Online)
Publisher: KeAi Communications Co., Ltd.
Country of publisher: China
LCC subjects: Medicine: Medicine (General); Science: Biology (General): Genetics
Website: https://www.keaipublishing.com/en/journals/genes-and-diseases/

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