p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice

• Published in: Journal of hepatology Vol. 57; no. 4; pp. 837 - 843
• Main Authors: Tomita, Kengo, Teratani, Toshiaki, Suzuki, Takahiro, Oshikawa, Tetsuya, Yokoyama, Hirokazu, Shimamura, Katsuyoshi, Nishiyama, Kiyoshi, Mataki, Norikazu, Irie, Rie, Minamino, Tohru, Okada, Yoshikiyo, Kurihara, Chie, Ebinuma, Hirotoshi, Saito, Hidetsugu, Shimizu, Ippei, Yoshida, Yohko, Hokari, Ryota, Sugiyama, Kazuo, Hatsuse, Kazuo, Yamamoto, Junji, Kanai, Takanori, Miura, Soichiro, Hibi, Toshifumi
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.10.2012; Elsevier
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Caspase 3 - metabolism; Choline Deficiency - complications; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Disease Models, Animal; Disease Progression; Fatty Liver - etiology; Fatty Liver - metabolism; Fatty Liver - pathology; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatocytes - metabolism; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Methionine - deficiency; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Non-alcoholic steatohepatitis; Other diseases. Semiology; P53; P66Shc; Primary Cell Culture; Proto-Oncogene Proteins p21(ras) - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; Shc Signaling Adaptor Proteins - metabolism; Signal Transduction - drug effects; Src Homology 2 Domain-Containing, Transforming Protein 1; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; Transforming growth factor-β; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Up-Regulation - drug effects; methionine-deficient and choline-deficient; NAFLD; non-alcoholic fatty liver disease; alanine aminotransferase; ALT; MDA; TUNEL; reactive oxygen species; TGF-β; malondialdehyde; polymerase chain reaction; PFT; hydroxynonenal; Col11; Col12; SMA; P66Shc; NASH; MCD; pifithrin; 2 (I) collagen; P53; 1 (I) collagen; terminal deoxy-nucleotidyl transferase-mediated nick end-labeling; transforming growth factor-β; ROS; HE; smooth muscle actin; haematoxylin-eosin; HNE; PCR; non-alcoholic steatohepatitis; Reactive oxygen species; Transforming growth factor-β; Non-alcoholic steatohepatitis; Human; Oxygen; Prognosis; Transforming growth factor β; p53 Protein; Rodentia; Hepatic disease; Free radical; Vertebrata; Mammalia; Mouse; Animal; Non alcoholic steatohepatitis; Gastroenterology; Digestive diseases; Evolution
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2012.05.013

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.