Curcumin limits the fibrogenic evolution of experimental steatohepatitis

Abstract

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 mg 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 a-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.

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

“…The antioxidant action of silibinin in our animal model was further confirmed by its effect on GSH levels. GSH levels are decreased in NASH patients [25,26] and in mice treated with a MCD diet [26]. Restoring mitochondrial GSH to normal levels by the administration of GSH precursors prevents the establishment of inflammation in the MCD diet model [36].…”

“…Liver injury was blindly evaluated according to the NAFLD activity score (NAS). Moreover, in order to investigate even modest deposition of extracellular matrix components Sirius Red staining was performed on formalin-fixed paraffin-embedded liver sections as previously described [25] with a single modification: briefly, after the usual steps to stain liver sections (2 m thick) in 0.1% Sirius Red F3B (Sigma-Aldrich, St. Louis, MO, USA) in a picric acid solution (1.2%) (Sigma-Aldrich), sections were further rapidly exposed to Harry's hematoxylin (2 s) in order to stain nuclei. Immunohistochemistry was performed on formalin-fixed paraffinembedded liver sections.…”

New Insights from Rodent Models of Fatty Liver Disease

“…Still, such a theory remains to be substantiated. To date, studies that have employed pharmacologic agents to inhibit oxidant stress in MCD-fed mice have demonstrated improvements in hepatic inflammation and fibrosis, without clearly distinguishing the effect from an improvement in hepatocellular injury (89,124). Inhibiting oxidant stress by knocking out thioredoxin binding protein-2 (tbp2), however, improves hepatic inflammation and fibrosis and at the same time significantly lowers serum ALT (1).…”

Targeting liver inflammatory myeloid cells with immunomodulatory liposomes improves nonalcoholic steatohepatitis in mice

“…Moreover intraperitoneal administration of 25ug curcumin limited MCD diet induced fibrosis by reducing macrophage and extracellular matrix gene expression (176). These studies indicate the therapeutic potential of curcumin to target NF-κB and its upstream cascades in inflammatory myeloid cells to reduce NASH progression.…”

“…This can be detected in the serum as elevation in ALT, a biomarker for hepatocyte damage. Oxidative stress is important in disease progression as mice lacking nuclear factor E2-related factor-2, a master antioxidant defence regulator, or pharmacological inhibition of oxidative stress reduces MCD-induced hepatic inflammation and fibrosis (176), (245), (246).…”