BACKGROUND/AIMS: Bacterial infection combined with hypotension results in exacerbation of the inflammatory response with release of interferon (IFN) gamma. This excessive inflammation may lead to development of hepatic damage and liver failure. This study investigates the effect of dietary lipids on release of IFN-gamma and development of hepatic damage following exposure to synthetic bacterial DNA (CpG-ODN) and hemorrhagic shock. METHODS: Rats were exposed to CpG-ODN 18h before hemorrhagic shock. Samples were taken 4h following shock. High-fat nutrition was administered at 18h, 2h and 45min before induction of shock. RESULTS: Enteral high-fat strongly reduced circulating IFN-gamma (0.2ng/ml, P<0.01) following exposure to CpG-ODN and hemorrhagic shock compared with fasted rats (2.7ng/ml). Concomitantly, plasma L-FABP was reduced (437+/-22ng/ml, P<0.01), and F-actin distribution was preserved. Furthermore, high-fat nutrition reduced apoptosis in the liver and preserved expression of the hepatoprotective protein ABIN-1. Interestingly, administration of anti-IFN-gamma antibodies was associated with reduced expression of ABIN-1. CONCLUSIONS: This study shows that enteral high-fat reduces IFN-gamma and decreases CpG-enhanced liver injury following hemorrhagic shock. Administration of high-fat nutrition may be an important new therapeutic strategy to reduce liver damage in a clinical setting of bacterial infection combined with hypotension.