Body fat mobilization during a negative energy balance (NEB) requires metabolic adaptations on the part of the liver. We investigated if responses of hepatic mRNA abundancies of genes involved in metabolism and immune system to an energy deficiency differ between lactational stages. Holstein dairy cows (n = 14) (control (CON) and restricted (RES) group) were fed with grass and additional concentrate from wk 3 ap until wk 12 pp, except the RES group receiving only grass during 1-wk feed-restrictions in wk 2, 5, 8, and 11 pp. At the end of the first restriction period, LPS from E. coli was infused intravenously (0.5 µg/kg BW) to induce an inflammatory status. Energy balance (EB) was calculated on a weekly basis. Blood was obtained weekly and liver tissue was collected for biopsy before and after restriction periods and at 8h after the systemic LPS challenge. Blood samples were analyzed for glucose, NEFA, and BHBA concentrations. Hepatic gene expression of 3-hydroxybutyrate dehydrogenase (BDH) 2, carnitine palmitoyltransferase (CPT) 1A and 2, mitochondrial glycerol-3-phosphate-acyltransferase (GPAM), 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS) 2, cytosolic phosphoenolpyruvate carboxykinase (PEPCKc), growth hormone receptor (GHR) 1A, insulin-like growth factor (IGF) 1, Hp (haptoglobin), serum amyloid A (SAA), and tumor necrosis factor (TNF) α were measured. Data were analyzed using a mixed model including group and wk as fixed effects. During restriction periods, RES had a more distinct negative EB (wk 2: Δ17 MJ NEL/d; wk 5: Δ19 MJ; wk 8: 6 MJ; wk 11 Δ13 MJ) and in wk 5 higher NEFA (0.64 mmol/L) and BHBA (0.65 mmol/L) concentrations compared with CON (0.39 and 0.37 mmol/L, resp.; P < 0.05). Hepatic mRNA abundances showed expression patterns depending on the lactational stage. During feed-restriction periods, expression of IGF-1 was upregulated in RES compared with CON (based on ratios between RES and CON: +11.1 in wk 2, +14.7 in wk 5, +2.9 in wk 8, +7.3 in wk 11; P < 0.05). At 8h after the initiation of the systemic LPS challenge, SAA, TNFα and Hp were downregulated in RES and CON, while GPAM, HMGCS2, GHR1A, CPT1A and 2, PEPCKc, and BDH2 were upregulated (P < 0.05). In conclusion the experiment showed that hepatic metabolism was clearly affected by feed-restrictions and systemic LPS-challenge.