Simple Summary Energy and nutrient demands of the early lactation period can result in the development of metabolic disorders, such as ketosis and fatty liver, in dairy cows. Variability in the incidence of these disorders suggests that some cows have an ability to adapt. The objective of this study was to discover differences in liver gene expression that are associated with a cow's susceptibility (disposition to disorder during typical conditions) or resistance (disposition to disorder onset and severity when presented a challenge) to metabolic disorders. Cows in a control treatment and a ketosis induction protocol treatment were retrospectively grouped into susceptibility and resistance groups, respectively, by a machine learning algorithm using lipid biomarker concentrations. Whole-transcriptome RNA sequencing was performed on liver samples from these cows. More susceptible cows had lower expression of glutathione metabolism genes, while less resistant cows had greater expression of eicosanoid-metabolism-related genes. Additionally, differentially expressed genes suggested a role for immune-response-related genes in conferring susceptibility and resistance to metabolic disorders. The overall inferred metabolism suggests that responses to oxidative stress may determine susceptibility and resistance to metabolic disorders, with novel implications for immunometabolism. Lipid-related metabolic disorders (LRMD) are prevalent in early lactation dairy cows, and have detrimental effects on productivity and health. Our objectives were to identify cows resistant or susceptible to LRMD using a ketosis induction protocol (KIP) to discover differentially expressed liver genes and metabolic pathways associated with disposition. Clustering cows based on postpartum lipid metabolite concentrations within dietary treatments identified cows more or less susceptible (MS vs. LS) to LRMD within the control treatment, and more or less resistant (MR vs. LR) within the KIP treatment. Whole-transcriptome RNA sequencing was performed on liver samples (-28, +1, and +14 days relative to calving) to assess differential gene and pathway expression (LS vs. MS; MR vs. LR; n = 3 cows per cluster). Cows within the MS and LR clusters had evidence of greater blood serum beta-hydroxybutyrate concentration and liver triglyceride content than the LS and MR clusters, respectively. The inferred metabolism of differentially expressed genes suggested a role of immune response (i.e., interferon-inducible proteins and major histocompatibility complex molecules). Additionally, unique roles for glutathione metabolism and eicosanoid metabolism in modulating susceptibility and resistance, respectively, were implicated. Overall, this research provides novel insight into the role of immunometabolism in LRMD pathology, and suggests the potential for unique control points for LRMD progression and severity.
