Dipartimento di Medicina Interna, University of Florence, Florence, Italy.
Lab Invest. 2010 Jan;90(1):104-15. doi: 10.1038/labinvest.2009.112. Epub 2009 Nov 9.
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.
非酒精性脂肪性肝炎的特征是脂肪变性与肝细胞损伤、肝小叶炎症和纤维化有关。姜黄素具有抗氧化、抗炎和抗纤维化的特性。本研究旨在测试姜黄素是否能限制非酒精性脂肪性肝炎小鼠模型中的纤维发生。雄性 C57BL/6 小鼠分为四组，分别喂食缺乏蛋氨酸和胆碱的饮食（MCD）或相同的饮食补充蛋氨酸和胆碱长达 10 周。姜黄素（每只小鼠 25 微克）或其载体（DMSO）每隔一天通过腹腔内给药。通过天狼星红染色和组织形态计量学评估纤维化。通过定量 PCR 测量肝内基因表达。通过 8-OH 脱氧鸟苷染色评估肝氧化应激。从正常人类肝组织中分离肝星状细胞（HSCs）。MCD 饮食引起的血清 ALT 增加在 4 周后明显被姜黄素降低。给予 MCD 饮食与组织学脂肪变性和坏死性炎症相关，而在接受姜黄素的小鼠中，这种炎症明显减少。姜黄素还抑制了肝氧化应激的产生。MCD 饮食 8 或 10 周后出现纤维化，也明显被姜黄素减少。姜黄素降低了单核细胞趋化蛋白-1、CD11b、I 型前胶原和金属蛋白酶组织抑制剂（TIMP）-1 的肝内基因表达，同时降低了纤维生成细胞标志物α-平滑肌肌动蛋白的蛋白水平。此外，姜黄素减少了培养的 HSCs 中活性氧的产生，并抑制了 TIMP-1 在基础条件下和氧化应激诱导后的分泌。总之，姜黄素的给药有效地限制了实验性脂肪性肝炎小鼠的纤维化发展和进展，并减少了培养的星状细胞中 TIMP-1 的分泌和氧化应激。
