Quercetin treatment ameliorates inflammation and fibrosis in mice with nonalcoholic steatohepatitis.
We investigated whether quercetin protects from steatosis and limits the expression of proinflammatory and fibrogenic genes in C57BL/6J mice with nonalcoholic steatohepatitis (NASH) induced by feeding a methionine-choline-deficient (MCD) diet. Quercetin (50 mg/kg) was given by oral route daily. Mice were randomly divided into 4 groups that received for 2 or 4 wk: the control diet plus vehicle, control diet plus quercetin, MCD diet plus vehicle, and MCD diet plus quercetin. At both 2 and 4 wk, feeding the MCD diet resulted in liver steatosis, inflammatory cell accumulation, oxidative stress evaluated by the concentration of TBARS, and fibrosis evidenced by the staining of α-smooth muscle actin-positive cells in the liver. At both 2 and 4 wk, the MCD diet induced an increase in the mRNA levels of Il6, Tnf, Ptgs2, and Hmgb1 and increased the protein concentrations of Toll-like receptor-4, c-Jun terminal kinase, and p65 NFκB subunit compared with control rats. Feeding the mice the MCD diet also triggered an increase of Col1a1, Col3a1, Plod3, Tgfb1, Smad3, Smad7, Pdgfb, Ctgf, Areg, Mmp9, and Timp1 mRNA levels. These effects were totally or partially prevented by treatment with quercetin. The data obtained suggest that attenuation of multiple profibrotic and proinflammatory gene pathways contributes to the beneficial effects of quercetin in mice with MCD diet-induced steatohepatitis.
Laboratory of Experimental Hepatology and Physiology, Porto Alegre Clinical Hospital, Federal University of Rio Grande do Sul, and Universidade Luterana do Brasil Porto Alegre, Brazil.
Eder
E
Marcolin
Beatriz
B
San-Miguel
Daniela
D
Vallejo
Juliana
J
Tieppo
Norma
N
Marroni
Javier
J
González-Gallego
María J
MJ
Tuñón
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002794:Choline / Q000008:administration & dosage; D002796:Choline Deficiency / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy* / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D015415:Biomarkers; D024042:Collagen Type I; D024061:Collagen Type III; D024243:HMGB1 Protein; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D051785:Smad Proteins; D017392:Thiobarbituric Acid Reactive Substances; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011794:Quercetin; D008715:Methionine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; D002794:Choline