Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2018; 24(15): 1622-1631
Published online Apr 21, 2018. doi: 10.3748/wjg.v24.i15.1622
Evaluation of safety for hepatectomy in a novel mouse model with nonalcoholic-steatohepatitis
Yusuke Ozawa, Takafumi Tamura, Yohei Owada, Yoshio Shimizu, Akira Kemmochi, Katsuji Hisakura, Takashi Matsuzaka, Hitoshi Shimano, Hiroko Isoda, Nobuhiro Ohkohchi
Yusuke Ozawa, Takafumi Tamura, Yohei Owada, Yoshio Shimizu, Akira Kemmochi, Katsuji Hisakura, Nobuhiro Ohkohchi, Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
Takashi Matsuzaka, Hitoshi Shimano, Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
Hiroko Isoda, Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan
Author contributions: Ozawa Y and Tamura T designed the study and wrote the initial draft of the manuscript; Ozawa Y, Owada Y, Shimizu Y and Kemmochi A performed the animal experiments, the biochemical analysis and gene expression analysis; Ozawa Y, Tamura T, Matsuzaka T and Shimano H contributed to the analysis and interpretation of the data; all of the other authors have critically reviewed the manuscript; the final version of the manuscript was approved by all of the authors.
Supported by Ministry of Education, Culture, Sports, Science, and Technology of Japan, KAKENHI, No. 26861059 and No. 16K10489.
Institutional review board statement: Animal experiments were performed in accordance with the university’s Regulations for Animal Experiments and Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions, under the jurisdiction of the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
Institutional animal care and use committee statement: Animal experiments were performed in human manner after receiving approval from Institutional University Experiment Committee of University of Tsukuba (protocol number: 17-312).
Conflict-of-interest statement: The authors report no relevant conflicts of interest.
Data sharing statement: No data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Nobuhiro Ohkohchi, MD, PhD, Professor, Surgeon, Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
Telephone: +81-29-8533221 Fax: +81-29-8533222
Received: February 14, 2018
Peer-review started: February 14, 2018
First decision: March 9, 2018
Revised: March 16, 2018
Accepted: March 25, 2018
Article in press: March 25,2018
Published online: April 21, 2018
Research background

The population of patients with nonalcoholic steatohepatitis (NASH) and NASH-related hepatocellular carcinoma (HCC) has been increasing. However, few animal models fully reflect both the histopathology and pathophysiology of NASH in humans, therefore, the metabolism of the residual liver after a hepatectomy with NASH has not been clarified. We succeeded to establish a novel experimental NASH model that had same characteristics of histopathology and pathophysiology of NASH in humans.

Research motivation

In NASH, continuous inflammation contributes to HCC. The cause of HCC is frequently infection with hepatitis B virus and hepatitis C virus (HCV). New antiviral medications for hepatitis are currently being used in clinics; therefore, the number of patients with virus-related HCC is expected to decrease in the future. By contrast, the number of patients with NASH-related HCC has been increasing recently, and this trend is expected to continue because no effective treatments are available

Research objectives

The aim of this study was to investigate whether a difference in liver resection volume in a novel NASH model influences surgical outcomes.

Research methods

To establishment of a NASH model, mice were fed a high-fat diet for 4 wk, administered CCl4 for the last 2 wk and administered T0901317 for the last 5 d. These mice were divided into two groups: A 30% partial hepatectomy (PH) of NASH liver group and a 70% PH of NASH liver group (control). Evaluate the survival rate, regeneration, apoptosis, necrosis and DNA expression level after PH.

Research results

In the 70% PH of NASH group, the survival rate was significantly decreased compared with that in the control and 30% PH of NASH groups (P < 0.01). 10 of 32 mice in the NASH 70% PH group died within 48 h after PH. serum aspartate aminotransferase (AST) levels and total bilirubin (T-Bil) in the NASH 70% PH group were significantly higher than the levels in the other two groups (AST: P < 0.05, T-Bil: P < 0.01). In both PH of NASH groups, signaling proteins involved in regeneration were expressed at lower levels than those in the control group (P < 0.01). The 70% PH of NASH group also exhibited a lower number of Ki-67-positive cells and higher rates of apoptosis and necrosis than the NASH 30% PH group (P < 0.01). In addition, DNA microarray assays showed differences in gene expression associated with cell cycle arrest and apoptosis.

Research conclusions

The residual NASH liver dysfunction after hepatectomy is attributed to a reduction in liver regeneration and cell proliferation. A larger residual volume is required to maintain liver functions in mice with NASH.

Research perspectives

This study suggests that the resection volume is a more limiting factor in patients with NASH than in those with a normal liver. Regarding liver surgery, the risk of complications for patients diagnosed with NASH by liver biopsy should be determined before hepatectomy. Further studies are needed to clarify therapeutic agents for NASH using our novel NASH model.