Franny Jongbloed

119 5 ABSENCE OF PROTEIN AND AMINO ACIDS PROTECT AGAINST HEPATIC IRI INTRODUCTION Dietary restriction (DR) is defined as a reduction in food intake without malnutrition 1 . Long-term DR is known to extend lifespan 1 , increase health span 2 and improve resistance to multiple stressors 1,3 in a wide variety of organisms 4-6 . Although the effect of DR on lifespan in humans is not known, studies show a favorable impact on metabolic parameters associated with long-term health 7-9 . In addition, previous studies showed that two weeks of 30% DR and three days of fasting increase stress resistance and protect against oxidative stress induced by ischemia-reperfusion injury (IRI) in mice 1,10 . During major liver surgery and liver transplantation IRI is inevitable and a risk factor for complications including primary graft dysfunction and primary non-function, thereby causing morbidity and mortality 11-13 . Cessation of the blood flow (ischemia) leads to hypoxia, nutrient deprivation and activation of anaerobic metabolic system 13 . Reperfusion of the liver promotes the activation of an inflammatory response, causing further cellular damage and the generation of reactive oxygen species (ROS) 13 . Therefore, counteracting the adverse effects of IRI could improve the outcome after liver transplantation and liver resection. Unfortunately, at this moment no effective treatment for IRI is available. Whether the protection by short-term DR is based on a reduction of calories or based on the reduction of specific nutrients is not yet completely unraveled. Also, the search for the underlying mechanisms of DR is still ongoing. In mice, liquid glucose supplementation did not interfere with the protective effect of three days of fasting against renal IRI 14 . In fruit flies, long-term protein restriction contributed more to extension of the life span compared to the reduction of carbohydrates or fat 15, 16 . We previously investigated the role of specific macronutrients by unrestricted feeding of protein-, carbohydrate-, and fat-free diets in inducing resistance against renal IRI. We showed that three days of a protein- but not a carbohydrate- or a fat-free diet, before the induction of renal IRI improved survival and kidney function similarly as DR and fasting 17 . These results point towards a role for specific nutrients in the protective effect against renal IRI. In the present study, we investigated the role of preoperative essential amino acid (EAA)-free diets by unrestricted feeding of methionine (Met)-free, leucine (Leu)-free and tryptophan (Trp)-free diets in reducing oxidative damage in the liver, and analyzed the transcriptomic response of the liver to these diets.