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Research Article | Open Access

Free fatty acids induce apoptosis in mammary epithelial cells from ketotic dairy cows via endoplasmic reticulum stress

Renxu Chang1,2, Yuanyuan Chen2, Xinyi Xu3, Hongdou Jia2, John Mauck4, Juan J. Loor4, Yehoshav A. Ben Meir5, Qiushi Xu2, Xudong Sun2( ), Chuang Xu1( )
College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801, USA
Department of Ruminant Science, Institute of Animal Sciences, Agricultural Research Organization, Volcani Institute, Rishon LeTsiyon 750101, Israel
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Highlights

• Key Findings on Ketosis-Induced ER Stress: High concentrations of free fatty acid (FFA) in ketotic dairy cows activate endoplasmic reticulum (ER) stress pathways, contributing to mammary epithelial cell apoptosis and reduced milk yield.

• Clinical Relevance for Dairy Health: Findings highlight ER stress as a therapeutic target for mitigating metabolic stress-induced apoptosis in the mammary gland, offering potential strategies to improve dairy cows productivity.

• Future Implications: The study sets the stage for in vivo trials to validate ER stress inhibitors like Tauroursodeoxycholate (TUDCA) as practical solutions for managing ketosis and enhancing dairy cows health.

Abstract

The mammary glands of dairy cows with ketosis face unique challenges, including the supraphysiological circulating concentrations of free fatty acids (FFA) and apoptosis of epithelial cells. The fact that endoplasmic reticulum (ER) stress and apoptosis are closely related processes (at least in nonruminants) suggests that mechanisms of metabolic stress-induced apoptosis in bovine mammary epithelial cells may involve the ER stress pathway. The objective of this study was to investigate (1) the status of the ER stress pathway in mammary gland of dairy cows with ketosis, and (2) the role of ER stress in the apoptosis of bovine mammary epithelial cells challenged with high concentrations of FFA. Ketosis or exogenous FFA activated the ER stress pathway in the mammary gland of dairy cows or MAC-T cells. Pretreatment with the ER stress activator Tunicamycin (Tun) aggravated ER stress and apoptosis in MAC-T cells induced by FFA. However, ER stress inhibitor Tauroursodeoxycholate (TUDCA) attenuated ER stress induced by FFA and also attenuated the apoptosis in MAC-T cells. In conclusion, the data confirmed that FFA induced apoptosis of bovine mammary epithelial cells in dairy cows with ketosis via ER stress signaling. Thus, timely resolution of ER stress may help counteract the negative effects of ketosis on the mammary gland.

Keywords

ketosisbovine mammary epithelial cellsER stressapoptosis

References

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Journal of Integrative Agriculture (JIA)
Volume 25 Issue 5,
May 2026
Pages 2014-2027
DOI: 10.1016/j.jia.2024.12.023

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Cite this article:
Chang R, Chen Y, Xu X, et al. Free fatty acids induce apoptosis in mammary epithelial cells from ketotic dairy cows via endoplasmic reticulum stress. Journal of Integrative Agriculture (JIA), 2026, 25(5): 2014-2027. https://doi.org/10.1016/j.jia.2024.12.023

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Received: 20 February 2024
Revised: 21 August 2024
Accepted: 04 December 2024
Published: 24 December 2024
© 2026 CAAS.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Peer review under responsibility of Editorial Board of Journal of Integrative Agriculture.