FGF21-MAPK1 Imbalance Disrupts Hepatic Lipid Metabolism in Dairy Cow Ketosis

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.