کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6102725 1211119 2014 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Research ArticleHepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی بیماری‌های گوارشی
پیش نمایش صفحه اول مقاله
Research ArticleHepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice
چکیده انگلیسی

Background & AimsNon-alcoholic-fatty-liver disease (NAFLD) is part of the metabolic syndrome. The spectrum of NAFLD includes NASH (non-alcoholic steatohepatitis), which is characterised by progressive inflammation associated with oxidative stress and apoptosis, finally triggering liver cirrhosis and hepatocellular carcinoma. HGF (hepatocyte growth factor)/mesenchymal-epithelial transition factor (c-Met) receptor signalling is known to activate distinct intracellular pathways mediating among others anti-apoptotic properties to hepatocytes. Therefore, the aim was to characterise the role of c-Met during NASH development.MethodsHepatocyte specific c-Met knockout mice (c-MetΔhepa) using the cre-loxP system and wild type controls (c-MetloxP/loxP) were fed a methionine-choline deficient (MCD) diet.ResultsMCD feeding triggered massive steatosis, decreased survival and higher transaminases in c-MetΔhepa livers compared to c-MetloxP/loxP. Gene array analysis demonstrated that genes involved in fatty acid metabolism were strongly upregulated in c-MetΔhepa livers correlating with higher amounts of hepatic free fatty acids. Consequently, c-MetΔhepa mice showed significantly more TUNEL positive cells and more superoxide anion production than c-MetloxPloxP animals. Additionally, c-MetΔhepa livers showed significantly larger fractions of infiltrating neutrophils, macrophages, and cytotoxic T cells. These changes correlated with an enhanced progression of liver fibrosis as evidenced by higher collagen deposition in c-MetΔhepa livers. As increased apoptosis was a prominent feature in c-MetΔhepa livers, we generated c-Met/Casp8Δhepa double knockout mice. In these animals compared to c-MetΔhepa animals the increase in apoptosis could be reverted.Conclusionsc-Met deletion in hepatocytes triggers NASH progression. A prominent mechanism is higher fatty acid accumulation and increased apoptosis, which in part can be reverted by blocking caspase 8.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Hepatology - Volume 61, Issue 4, October 2014, Pages 883-890
نویسندگان
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