Arginine, glutamine, citrulline and the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD) – NAFLD-citrulline

Poor nutritional habits, unbalanced energy intake and a sedentary way of life are at the onset of the present obesity epidemic. In parallel, prevalence of non-alcoholic fatty liver disease (NAFLD), a manifestation of the metabolic syndrome and a major cause of chronic liver disease, has increased with that of obesity, and the excessive dietary consumption of fructose could be involved in the development of NAFLD. Indeed, fructose is increasingly used to sweeten various kinds of foods (e.g. soft drinks, sweets, yoghurts) and has been suspected to affect the gut-liver axis through changes in gut function and liver metabolism contributing to the aetiology of NAFLD. Several aspects of the pathophysiology of the disease remain unanswered and a better understanding would give new leads for the treatment of NAFLD.
Interestingly, the development of insulin resistance and obesity is associated with alterations in amino acid metabolism and notably in arginine bioavailability. Arginine has been shown to be effective insulin sensitizing amino acid and an effector of gut trophicity. The interorgan exchanges of two other related amino acids, namely glutamine and citrulline, may also be affected. This could be of importance in this context since glutamine plays a central role in the physiology of absorbing epithelial cells (as their main oxidative energy substrate and as a precursor for the synthesis of glutathione required for antioxidative defences), and since citrulline, a product of arginine and glutamine intestinal metabolism and an arginine precursor, favours protein anabolism and improves energy metabolism. Of note, the intestinal metabolisms of these three amino acids are closely related, the intestine being the main endogenous source of citrulline for de novo renal arginine synthesis. Fructose-induced alterations in the metabolism of these amino acids, taking into account their effect on insulin sensitivity and intestinal trophicity, could make a significant contribution to the development of NAFLD. The aim of this project is to evaluate the effect of fructose-induced NAFLD on intestinal and hepatic arginine, glutamine and citrulline metabolism and to determine the role of alterations in arginine, glutamine and citrulline availability in the development of fructose-induced disorders at both the intestinal and hepatic levels.
This translational research project will involve the collaboration between one german team (Dept. of Nutritional Medicine) from Hohenheim University (Stuttgart), and three French team at Paris Descartes University (EA 4466 and EA 4065) and Evry-Val d'Essonne University (Inserm UMR829), respectively.