P53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice

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 YamamotoTakanori Kanai, Soichiro Miura, Toshifumi Hibi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)837-843
Number of pages7
JournalJournal of Hepatology
Volume57
Issue number4
DOIs
Publication statusPublished - 2012 Oct

Fingerprint

Fatty Liver
Liver
Transforming Growth Factors
Hepatocytes
Reactive Oxygen Species
Apoptosis
Hepatocyte Growth Factor
Choline
Methionine
Lipid Peroxidation
Liver Diseases
Diet
Messenger RNA
Therapeutics
Non-alcoholic Fatty Liver Disease

Keywords

  • Non-alcoholic steatohepatitis
  • P53
  • P66Shc
  • Reactive oxygen species
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Hepatology

Cite this

P53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. / 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.

In: Journal of Hepatology, Vol. 57, No. 4, 10.2012, p. 837-843.

Research output: Contribution to journalArticle

Tomita, K, Teratani, T, Suzuki, T, Oshikawa, T, Yokoyama, H, Shimamura, K, Nishiyama, K, Mataki, N, Irie, R, Minamino, T, Okada, Y, Kurihara, C, Ebinuma, H, Saito, H, Shimizu, I, Yoshida, Y, Hokari, R, Sugiyama, K, Hatsuse, K, Yamamoto, J, Kanai, T, Miura, S & Hibi, T 2012, 'P53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice', Journal of Hepatology, vol. 57, no. 4, pp. 837-843. https://doi.org/10.1016/j.jhep.2012.05.013
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. / P53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. In: Journal of Hepatology. 2012 ; Vol. 57, No. 4. pp. 837-843.
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abstract = "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.",
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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

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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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