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©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
Preserved liver regeneration capacity after partial hepatectomy in rats with non-alcoholic steatohepatitis
David Haldrup, Sara Heebøll, Karen Louise Thomsen, Kasper Jarlhelt Andersen, Michelle Meier, Frank Viborg Mortensen, Jens Randel Nyengaard, Stephen Hamilton-Dutoit, Henning Grønbæk
David Haldrup, Sara Heebøll, Karen Louise Thomsen, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
David Haldrup, Department of Internal Medicine, Randers Regional Hospital, Randers NØ DK-8930, Denmark
Kasper Jarlhelt Andersen, Michelle Meier, Frank Viborg Mortensen, Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
Jens Randel Nyengaard, Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus C DK-8000, Denmark
Stephen Hamilton-Dutoit, Institute of Pathology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
Author contributions: Haldrup D and Heebøll S performed the majority of the experiments with assistance and supervision by Thomsen KL, Andersen KJ, Meier M and Nyengaard JR; Thomsen KL, Andersen KJ, Meier M, Mortensen FV, Nyengaard JR and Grønbæk H concived and designed the study; Thomsen KL performed the statistical analysis; Hamilton-Dutoit S performed the histological evaluation; all authors contributed to the analysis and interpretation of data; Haldrup D wrote the original manuscript draft; Heebøll S, Thomsen KL, Andersen KJ, Meier M, Nyengaard JR, Mortensen FV, Nyengaard JR, Hamilton-Dutiot S and Grønbæk H critically revised the manuscript for important intellectual content; all authors saw and approved the final manuscript.
Supported by NOVO Nordisk Foundation (grant number 1013267) and Savværksejer Jeppe Juhl og Hustru Ovita Juhls Mindelegat to Grønbæk H; Villum Fonden to Nyengaard JR.
Institutional animal care and use committee statement: All animal work was conducted according to the national guidelines. The Danish Animal Experiments Inspectorate approved the study (2014-15-2934-00997).
Conflict-of-interest statement: To the best of our knowledge there are no competing interests.
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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: David Haldrup, MD, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Nørrebrogade 44, Aarhus C DK-8000, Denmark. davihald@rm.dk
Telephone: +45-20912152
Received: October 12, 2017
Peer-review started: October 13, 2017
First decision: November 7, 2017
Revised: November 20, 2017
Accepted: December 6, 2017
Article in press: December 6, 2017
Published online: January 27, 2018
AIM
To evaluate the liver regeneration capacity (LRC) after partial hepatectomy (PH) in experimental non-alcoholic steatohepatitis (NASH).
METHODS
Fifty-four female rats were fed a high-fat, high-cholesterol diet (HFCD, 65% fat, 1% cholesterol) or standard diet (STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d post-PH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio (RPR), prothrombin-proconvertin ratio (PP), and mRNA expression of genes related to regeneration.
RESULTS
The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline (P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH (P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline, (P < 0.0001), day 2 after PH (P = 0.06) and day 5 after PH (P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes (e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups (P < 0.05).
CONCLUSION
NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.
Core tip: Liver regeneration capacity has been studied in different animal models of non-alcoholic steatohepatitis. This study is the first to use a high fat high cholesterol model which mimic the pathogenesis of human non-alcoholic steatohepatitis better than previous animal models. Liver regeneration capacity was evaluated using: (1) The total number of Ki-67 positive hepatocytes in the caudate lobe, evaluated in a stereology based design; (2) the regenerated protein content to describe the regenerated liver mass; and (3) the plasma concentration of coagulation factors as a marker of liver function. We found a preserved liver regeneration capacity in rats with non-alcoholic steatohepatitis, adding important knowledge to the subject.
