title: n-3 polyunsaturated fatty acids worsen inflammation and fibrosis in experimental nonalcoholic steatohepatitis.
abstract: OBJECTIVE
  n-3 polyunsaturated fatty acids (PUFA) ameliorate fatty liver in experimental models, but their effects on inflammation and fibrosis during steatohepatitis are either controversial or lacking. We compared the effects of supplementation with olive oil (OO) alone or OO and n-3 PUFA on the development and progression of experimental steatohepatitis.
  
  
  METHODS
  Balb/C mice (≥5 mice/group) were fed a methionine- and choline-deficient (MCD) diet or a control diet for 4 or 8 weeks. At the same time, mice were supplemented with n-3 PUFA (eicosapentaenoic and docosahexahenoic acid, 25 mg together with 75 mg OO), or OO alone (100 mg), two times a week by intragastric gavage.
  
  
  RESULTS
  After 8 weeks, mice on MCD/n-3 had higher ALT levels compared to MCD/OO and more severe scores of inflammation, including a significant increase in the number of lipogranulomas (26.4 ± 8.4 vs. 5.1 ± 5 per field, P < 0.001). Intrahepatic expression of TNF-α and CCL2 was higher in MCD/n-3 mice at both time points. In addition, increased expression of the profibrogenic genes TIMP-1 and TGF-β, and more severe histological scores of fibrosis were evident in MCD/n-3 mice. After 8 week of MCD diet, portal pressure was higher in mice receiving n-3 than in those on OO alone (5.1 ± 1.4 vs. 7.0 ± 0.9 mmHg, P < 0.05). Analysis of hepatic fatty acid profile showed that supplementation resulted in effective incorporation of n-3 PUFA.
  
  
  CONCLUSIONS
  In a murine model of steatohepatitis, supplementation with n-3 PUFA and OO is associated with more severe necro-inflammation and fibrosis than in mice treated with OO only.
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Provenzano
authors.forename: Stefano
authors.initials: S
authors.lastname: Milani
authors.forename: Francesco
authors.initials: F
authors.lastname: Vizzutti
authors.forename: Wanda
authors.initials: W
authors.lastname: Delogu
authors.forename: Nadia
authors.initials: N
authors.lastname: Navari
authors.forename: Erica
authors.initials: E
authors.lastname: Novo
authors.forename: Marina
authors.initials: M
authors.lastname: Maggiora
authors.forename: Valter
authors.initials: V
authors.lastname: Maurino
authors.forename: Giacomo
authors.initials: G
authors.lastname: Laffi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.forename: Fabio
authors.initials: F
authors.lastname: Marra
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002796:Choline Deficiency / Q000150:complications; D019587:Dietary Supplements / Q000633:toxicity*; D004195:Disease Models, Animal; D043371:Fatty Acids, Omega-6 / Q000633:toxicity*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D008807:Mice, Inbred BALB C; D009336:Necrosis; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000069463:Olive Oil; D010938:Plant Oils; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; D043371:Fatty Acids, Omega-6; D018836:Inflammation Mediators; D000069463:Olive Oil; D010938:Plant Oils; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D008715:Methionine