Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression

Yuko Akazawa, Ryoma Nakashima, Katsuya Matsuda, Koji Okamaoto, Ran Hirano, Hiroko Kawasaki, Satoshi Miuma, Hisamitsu Miyaaki, Harmeet M Malhi, Seigo Abiru, Masahiro Itoh, Hisayohi Kondo, Junya Fukuoka, Kazuhiko Nakao, Masahiro Nakashima

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Nonalcoholic fatty liver disease is a major liver disease that leads to cirrhosis and/or hepatocellular carcinoma in a subset of patients. The mechanism underlying disease progression is largely unknown. p53-binding protein 1 (53BP1) is a DNA damage response protein that rapidly localizes at the site of DNA double-strand breaks. In this study, we investigated nuclear 53BP1-positive foci formation as an indicator of DNA double-strand breaks in human nonalcoholic fatty liver disease liver tissues by immunofluorescence microscopy. A total of 52 liver tissue samples, including 43 nonalcoholic fatty liver disease samples and 9 controls, were studied. Our results show that the number of abnormal 53BP1-positive foci in hepatocytes (defined as three or more discrete nuclear foci and/or large foci greater than 1 μM) was significantly increased in nonalcoholic fatty liver disease patients compared to that in controls, both in nonalcoholic fatty liver (p < 0.01) and nonalcoholic steatohepatitis patients (p < 0.01). The number of large foci was significantly increased in the nonalcoholic steatohepatitis cases compared to that in the nonalcoholic fatty liver cases (p < 0.05) and correlated with increased stage of fibrosis. The number of large-foci-expressing hepatocytes was positively correlated with increased age (p < 0.01) and negatively correlated with serum platelet count (p < 0.05). In addition, we performed an in vitro assay using rat hepatocytes treated with the saturated free fatty acid palmitate. Treatment appeared to augment the number of abnormal foci, indicating an induction of double-strand breaks in the hepatocytes through free fatty acid treatment in a caspase-dependent manner. This study demonstrates that 53BP1-positive nuclear foci formation is associated with disease progression in nonalcoholic fatty liver disease patients. Analysis of 53BP1 expression might be a feasible technique to estimate genomic instability in nonalcoholic fatty liver disease.

Original languageEnglish (US)
JournalModern Pathology
StatePublished - Jan 1 2019


ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Akazawa, Y., Nakashima, R., Matsuda, K., Okamaoto, K., Hirano, R., Kawasaki, H., Miuma, S., Miyaaki, H., Malhi, H. M., Abiru, S., Itoh, M., Kondo, H., Fukuoka, J., Nakao, K., & Nakashima, M. (2019). Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression. Modern Pathology.