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Lab Invest. 2010 Feb;90(2):245-56. doi: 10.1038/labinvest.2009.123. Epub 2009 Nov 30.

Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine-choline-deficient diet.

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Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.


Fatty liver disease has become a health problem related to metabolic syndrome worldwide, although its molecular pathogenesis requires further study. It is also unclear whether advanced fibrosis of steatohepatitis will regress when diet is controlled. The aim of this study was to investigate whether the resolution of fibrosis occurs in steatohepatitis induced by a methionine-choline-deficient diet (MCDD). Manifestation of endoplasmic reticulum (ER) stress in this model was also studied. Nonalcoholic steatohepatitis with advanced fibrosis was induced in rats by feeding them an MCDD for 10 weeks. Instead of MCDD, a methionine-choline control diet (CD) was given for the last 2 weeks to the experimental group. Fibrosis and inflammation were determined by tissue staining. Protein and gene expressions were determined by immunoblotting and quantitative reverse transcription-PCR (RT-PCR), respectively. Expressions of caspase-7, caspase-12, glucose-regulated protein 78 (GRP78), and protein disulfide isomerase were evaluated to clarify the presence of ER stress. Changing the diet from MCDD to CD triggered the reduction of fat in hepatocytes, a decrease in inflammatory gene expression and oxidative stress, and regression of fibrosis accompanied by the disappearance of activated stellate cells and macrophages. Immunohistochemistry, immunoblotting, and RT-PCR analysis all indicated the occurrence of ER stress in steatohepatitis, while it recovered immediately after changing the diet from MCCD to CD. The ratio of hepatocyte proliferation/apoptotis increased significantly during the recovery stage. This simple experiment clearly shows that changing the diet from MCDD to a normal diet (CD) triggers the resolution of hepatic inflammatory and fibrotic reactions and hepatocyte apoptosis, suggesting that MCDD-induced steatohepatitis is also reversible. ER stress appears and disappears in association with the generation and regression of steatohepatitis, respectively, with fibrosis.

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