Curcumin limits the fibrogenic evolution of experimental steatohepatitis.
Nonalcoholic steatohepatitis is characterized by the association of steatosis with hepatic cell injury, lobular inflammation and fibrosis. Curcumin is known for its antioxidant, anti-inflammatory and antifibrotic properties. The aim of this study was to test whether the administration of curcumin limits fibrogenic evolution in a murine model of nonalcoholic steatohepatitis. Male C57BL/6 mice were divided into four groups and fed a diet deficient in methionine and choline (MCD) or the same diet supplemented with methionine and choline for as long as 10 weeks. Curcumin (25 microg per mouse) or its vehicle (DMSO) was administered intraperitoneally every other day. Fibrosis was assessed by Sirius red staining and histomorphometry. Intrahepatic gene expression was measured by quantitative PCR. Hepatic oxidative stress was evaluated by staining for 8-OH deoxyguanosine. Myofibroblastic hepatic stellate cells (HSCs) were isolated from normal human liver tissue. The increase in serum ALT caused by the MCD diet was significantly reduced by curcumin after 4 weeks. Administration of the MCD diet was associated with histological steatosis and necro-inflammation, and this latter was significantly reduced in mice receiving curcumin. Curcumin also inhibited the generation of hepatic oxidative stress. Fibrosis was evident after 8 or 10 weeks of MCD diet and was also significantly reduced by curcumin. Curcumin decreased the intrahepatic gene expression of monocyte chemoattractant protein-1, CD11b, procollagen type I and tissue inhibitor of metalloprotease (TIMP)-1, together with protein levels of alpha-smooth muscle-actin, a marker of fibrogenic cells. In addition, curcumin reduced the generation of reactive oxygen species in cultured HSCs and inhibited the secretion of TIMP-1 both in basal conditions and after the induction of oxidative stress. In conclusion, curcumin administration effectively limits the development and progression of fibrosis in mice with experimental steatohepatitis, and reduces TIMP-1 secretion and oxidative stress in cultured stellate cells.
Vizzutti
Francesco
F
Dipartimento di Medicina Interna, University of Florence, Florence, Italy.
Provenzano
Angela
A
Galastri
Sara
S
Milani
Stefano
S
Delogu
Wanda
W
Novo
Erica
E
Caligiuri
Alessandra
A
Zamara
Elena
E
Arena
Umberto
U
Laffi
Giacomo
G
Parola
Maurizio
M
Pinzani
Massimo
M
Marra
Fabio
F
D000199:Actins / Q000037:antagonists & inhibitors; D000410:Alanine Transaminase / Q000037:antagonists & inhibitors / Q000097:blood; D000818:Animals; D039481:CD11b Antigen / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D002794:Choline / Q000008:administration & dosage; D002796:Choline Deficiency; D024042:Collagen Type I / Q000037:antagonists & inhibitors; D003474:Curcumin / Q000494:pharmacology*; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005234:Fatty Liver / Q000150:complications*; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors
D000199:Actins; D039481:CD11b Antigen; D018932:Chemokine CCL2; D024042:Collagen Type I; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019715:Tissue Inhibitor of Metalloproteinase-1; D008715:Methionine; D000410:Alanine Transaminase; D003474:Curcumin; D002794:Choline