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World J Gastroenterol. Jul 7, 2026; 32(25): 118597
Published online Jul 7, 2026. doi: 10.3748/wjg.118597
Calcium-dependent signaling protein family member S100A11 promotes liver and adipose lipid accumulation through fibroblast growth factor 21
Qian-Qian Zhang, Xiao-Qing Lu, Bing-Zhen Shang, Ling-Chao Liu, En-Ting Lu, Hua-Yang Li, Ming-Ming Xia, Yu-Xin Jin, Wei-Zhen Zhang, Yi Zhang, Jing-Yan Han, Yin Li
Qian-Qian Zhang, Xiao-Qing Lu, Yu-Xin Jin, Jing-Yan Han, Yin Li, Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China
Bing-Zhen Shang, Department of Clinical Trial Ward, Clinical Trial and Conversion Center, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
Ling-Chao Liu, Wei-Zhen Zhang, Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
En-Ting Lu, Hua-Yang Li, Ming-Ming Xia, Yi Zhang, Department of Gynecology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
Co-first authors: Qian-Qian Zhang and Xiao-Qing Lu.
Co-corresponding authors: Jing-Yan Han and Yin Li.
Author contributions: Zhang QQ, Lu XQ, Liu LC, Lu ET, Li HY, Xia MM, and Jin YX collected the data, Zhang QQ and Lu XQ contributed equally to this article and are co-first authors of this manuscript; Zhang QQ, Lu XQ, Shang BZ, Lu ET, Li HY, and Xia MM prepared the original draft; Shang BZ, Zhang Y, and Li Y reviewed and edited the manuscript; Zhang WZ, Zhang Y, Han JY, and Li Y supervised the project; Zhang Y and Li Y contributed to funding acquisition; Han JY and Li Y contributed equally to this article and are co-corresponding authors of this manuscript; all authors thoroughly reviewed and approve the final manuscript.
Supported by the National Key Research and Development Program of China, No. 2020YFA0803801; the National Natural Science Foundation of China, No. 81873568; and the Key Research and Liao Ning Revitalization Talents Program, No. XLYC2412037.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Animal Research Ethics Committee of Peking University, approval No. LA2018061.
Conflict-of-interest statement: The authors report no relevant conflicts of interest for this article.
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: Yin Li, MD, PhD, Associate Professor, Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, No. 38 Xueyuan Road, Haidian District, Beijing 100191, China.
yinli@bjmu.edu.cn
Received: January 8, 2026
Revised: February 2, 2026
Accepted: February 26, 2026
Published online: July 7, 2026
Processing time: 174 Days and 10.8 Hours
BACKGROUND
S100A11, a calcium-binding protein implicated in cholesterol metabolism, and fibroblast growth factor (FGF) 21, a key liver-fat signaling factor elevated in metabolic disorders, were investigated for their roles in obesity and fatty liver.
AIM
To determine if S100A11 promotes hepatic lipid accumulation via FGF21.
METHODS
Transgenic mice overexpressing S100A11 in the liver and normal control wild-type mice were fed with normal or high-fat diet. S100A11 was overexpressed or knocked down in liver cell lines. Expression of triglycerides (TGs) and genes related to liver lipid metabolism was measured by real-time reverse transcription polymerase chain reaction. The liver tissues of mice fed with a high-fat diet were used for proteomic analysis. FGF21 neutralizing antibody was administered in both in vivo and in vitro models to validate its role in S100A11-induced hepatic and adipose lipid accumulation.
RESULTS
S100A11 overexpression elevated hepatic TGs and FGF21 in male mice. In hepatocytes, S100A11 overexpression upregulated TGs, lipogenic genes, and FGF21, which were reversed by S100A11 silencing. Coculture of S100A11-overexpressing hepatocytes with adipocytes suppressed brown-fat-related genes and promoted white-fat-related genes upon oleic acid stimulation. Proteomic analysis highlighted enrichment of the peroxisome proliferator-activated receptor pathway, where FGF21 is pivotal. Hepatic and adipose FGF21 was upregulated by S100A11 but downregulated upon its silencing. FGF21-neutralizing antibody partially reversed S100A11-induced hepatic and adipose lipid accumulation.
CONCLUSION
S100A11 promotes hepatic and adipose lipid accumulation in male mice, a process mediated by FGF21. This identifies S100A11 as a potential therapeutic target for obesity-related metabolic diseases.
Core Tip: This study reveals that the calcium-binding protein S100A11 promotes hepatic and adipose lipid accumulation by upregulating fibroblast growth factor 21, identifying S100A11 as a novel potential therapeutic target for obesity-related metabolic disorders.
