Franny Jongbloed

118 CHAPTER 5 ABSTRACT Ischemia-reperfusion injury (IRI) is inevitable during major liver surgery and liver transplantation leading to oxidative stress. Preoperative short-term 30% dietary restriction (DR), 3-days of fasting and 3-days of a protein-free diet protect against IRI. Here, we further disentangled the role of essential amino acids on the effects of DR on liver IRI. Male C57BL/6 mice were randomized to preoperative ad libitum control food or 3 days of 30% DR, methionine-free, leucine-free or tryptophan-free diet for three days. Liver IRI was induced by partial occlusion of the blood flow (70%) of the liver for 75 minutes. Food intake and body weight were monitored until postoperative day 1. Hepatic damage was measured biochemically and histologically at six and 24 hours after IRI. After completing each diet, liver gene expression profiles we determined by microarray analysis. All amino acid free diets resulted in body weight loss prior to IRI. Liver IRI was already significantly decreased by both the leucine- and tryptophan-free diets at six hours after IRI, and by the methionine-free diet at 24 hours. Microarray analysis showed similar transcriptomic responses in all amino acid-free diets, yet with a lower magnitude in the methionine-free diet. Detailed analysis of overlapping genes suggested a role for pathways involved in nuclear receptor signaling, stress resistance and cell cycle regulation via transcription factors NRF2, FOXM1, SREBF2 and SMARCB1. A short-term preoperative tryptophan-free, leucine-free and methionine-free diet protect against hepatic IRI similar to a protein-free diet, through a network of pathways potentially activated by NRF2, FOXM1, SREBF2 and SMARCB1.