title: Citrulline and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver Disease in Rats.
abstract: BACKGROUND
  Fructose induces nonalcoholic fatty liver disease (NAFLD). Citrulline (Cit) may exert a beneficial effect on steatosis.
  
  
  OBJECTIVE
  We compared the effects of Cit and an isonitrogenous mixture of nonessential amino acids (NEAAs) on fructose-induced NAFLD.
  
  
  METHODS
  Twenty-two male Sprague Dawley rats were randomly assigned into 4 groups (n = 4-6) to receive for 8 wk a 60% fructose diet, either alone or supplemented with Cit (1 g · kg(-1) · d(-1)), or an isonitrogenous amount of NEAAs, or the same NEAA-supplemented diet with starch and maltodextrin instead of fructose (controls). Nutritional and metabolic status, liver function, and expression of genes of hepatic lipid metabolism were determined.
  
  
  RESULTS
  Compared with controls, fructose led to NAFLD with significantly higher visceral fat mass (128%), lower lean body mass (-7%), insulin resistance (135%), increased plasma triglycerides (TGs; 67%), and altered plasma amino acid concentrations with decreased Arg bioavailability (-27%). This was corrected by both NEAA and Cit supplementation. Fructose caused a 2-fold increase in the gene expression of fatty acid synthase (Fas) and 70% and 90% decreases in that of carnitine palmitoyl-transferase 1a and microsomal TG transfer protein via a nearly 10-fold higher gene expression of sterol regulatory element-binding protein-1c (Srebp1c) and carbohydrate-responsive element-binding protein (Chrebp), and a 90% lower gene expression of peroxisome proliferator-activated receptor α (Ppara). NEAA or Cit supplementation led to a Ppara gene expression similar to controls and decreased those of Srebp1c and Chrebp in the liver by 50-60%. Only Cit led to Fas gene expression and Arg bioavailability similar to controls.
  
  
  CONCLUSIONS
  In our rat model, Cit and NEAAs effectively prevented fructose-induced NAFLD. On the basis of literature data and our findings, we propose that NEAAs may exert their effects specifically on the liver, whereas Cit presumably acts at both the hepatic and whole-body level, in part via improved peripheral Arg metabolism.
authors.affiliation: Nutrition Biology Laboratory, Faculty of Pharmacy, Paris Descartes University, Paris, France;
authors.forename: Prasanthi
authors.initials: P
authors.lastname: Jegatheesan
authors.affiliation: Nutrition Biology Laboratory, Faculty of Pharmacy, Paris Descartes University, Paris, France;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Beutheu
authors.affiliation: Nutrition Biology Laboratory, Faculty of Pharmacy, Paris Descartes University, Paris, France;
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Ventura
authors.affiliation: Nutrition Biology Laboratory, Faculty of Pharmacy, Paris Descartes University, Paris, France;
authors.forename: Esther
authors.initials: E
authors.lastname: Nubret
authors.affiliation: Clinical Chemistry Department, Paris Center University Hospitals, Public Assistance Hospitals of Paris, Paris, France; and.
authors.forename: Gilles
authors.initials: G
authors.lastname: Sarfati
authors.affiliation: Institut of Nutrition, SD Model Systems of Molecular Nutrition, Friedrich-Schiller University Jena, Jena, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Bergheim
authors.affiliation: Nutrition Biology Laboratory, Faculty of Pharmacy, Paris Descartes University, Paris, France; Clinical Chemistry Department, Paris Center University Hospitals, Public Assistance Hospitals of Paris, Paris, France; and jean-pascal.de-bandt@parisdescartes.fr.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: De Bandt
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000097:blood / Q000627:therapeutic use*; D000818:Animals; D001120:Arginine / Q000097:blood; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002956:Citrulline / Q000627:therapeutic use*; D019587:Dietary Supplements; D054890:Fatty Acid Synthase, Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005632:Fructose / Q000009:adverse effects / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009952:Ornithine / Q000097:blood; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers; C442825:Mlxipl protein, rat; D047493:PPAR alpha; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D002956:Citrulline; D005632:Fructose; D001120:Arginine; D009952:Ornithine; D054890:Fatty Acid Synthase, Type I
keywords: citrulline; fructose; nonalcoholic fatty liver disease; nonessential amino acids; steatosis