title: Preventive effects of citrulline on Western diet-induced non-alcoholic fatty liver disease in rats.
abstract: A Western diet induces insulin resistance, liver steatosis (non-alcoholic fatty liver disease (NAFLD)) and intestinal dysbiosis, leading to increased gut permeability and bacterial translocation, thus contributing to the progression of NAFLD to non-alcoholic steatohepatitis. In the present study, we sought, in a model of Western diet-induced NAFLD, to determine whether citrulline (Cit), an amino acid that regulates protein and energy metabolism, could decrease Western diet-induced liver injuries, as well as the mechanisms involved. Sprague-Dawley rats were fed a high-fat diet (45 %) and fructose (30 %) in drinking water or a control diet associated with water (group C) for 8 weeks. The high-fat, high-fructose diet (Western diet) was fed either alone (group WD) or with Cit (1 g/kg per d) (group WDC) or an isonitrogenous amount of non-essential amino acids (group WDA). We evaluated nutritional and metabolic status, liver function, intestinal barrier function, gut microbiota and splanchnic inflammatory status. Cit led to a lower level of hepatic TAG restricted to microvesicular lipid droplets and to a lower mRNA expression of CCAAT-enhancer-binding protein homologous protein, a marker of endoplasmic reticulum stress, of pro-inflammatory cytokines Il6 (P<0·05) and Tnfα, and of toll-like receptor 4 (Tlr4) (P<0·05). Cit also improved plasma TAG and insulin levels. In the colon, it decreased inflammation (Tnfα and Tlr4 expressions) and increased claudin-1 protein expression. This was associated with higher levels of Bacteroides/Prevotella compared with rats fed the Western diet alone. Cit improves Western diet-induced liver injuries via decreased lipid deposition, increased insulin sensitivity, lower inflammatory process and preserved antioxidant status. This may be related in part to its protective effects at the gut level.
authors.affiliation: 1EA4466, Faculty of Pharmacy,Paris Descartes University,Sorbonne Paris Cité,75006 Paris,France.
authors.forename: Prasanthi
authors.initials: P
authors.lastname: Jegatheesan
authors.affiliation: 1EA4466, Faculty of Pharmacy,Paris Descartes University,Sorbonne Paris Cité,75006 Paris,France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Beutheu
authors.affiliation: 1EA4466, Faculty of Pharmacy,Paris Descartes University,Sorbonne Paris Cité,75006 Paris,France.
authors.forename: Kim
authors.initials: K
authors.lastname: Freese
authors.affiliation: 2EA4065, Faculty of Pharmacy,Paris Descartes University,Sorbonne Paris Cité,75006 Paris,France.
authors.forename: Anne-Judith
authors.initials: AJ
authors.lastname: Waligora-Dupriet
authors.affiliation: 1EA4466, Faculty of Pharmacy,Paris Descartes University,Sorbonne Paris Cité,75006 Paris,France.
authors.forename: Esther
authors.initials: E
authors.lastname: Nubret
authors.affiliation: 2EA4065, Faculty of Pharmacy,Paris Descartes University,Sorbonne Paris Cité,75006 Paris,France.
authors.forename: Marie-Jo
authors.initials: MJ
authors.lastname: Butel
authors.affiliation: 3Institute of Nutritional Science,SD Model Systems of Molecular Nutrition,Friedrich-Schiller University Jena,07743 Jena,Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Bergheim
authors.affiliation: 1EA4466, Faculty of Pharmacy,Paris Descartes University,Sorbonne Paris Cité,75006 Paris,France.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: De Bandt
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001439:Bacteroides / Q000187:drug effects / Q000254:growth & development; D002956:Citrulline / Q000494:pharmacology* / Q000627:therapeutic use; D062445:Claudin-1 / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D066273:Diet, Western / Q000009:adverse effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D066292:Lipid Droplets; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000209:etiology; D018720:Prevotella / Q000187:drug effects / Q000254:growth & development; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D062445:Claudin-1; D007328:Insulin; D015850:Interleukin-6; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D002956:Citrulline
keywords: AA amino acid; Arg arginine; ChREBP carbohydrate-responsive element-binding protein; Cit citrulline; Gln glutamine; Gut permeability; IR insulin resistance; Liver; MPO myeloperoxidase; Microbiota; NAFLD non-alcoholic fatty liver disease; NASH non-alcoholic steatohepatitis; NEAA non-essential amino acids; Non-alcoholic steatohepatitis; Non-essential amino acids; TLR4 toll-like receptor 4; WD Western diet; WDA Western diet+non-essential amino acids; WDC Western diet+citrulline