Nutrition-induced ketosis alters metabolic and signaling gene networks in liver of periparturient dairy cows

Dairy cows are highly susceptible after parturition to developing liver lipidosis and ketosis, which are costly diseases to farmers. A bovine microarray platform consisting of 13,257-annotated oligonucleotides was used to study hepatic gene networks underlying nutrition-induced ketosis. On day 5 postpartum, 14 Holstein cows were randomly assigned to ketosis-induction (n = 7) or control (n = 7) groups. Cows in the ketosis-induction group were fed at 50% of day 4 intake until they developed signs of clinical ketosis, and cows in the control group were fed ad libitum throughout the treatment period. Liver was biopsied at 10-14 (ketosis) or 14 days postpartum (controls). Feed restriction increased blood concentrations of nonesterified fatty acids and β-hydroxybutyrate, but decreased glucose. Liver triacylglycerol concentration also increased. A total of 2,415 genes were altered by ketosis (false discovery rate = 0.05). Ingenuity Pathway Analysis revealed downregulation of genes associated with oxidative phosphorylation, protein ubiquitination, and ubiquinone biosynthesis with ketosis. Other molecular adaptations included upregulation of genes and nuclear receptors associated with cytokine signaling, fatty acid uptake/transport, and fatty acid oxidation. Genes downregulated during ketosis included several associated with cholesterol metabolism, growth hormone signaling, proton transport, and fatty acid desaturation. Feed restriction and ketosis resulted in previously unrecognized alterations in gene network expression underlying key cellular functions and discrete metabolic events. These responses might help explain well-documented physiological adaptations to reduced feed intake in early postpartum cows and, thus, provide molecular targets that might be useful in prevention and treatment of liver lipidosis and ketosis.