Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.
OBJECTIVE
Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease.


METHODS
Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota.


RESULTS
In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation.


CONCLUSIONS
While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis.
Nutrition Biology Laboratory, EA4466, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France. Electronic address: pira_jegatheesan@hotmail.com.
Prasanthi
P
Jegatheesan
Nutrition Biology Laboratory, EA4466, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France. Electronic address: dianesbeutheu@yahoo.fr.
Stéphanie
S
Beutheu
Nutrition Biology Laboratory, EA4466, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France. Electronic address: gabrielle.ventura@nutrition-paris5.org.
Gabrielle
G
Ventura
Clinical Chemistry Department, Hôpitaux Universitaires Paris Centre, APHP, Paris, France. Electronic address: gilles.sarfati@cch.aphp.fr.
Gilles
G
Sarfati
Nutrition Biology Laboratory, EA4466, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France. Electronic address: esther.nubret@parisdescartes.fr.
Esther
E
Nubret
Microbiology, EA4065, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France. Electronic address: nathalie.kapel@psl.aphp.fr.
Nathalie
N
Kapel
Microbiology, EA4065, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France. Electronic address: anne-judith.waligora@parisdescartes.fr.
Anne-Judith
AJ
Waligora-Dupriet
Institut of Nutrition, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany. Electronic address: ina.bergheim@uni-jena.de.
Ina
I
Bergheim
Nutrition Biology Laboratory, EA4466, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France; Clinical Chemistry Department, Hôpitaux Universitaires Paris Centre, APHP, Paris, France. Electronic address: luc.cynober@univ-paris5.fr.
Luc
L
Cynober
Nutrition Biology Laboratory, EA4466, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France; Clinical Chemistry Department, Hôpitaux Universitaires Paris Centre, APHP, Paris, France. Electronic address: jean-pascal.de-bandt@parisdescartes.fr.
Jean-Pascal
JP
De-Bandt
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002956:Citrulline / Q000494:pharmacology*; D019587:Dietary Supplements; D005632:Fructose / Q000009:adverse effects*; D005973:Glutamine / Q000494:pharmacology*; D015228:Hypertriglyceridemia / Q000517:prevention & control; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007408:Intestinal Absorption / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D005973:Glutamine; D002956:Citrulline; D005632:Fructose; D001120:Arginine; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin
Arginine; Citrulline; Glutamine; Non-alcoholic fatty liver disease