Xu Jun-Jie, Yang Fan, Chen Zhi-Xi, Wang Zhi-Peng, Wang Zi-Xuan, Deng Zi-Han, Xu Chen-Jie, Chen Fang-Hui, Zhang Wei, Liu Yang, Cai Ya-Fei
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
Department of Human Anatomy, Bengbu Medical University, Bengbu 233030, China.
Life (Basel). 2025 Aug 24;15(9):1339. doi: 10.3390/life15091339.
Aberrant hepatic lipid metabolism is a key predisposing factor for dairy cow ketosis, with genetic factors playing a pivotal role in disease pathogenesis. However, systematic screening and functional validation of candidate genes for bovine ketosis remain limited. In this study, we aimed to identify genetic markers associated with clinical ketosis and explore their potential functional mechanisms underlying disease susceptibility.
We conducted simplified genome sequencing (SuperGBS), genome-wide association studies (GWAS), and Sanger sequencing on Chinese Holstein cows, both healthy and with ketosis.
We reported that mitogen-activated protein kinase 1 (MAPK1) was significantly associated with clinical ketosis. Further investigation revealed concurrent upregulation of MAPK1 protein and disrupted hepatic lipid homeostasis in hepatocytes from in vivo and in vitro models. Critically, siRNA-mediated knockdown of MAPK1 reversed lipid metabolism processes and reduced lipid accumulation in β-Hydroxybutyric acid (BHB)-exposed bovine hepatocytes, thereby establishing MAPK1 activation as a driver of lipotoxicity in dairy cow ketosis. Additionally, we identified that supplementation of fibroblast growth factor 21 (FGF21) fusion protein not only reduced MAPK1 expression but also normalized hepatic lipid metabolism in BHB-exposed bovine hepatocytes.
FGF21-MAPK1 imbalance is a reason for hepatic lipid metabolic dysfunction, providing a potential intervention approach to mitigate dairy cows' ketosis.
肝脏脂质代谢异常是奶牛酮病的关键易感因素，遗传因素在疾病发病机制中起关键作用。然而，对牛酮病候选基因的系统筛选和功能验证仍然有限。在本研究中，我们旨在鉴定与临床酮病相关的遗传标记，并探索其潜在的疾病易感性功能机制。
我们对健康和患有酮病的中国荷斯坦奶牛进行了简化基因组测序（SuperGBS）、全基因组关联研究（GWAS）和桑格测序。
我们报告丝裂原活化蛋白激酶1（MAPK1）与临床酮病显著相关。进一步研究发现，在体内和体外模型的肝细胞中，MAPK1蛋白同时上调且肝脏脂质稳态受到破坏。至关重要的是，siRNA介导的MAPK1敲低逆转了脂质代谢过程，并减少了暴露于β-羟基丁酸（BHB）的牛肝细胞中的脂质积累，从而确定MAPK1激活是奶牛酮病中脂毒性的驱动因素。此外，我们发现补充成纤维细胞生长因子21（FGF21）融合蛋白不仅降低了MAPK1表达，还使暴露于BHB的牛肝细胞中的肝脏脂质代谢正常化。
FGF21-MAPK1失衡是肝脏脂质代谢功能障碍的一个原因，为减轻奶牛酮病提供了一种潜在的干预方法。
