Zhu F, Lin BR, Lin SH, Yu CH, Yang YM. Hepatic-specific vitamin D receptor downregulation alleviates aging-related metabolic dysfunction-associated steatotic liver disease. World J Gastroenterol 2025; 31(14): 104117 [PMID: 40248374 DOI: 10.3748/wjg.v31.i14.104117]
Corresponding Author of This Article
Chao-Hui Yu, PhD, Chief Physician, Professor, Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. zyyyych@zju.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Feng Zhu, Bing-Ru Lin, Shi-Hua Lin, Chao-Hui Yu, Yun-Mei Yang
Feng Zhu, Shi-Hua Lin, Yun-Mei Yang, Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Bing-Ru Lin, Chao-Hui Yu, Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Yun-Mei Yang, Key Laboratory of Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
Co-corresponding authors: Chao-Hui Yu and Yun-Mei Yang.
Author contributions: Yu CH and Yang YM designed and supervised the study; Zhu F, Lin BR, and Lin SH performed the experiments and acquired and analyzed the data; Zhu F and Lin BR interpreted the data; Zhu F wrote the manuscript; All authors approved the final version of the article; Yu CH and Yang YM contributed equally to this work in the design and supervision of the study, and review and revision of the paper, meriting the co-corresponding authorship designation.
Supported by the National Natural Science Foundation of China, No. 820300089.
Institutional review board statement: The study did not involve human participants, human data, or human tissue.
Institutional animal care and use committee statement: All animal procedures were approved by the Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine (No. 2024-1652).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Corresponding author: Chao-Hui Yu, PhD, Chief Physician, Professor, Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. zyyyych@zju.edu.cn
Received: December 11, 2024 Revised: February 21, 2025 Accepted: March 21, 2025 Published online: April 14, 2025 Processing time: 121 Days and 20.3 Hours
Abstract
BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by the abnormal lipid deposition in hepatocytes. The prevalence of MASLD is significantly increased in the elderly population, suggesting that aging may be related to the occurrence of MASLD. Emerging evidences suggest that vitamin D receptor (VDR) may be implicated in the progression of MASLD. Therefore, additional researches are warranted to elucidate whether VDR plays a role in aging-related MASLD.
AIM
To investigate the relationship between aging and MASLD and explore the role and related mechanisms of VDR in aging-related MASLD.
METHODS
Cellular senescence models were established, and the senescence phenotype of telomerase RNA component knockout mice was validated. These mice were then used as a senescence model for subsequent studies. Changes in VDR expression in the livers of aging mice were examined. VDR knockdown models, including cell knockdown models and hepatic-specific VDR knockout mice, were constructed, and MASLD was established in these models. Additionally, vitamin D (VD)-supplemented models, including senescent liver cell lines and senescent mice, were constructed.
RESULTS
The steatosis in senescent liver cells was more severe than in normal cells (P < 0.05). Moreover, hepatic steatosis was significantly more pronounced in senescence model mice compared to control group when the MASLD model was successfully induced (P < 0.05). Therefore, we concluded that aging aggravated hepatic steatosis. The hepatic expression of VDR increased after aging. VDR knockdown in senescent liver cells and senescent mice alleviated hepatic steatosis (P < 0.05). When senescent liver cells were stimulated with VD, cellular steatosis was aggravated (P < 0.05). However, VD supplementation had no effect on aging mice.
CONCLUSION
Aging can lead to increased hepatic steatosis, and the hepatic-specific knockdown of VDR alleviated aging-related MASLD. VDR could serve as a potential molecular target for aging-related MASLD.
Core Tip: We showed that aging exacerbated the pathogenesis of metabolic dysfunction-associated steatotic liver disease. Hepatic-specific knockdown of vitamin D receptor alleviated the progression of aging-related metabolic dysfunction-associated steatotic liver disease. Vitamin D receptor is a crucial factor implicated in steatosis.
