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

Research output: Contribution to journalArticle

Abstract

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
DOIs
StatePublished - Jan 1 2019

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DNA Damage
Carrier Proteins
Hepatocytes
Double-Stranded DNA Breaks
Nonesterified Fatty Acids
Disease Progression
Fibrosis
Non-alcoholic Fatty Liver Disease
Genomic Instability
Palmitates
Liver
Caspases
Platelet Count
Fluorescence Microscopy
Liver Diseases
Hepatocellular Carcinoma
Fatty Acids
Therapeutics
Serum

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression. / Akazawa, Yuko; Nakashima, Ryoma; Matsuda, Katsuya; Okamaoto, Koji; Hirano, Ran; Kawasaki, Hiroko; Miuma, Satoshi; Miyaaki, Hisamitsu; Malhi, Harmeet M; Abiru, Seigo; Itoh, Masahiro; Kondo, Hisayohi; Fukuoka, Junya; Nakao, Kazuhiko; Nakashima, Masahiro.

In: Modern Pathology, 01.01.2019.

Research output: Contribution to journalArticle

Akazawa, Y, Nakashima, R, Matsuda, K, Okamaoto, K, Hirano, R, Kawasaki, H, Miuma, S, Miyaaki, H, Malhi, HM, 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. https://doi.org/10.1038/s41379-019-0218-8
Akazawa, Yuko ; Nakashima, Ryoma ; Matsuda, Katsuya ; Okamaoto, Koji ; Hirano, Ran ; Kawasaki, Hiroko ; Miuma, Satoshi ; Miyaaki, Hisamitsu ; Malhi, Harmeet M ; Abiru, Seigo ; Itoh, Masahiro ; Kondo, Hisayohi ; Fukuoka, Junya ; Nakao, Kazuhiko ; Nakashima, Masahiro. / Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression. In: Modern Pathology. 2019.
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abstract = "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.",
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