- 作者：Kengo Tomita ; Toshiaki Teratani ; Takahiro Suzuki ; Tetsuya Oshikawa ; Hirokazu Yokoyama ; Katsuyoshi Shimamura ; Kiyoshi Nishiyama ; Norikazu Mataki ; Rie Irie ; Tohru Minamino ; Yoshikiyo Okada ; Chie Kurihara ; Hirotoshi Ebinuma ; Hidetsugu Saito ; Ippei Shimizu ; Yohko Yoshida ; Ryota Hokari ; Kazuo Sugiyama ; Kazuo Hatsuse ; Junji Yamamoto ; et al.
- 关键词：NAFLD ; non-alcoholic fatty liver disease ; NASH ; non-alcoholic steatohepatitis ; ROS ; reactive oxygen species ; MCD ; methionine-deficient and choline-deficient ; ALT ; alanine aminotransferase ; HE ; haematoxylin-eosin ; HNE ; hydroxynonenal ; TUNEL ; terminal deoxy
- 刊名：Journal of Hepatology
- 出版年：2012
- 出版时间：October, 2012
- 年：2012
- 卷：57
- 期：4
- 页码：837-843
- 全文大小：1138 K
Background & Aims
The tumor suppressor p53 is a primary sensor of stressful stimuli, controlling a number of biologic processes. The aim of our study was to examine the roles of p53 in non-alcoholic steatohepatitis (NASH).Methods
Male wild type and p53-deficient mice were fed a methionine- and choline-deficient diet for 8 weeks to induce nutritional steatohepatitis. mRNA expression profiles in normal liver samples and liver samples from patients with non-alcoholic liver disease (NAFLD) were also evaluated.
Results
Hepatic p53 and p66Shc signaling was enhanced in the mouse NASH model. p53 deficiency suppressed the enhanced p66Shc signaling, decreased hepatic lipid peroxidation and the number of apoptotic hepatocytes, and ameliorated progression of nutritional steatohepatitis. In primary cultured hepatocytes, transforming growth factor (TGF)-¦Â treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-¦Â-induced p66Shc signaling, ROS accumulation, and hepatocyte apoptosis. Furthermore, expression levels of p53, p21, and p66Shc were significantly elevated in human NAFLD liver samples, compared with results obtained with normal liver samples. Among NAFLD patients, those with NASH had significantly higher hepatic expression levels of p53, p21, and p66Shc compared with the group with simple steatosis. A significant correlation between expression levels of p53 and p66Shc was observed.
Conclusions
p53 in hepatocytes regulates steatohepatitis progression by controlling p66Shc signaling, ROS levels, and apoptosis, all of which may be regulated by TGF-¦Â. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH.