p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice
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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Senescent hepatocytes are involved in the activation of hepatic stellate cells and the development of liver fibrosis.
“This finding supports the involvement of senescent hepatocytes in the activation of hepatic stellate cells and the development of liver fibrosis.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [156]
In p53-deficient mice with nutrition-induced steatohepatitis, reduced levels of hepatocyte p21 and decreased activation of hepatic stellate cells and expression of fibrotic markers such as SMA and collagen were observed.
“It was discovered that these mice displayed reduced levels of hepatocyte p21, as well as decreased activation of hepatic stellate cells and expression of fibrotic markers such as SMA and collagen.156”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [156]
Cites
The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study
Adams, L. A., Lymp, J. F., St. Sauver, J., Sanderson, S. O., Lindor, K. D., Feldstein, A., & Angulo, P. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.04.014 · Cited by 2,890 · see citing works
The p66shc adaptor protein controls oxidative stress response and life span in mammals
Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Pandolfi, P. P., Lanfrancone, L., & Pelicci, P. G. (1999) · Nature · doi:10.1038/46311 · Cited by 1,712 · see citing works
A Chemical Inhibitor of p53 That Protects Mice from the Side Effects of Cancer Therapy
Komarov, P. G., Komarova, E. A., Kondratov, R. V., Christov-Tselkov, K., Coon, J. S., Chernov, M. V., & Gudkov, A. V. (1999) · Science · doi:10.1126/science.285.5434.1733 · Cited by 1,270 · see citing works
CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis
Leclercq, I. A., Farrell, G. C., Field, J., Bell, D., Gonzalez, F. J., & Robertson, G. R. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8814 · Cited by 763 · see citing works
Clinical Features and Natural History of Nonalcoholic Steatosis Syndromes
Falck-Ytter, Y. T., Younossi, Z. M., Marchesini, G., & McCullough, A. J. (2001) · Seminars in Liver Disease · doi:10.1055/s-2001-12926 · Cited by 668 · see citing works
Pathogenesis of liver fibrosis: role of oxidative stress
Poli, G. (2000) · Molecular Aspects of Medicine · doi:10.1016/s0098-2997(00)00004-2 · Cited by 631 · see citing works
Tomita, K., Tamiya, G., Ando, S., Ohsumi, K., Chiyo, T., Mizutani, A., Kitamura, N., Toda, K., Kaneko, T., Horie, Y., et al. (2005) · Gut · doi:10.1136/gut.2005.071118 · Cited by 439 · see citing works
Self-citationTrinei, M., Giorgio, M., Cicalese, A., Barozzi, S., Ventura, A., Migliaccio, E., Milia, E., Padura, I. M., Raker, V. A., Maccarana, M., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205513 · Cited by 436 · see citing works
Hwang, P. M., Bunz, F., Yu, J., Rago, C., Chan, T. A.-T., Murphy, M. P., Kelso, G. F., Smith, R. A. J., Kinzler, K. W., & Vogelstein, B. (2001) · Nature Medicine · doi:10.1038/nm1001-1111 · Cited by 424 · see citing works
Bissell, D. M., Wang, S. S., Jarnagin, W. R., & Roll, F. J. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118055 · Cited by 419 · see citing works
Ribeiro, P. S., Cortez‐Pinto, H., Solá, S., Castro, R. E., Ramalho, R. M., Baptista, A., de Moura, M. C., Camilo, M., & Rodrigues, C. M. (2004) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2004.40009.x · Cited by 392 · see citing works
Matsuoka, M., & Tsukamoto, H. (1990) · Hepatology · doi:10.1002/hep.1840110412 · Cited by 291 · see citing works
Galli, A., Svegliati‐Baroni, G., Ceni, E., Milani, S., Ridolfi, F., Salzano, R., Tarocchi, M., Grappone, C., Pellegrini, G., Benedetti, A., et al. (2005) · Hepatology · doi:10.1002/hep.20683 · Cited by 235 · see citing works
Genes or environment to determine alcoholic liver disease and non‐alcoholic fatty liver disease
Day, C. (2006) · Liver International · doi:10.1111/j.1478-3231.2006.01323.x · Cited by 162 · see citing works
Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression
Farrell, G. C., Larter, C. Z., Hou, J. Y., Zhang, R. H., Yeh, M. M., Williams, J., Peňa, A. D., Francisco, R., Osvath, S. R., Brooling, J. T., et al. (2009) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2009.05785.x · Cited by 137 · see citing works
Expression of p53, Bax and Bcl-2 proteins in hepatocytes in non-alcoholic fatty liver disease
Panasiuk, A. (2006) · World Journal of Gastroenterology · doi:10.3748/wjg.v12.i38.6198 · Cited by 121 · see citing works
Tomita, K., Oike, Y., Teratani, T., Taguchi, T., Noguchi, M., Suzuki, T., Mizutani, A., Yokoyama, H., Irie, R., Sumimoto, H., et al. (2008) · Hepatology · doi:10.1002/hep.22365 · Cited by 118 · see citing works
Self-citationPentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet
Koppe, S., Sahai, A., Malladi, P., Whitington, P. F., & Green, R. M. (2004) · Journal of Hepatology · doi:10.1016/j.jhep.2004.06.030 · Cited by 117 · see citing works
Derdák, Z., Lang, C. H., Villegas, K. A., Tong, M., Mark, N. M., de la Monte, S. M., & Wands, J. R. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.08.007 · Cited by 114 · see citing works
Fatty liver and the metabolic syndrome
Neuschwander‐Tetri, B. A. (2007) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e32801421a9 · Cited by 112 · see citing works
Inhibition of p53 protects liver tissue against endotoxin‐induced apoptotic and necrotic cell death
Schäfer, T., Scheuer, C., Roemer, K., Menger, M. D., & Vollmar, B. (2003) · The FASEB Journal · doi:10.1096/fj.02-0774com · Cited by 104 · see citing works
STAT-3 Overexpression and p21 Up-Regulation Accompany Impaired Regeneration of Fatty Livers
Torbenson, M. S., Yang, S. Q., Liu, H. Z., Huang, J., Gage, W. R., & Diehl, A. M. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64167-3 · Cited by 95 · see citing works
Cheng, P., Chang, M.-H., Chao, C.-H., & Lee, Y. W. (2004) · Oncogene · doi:10.1038/sj.onc.1208066 · Cited by 69 · see citing works
Tied Up in Loops: Positive and Negative Autoregulation of p53Preprint
Lü, X. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000984 · Cited by 58 · see citing works
Black, D., Lyman, S., Qian, T., Lemasters, J. J., Rippe, R. A., Nitta, T., Js, K., & Behrns, K. E. (2007) · Biochimie · doi:10.1016/j.biochi.2007.09.001 · Cited by 52 · see citing works
(2001) · Nature Medicine · doi:10.1038/nm1101-1255a · Cited by 41 · see citing works
Haga, S., Morita, N., Irani, K., Fujiyoshi, M., Ogino, T., Ozawa, T., & Ozaki, M. (2010) · Laboratory Investigation · doi:10.1038/labinvest.2010.119 · Cited by 37 · see citing works
Primary cirrhotic hepatocytes resist TGF$beta;-induced apoptosis through a ROS-dependent mechanism
BLACK, D. (2004) · Journal of Hepatology · doi:10.1016/j.jhep.2004.02.031 · Cited by 37 · see citing works
Non-Invasive Diagnostic Tests for Non-Alcoholic Fatty Liver Disease
Estep, M., Birerdinc, A., & Younossi, Z. M. (2010) · Current Molecular Medicine · doi:10.2174/156652410790963321 · Cited by 31 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443 · see citing works
“It was discovered that these mice displayed reduced levels of hepatocyte p21, as well as decreased activation of hepatic stellate cells and expression of fibrotic markers such as SMA and collagen.(156) This finding supports the involvement of senescent hepatocytes in the activation of hepatic stellate cells and the de…”
BackgroundMDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
Yang, L., Roh, Y. S., Song, J., Zhang, B., Liu, C., Loomba, R., & Seki, E. (2014) · Hepatology · doi:10.1002/hep.26698 · Cited by 275 · see citing works
Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis
Cai, B., Dongiovanni, P., Corey, K. E., Wang, X., Shmarakov, I. O., Zheng, Z., Kasikara, C., Davra, V., Meroni, M., Chung, R. T., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.013 · Cited by 266 · see citing works
Aravinthan, A., Pietrosi, G., Hoare, M., Jupp, J., Marshall, A., Verrill, C., Davies, S., Bateman, A., Sheron, N., Allison, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072904 · Cited by 117 · see citing works
The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease
Engelmann, C., & Tacke, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020652 · Cited by 61 · see citing works
- Authors
- 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.
- Affiliations
- Keio University (JP)
- National Defense Medical College Hospital (JP)
- Kawasaki Municipal Hospital (JP)
- Chiba University (JP)
- Corresponding author
- Tomita, Kengo
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 57
- Issue
- 4
- Pages
- 837-843
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W1973185531
- Cited by
- 127
- References
- 29
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 9 · 2023: 12 · 2022: 13 · 2021: 17 · 2020: 11 · 2019: 6 · 2018: 11 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 8 · 2013: 7 · 2012: 2
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Defense Medical College
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- p53, p66Shc, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, TGF-beta signaling, reactive oxygen species, hepatocyte apoptosis, lipid peroxidation, p21, methionine-choline-deficient diet, p53-deficient mice
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Animals, Choline Deficiency, Disease Models, Animal, Fatty Liver, Humans, Male, Methionine, Mice, Inbred C57BL, RNA, Messenger, Signal Transduction, Up-Regulation, Tumor Suppressor Protein p53, Transforming Growth Factor beta, Proto-Oncogene Proteins p21(ras), Apoptosis, Reactive Oxygen Species, Mice, Knockout, Disease Progression, Hepatocytes, Cyclin-Dependent Kinase Inhibitor p21, Mice, Caspase 3, Shc Signaling Adaptor Proteins, Primary Cell Culture, Non-alcoholic Fatty Liver Disease
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