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Journal of Integrative Agriculture  2026, Vol. 25 Issue (5): 2014-2027    DOI: 10.1016/j.jia.2024.12.023
Animal Science · Veterinary Medicine Advanced Online Publication | Current Issue | Archive | Adv Search |
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#

1 College of Veterinary Medicine, China Agricultural University, Beijing 100193, China

2 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

3 College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA

4 Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801, USA

5 Department of Ruminant Science, Institute of Animal Sciences, Agricultural Research Organization, Volcani Institute, Rishon LeTsiyon 750101, Israel

 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.
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摘要  

酮病奶牛的乳腺组织面临血液中游离脂肪酸(FFA浓度显著升高和乳腺上皮细胞凋亡的严峻挑战。非反刍动物研究已经证实,内质网(ER)应激与细胞凋亡之间密切相关,表明代谢应激可能通过ER应激通路诱导奶牛乳腺上皮细胞的凋亡。因此,本研究的目的是探讨:(1) 酮病奶牛乳腺中ER应激通路的状态;(2) ER应激在高浓度FFA诱导奶牛乳腺上皮细胞凋亡中的作用。研究发现,酮病或外源性FFA能够激活奶牛乳腺组织或MAC-T细胞中的ER应激通路。通过ER应激激活剂TunicamycinTun)预处理,进一步加重了FFA诱导的MAC-T细胞中的ER应激和凋亡。相反,ER应激抑制剂TauroursodeoxycholateTUDCA预处理缓解了FFA诱导的ER应激以及MAC-T细胞凋亡。综上所述,研究证实FFA通过ER应激信号通路诱导酮病奶牛乳腺上皮细胞凋亡。因此,缓解ER应激可能有助于减轻酮病引起的奶牛乳腺组织损伤



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:  ketosis       bovine mammary epithelial cells        ER stress        apoptosis  
Received: 20 February 2024   Accepted: 04 December 2024 Online: 24 December 2024  
Fund: 

This work was supported by the National Key R&D Program of China (2023YFD1802100), the National Natural Science Foundation of China (32072931) and the Earmarked Fund for CARS36. 

About author:  Renxu Chang, E-mail: changrenxv@163.com; #Correspondence Xudong Sun, E-mail: sunxudong0323@163.com; Chuang Xu, E-mail: xuchuang@cau.edu.cn; xuchuang7175@163.com

Cite this article: 

Renxu Chang, Yuanyuan Chen, Xinyi Xu, Hongdou Jia, John Mauck, Juan J. Loor, Yehoshav A. Ben Meir, Qiushi Xu, Xudong Sun, Chuang Xu. 2026. Free fatty acids induce apoptosis in mammary epithelial cells from ketotic dairy cows via endoplasmic reticulum stress. Journal of Integrative Agriculture, 25(5): 2014-2027.

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