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<p>Type II ketosis in dairy cows is a common metabolic disorder characterized by hepatic lipid metabolism dysregulation. To investigate hepatic tissue heterogeneity and underlying molecular mechanisms in type II ketosis, this study utilized an integrated multi-omics and functional validation strategy. Serum (<i>n</i> = 20), plasma (<i>n</i> = 6), and liver tissue (<i>n</i> = 1 to 3) samples were obtained from Holstein cows in the early postpartum period (3 to 15 days), comparing ketotic and healthy groups. The experimental design combined plasma metabolomics (3 d postpartum, <i>n</i> = 6), cellular metabolomics (<i>n</i> = 6), single-nucleus RNA sequencing (snRNA-seq; 3 d postpartum, <i>n</i> = 1), bulk RNA-seq of hepatocytes (<i>n</i> = 6), and functional assays performed in primary bovine hepatocytes isolated from healthy donor livers (<i>n</i> = 3). This comprehensive framework enabled a systematic exploration of metabolic dysregulation, cellular diversity, and key disease-associated regulatory pathways. The study identified 15 potential biomarkers and extensive dysregulation of metabolic pathways. Liver tissues comprised 14 distinct cell types, with spatially heterogeneous hepatocyte subpopulations localized in periportal, midlobular, and central venous zones. Central venous hepatocytes were pivotal in lipid metabolism, whose reduction amplified interactions between hepatic stellate and endothelial cells, activating lipid-related pathways and driving disease progression. Critically, the ketone body-butyrate-HADHA axis was identified as a central pathogenic pathway. Silencing <i>HADHA</i> alleviated lipid metabolic dysfunction in hepatocytes induced by exogenous NEFA. Notably, <i>HADHA</i> exhibited dual regulatory roles in hepatic lipid metabolism under distinct pathological contexts. This study bridges hepatic cellular dynamics with systemic metabolic dysregulation, laying a theoretical foundation for mitigating lipid metabolism disorders in dairy cattle and informing translational applications in veterinary medicine.</p>

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Identification of novel biomarkers and therapeutic targets for type II ketosis in dairy cows through metabolomics and snRNA-Seq

  • 期刊论文

  • 发表日期：

    2026年1月2日

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  • Xue Feng,
  • Qi Feng,
  • Shuang Liu,
  • Lingkai Zhang,
  • Sayed Haidar Abbas Raza,
  • Bei Cai,
  • Yanfen Ma,
  • Fen Li,
  • Yun Ma

摘要

Type II ketosis in dairy cows is a common metabolic disorder characterized by hepatic lipid metabolism dysregulation. To investigate hepatic tissue heterogeneity and underlying molecular mechanisms in type II ketosis, this study utilized an integrated multi-omics and functional validation strategy. Serum (n = 20), plasma (n = 6), and liver tissue (n = 1 to 3) samples were obtained from Holstein cows in the early postpartum period (3 to 15 days), comparing ketotic and healthy groups. The experimental design combined plasma metabolomics (3 d postpartum, n = 6), cellular metabolomics (n = 6), single-nucleus RNA sequencing (snRNA-seq; 3 d postpartum, n = 1), bulk RNA-seq of hepatocytes (n = 6), and functional assays performed in primary bovine hepatocytes isolated from healthy donor livers (n = 3). This comprehensive framework enabled a systematic exploration of metabolic dysregulation, cellular diversity, and key disease-associated regulatory pathways. The study identified 15 potential biomarkers and extensive dysregulation of metabolic pathways. Liver tissues comprised 14 distinct cell types, with spatially heterogeneous hepatocyte subpopulations localized in periportal, midlobular, and central venous zones. Central venous hepatocytes were pivotal in lipid metabolism, whose reduction amplified interactions between hepatic stellate and endothelial cells, activating lipid-related pathways and driving disease progression. Critically, the ketone body-butyrate-HADHA axis was identified as a central pathogenic pathway. Silencing HADHA alleviated lipid metabolic dysfunction in hepatocytes induced by exogenous NEFA. Notably, HADHA exhibited dual regulatory roles in hepatic lipid metabolism under distinct pathological contexts. This study bridges hepatic cellular dynamics with systemic metabolic dysregulation, laying a theoretical foundation for mitigating lipid metabolism disorders in dairy cattle and informing translational applications in veterinary medicine.