Depleting apolipoprotein C3 alleviates acute pancreatitis in hamsters but not in mice

doi:10.3748/wjg.119570

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Aug 21, 2026; 32(31): 119570
Published online Aug 21, 2026. doi: 10.3748/wjg.119570

Depleting apolipoprotein C3 alleviates acute pancreatitis in hamsters but not in mice

Gong-Lie Chen, Kai-Kai Lu, Wen-Xi Zhang, Ping-Ping Lai, Yi-Tong Xu, Yu-Fei Han, Zi-Hao Zhou, Wei Huang, Yu-Hui Wang, Yue Zhang, Xun-De Xian

Gong-Lie Chen, Kai-Kai Lu, Ping-Ping Lai, Yi-Tong Xu, Yu-Fei Han, Wei Huang, Yu-Hui Wang, Xun-De Xian, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China

Wen-Xi Zhang, Department of Pathophysiology, Second Military Medical University, Shanghai 200433, China

Zi-Hao Zhou, Department of Laboratory Medicine, Peking University Third Hospital, Beijing 100191, China

Yue Zhang, Department of Health Management, The First Affiliated Hospital, Jiangxi Medical College Nanchang University, Nanchang 330006, Jiangxi Province, China

Co-first authors: Gong-Lie Chen and Kai-Kai Lu.

Co-corresponding authors: Yue Zhang and Xun-De Xian.

Author contributions: Huang W conceived the research. Chen GL and Lu KK conducted the experiments, performed the data analysis, and wrote the manuscript with figures, and contributed equally as co-first authors. Zhang WX, Lai PP, Xu YT, Han YF, and Zhou ZH assisted in sample collection. Wang YH, Zhang Y, and Xian XD reviewed and supervised the study. Zhang Y, and Xian XD contributed equally as co-corresponding authors. All authors have reviewed the final manuscript and confirm its approval for publication.

AI contribution statement: Only Grammarly was used during the preparation of this manuscript and answering-reviewers. The main text was originally written by the authors. AI tools were only used for language polishing and writing assistance. No portion of the main text was directly generated by AI. AI tools were used for language polishing and writing assistance, but not for translation and data analysis. The study design and interpretation of results were performed solely by the authors. All images were created by the authors using non-AI-based software or acquired from experimental results.

Supported by the Jiangxi Provincial Natural Science Foundation, China, No. 20212BAB216022; the National Natural Science Foundation of China, No. 82270479 and No. 82501040; and China Postdoctoral Science Foundation, No. 2025M771442.

Institutional animal care and use committee statement: All experimental procedures were conducted in accordance with the guidelines approved by the Institutional Animal Care and Use Committee of Peking University (No. LA2015-012).

Conflict-of-interest statement: The authors declare that they have no conflicts 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: Xun-De Xian, PhD, Professor, Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Peking University Health Science Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, No. 38 Xueyuan Road, Huayuanlu Subdistrict, Haidian District, Beijing 100191, China. xianxunde@bjmu.edu.cn

Received: February 2, 2026
Revised: April 8, 2026
Accepted: May 18, 2026
Published online: August 21, 2026
Processing time: 185 Days and 13.5 Hours

Abstract

BACKGROUND

Acute pancreatitis (AP) is an inflammatory disease with a complex pathogenesis. A subset of cases is closely associated with hypertriglyceridemia (HTG). Apolipoprotein C3 (ApoC3) is a key regulator of lipid metabolism in circulation, and previous studies primarily focus on its roles in metabolic diseases such as atherosclerosis and metabolic dysfunction-associated steatotic liver disease. However, its impact on HTG-associated AP has not been fully clarified.

AIM

To investigate ApoC3’s role in AP under different lipotoxic conditions and to assess whether targeting ApoC3 alleviates pancreatic injury.

METHODS

ApoC3 knockout (ApoC3^-^/^-) hamsters and mice were generated, and three AP models were established: Caerulein-induced AP, ethanol plus palmitoleic acid [ethanol (EtOH) + palmitoleic acid (POA)]-induced AP, and a high-fat diet (HFD) combined with caerulein (HFD + caerulein)-induced AP. Multiple parameters were evaluated, including plasma lipid levels, pancreatic enzyme activity, histological damage scores, expression of inflammatory markers, and immune cell infiltration.

RESULTS

In the caerulein-induced AP model, loss of ApoC3 did not confer significant protection in mice. However, in hamsters, ApoC3 deficiency significantly reduced plasma triglyceride and nonesterified fatty acid levels, attenuated the elevated levels of pancreatic enzymes and tissue injury, downregulated the mRNA expression of pro-inflammatory and pro-apoptotic genes such as Tnf-α, interleukin-6, interleukin-18, Nlrp3, and Bax, and reduced infiltration of myeloperoxidase-positive neutrophils and cluster of differentiation 68-positive macrophages. Moreover, these beneficial effects were also observed in ApoC3^-^/^- hamsters with AP induced by EtOH + POA or HFD + caerulein, suggesting that ApoC3 plays a pathogenic role under various lipotoxic conditions.

CONCLUSION

ApoC3 promotes HTG-associated AP. Its deficiency protects against AP by improving lipid profiles, reducing inflammation and apoptosis, and alleviating pancreatic injury, supporting therapeutic targeting.

Keywords: Acute pancreatitis; Apolipoprotein C3; Hypertriglyceridemia; Hamster model; Inflammation

Core Tip: Hypertriglyceridemia (HTG) has been shown to cause acute pancreatitis (AP), but the mechanisms remain unclear. This study identified apolipoprotein C3 (ApoC3) as a key player in AP pathogenesis. In three hamster AP models, ApoC3 deficiency significantly reduced pancreatic injury by improving lipid metabolism, suppressing inflammatory cytokine production, and limiting immune cell infiltration. In contrast, ApoC3 deficiency showed no protective effect in mice, underscoring the importance of appropriate model selection. Our findings establish ApoC3 as a critical molecular bridge between dyslipidemia and pancreatic inflammation, highlighting its potential as a novel therapeutic target for HTG-related AP.