TY - JOUR
T1 - P53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice
AU - Tomita, Kengo
AU - Teratani, Toshiaki
AU - Suzuki, Takahiro
AU - Oshikawa, Tetsuya
AU - Yokoyama, Hirokazu
AU - Shimamura, Katsuyoshi
AU - Nishiyama, Kiyoshi
AU - Mataki, Norikazu
AU - Irie, Rie
AU - Minamino, Tohru
AU - Okada, Yoshikiyo
AU - Kurihara, Chie
AU - Ebinuma, Hirotoshi
AU - Saito, Hidetsugu
AU - Shimizu, Ippei
AU - Yoshida, Yohko
AU - Hokari, Ryota
AU - Sugiyama, Kazuo
AU - Hatsuse, Kazuo
AU - Yamamoto, Junji
AU - Kanai, Takanori
AU - Miura, Soichiro
AU - Hibi, Toshifumi
N1 - Funding Information:
This study was supported by a grant from the National Defense Medical College, and the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
PY - 2012/10
Y1 - 2012/10
N2 - 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)-β treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-β-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-β. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH.
AB - 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)-β treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-β-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-β. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH.
KW - Non-alcoholic steatohepatitis
KW - P53
KW - P66Shc
KW - Reactive oxygen species
KW - Transforming growth factor-β
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UR - http://www.scopus.com/inward/citedby.url?scp=84866348839&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2012.05.013
DO - 10.1016/j.jhep.2012.05.013
M3 - Article
C2 - 22641095
AN - SCOPUS:84866348839
SN - 0168-8278
VL - 57
SP - 837
EP - 843
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 4
ER -