Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2017; 23(22): 3999-4006
Published online Jun 14, 2017. doi: 10.3748/wjg.v23.i22.3999
Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis
Robert G Bennett, Ronda L Simpson, Frederick G Hamel
Robert G Bennett, Ronda L Simpson, Frederick G Hamel, Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68198, United States
Robert G Bennett, Ronda L Simpson, Frederick G Hamel, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
Robert G Bennett, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
Frederick G Hamel, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
Author contributions: Bennett RG, Simpson RL and Hamel FG substantially contributed to the design of the study and the interpretation of the data; Bennett RG drafted the article; and all authors contributed to the collection of data, and approved the final version of the article to be published.
Supported by The United States Department of Veterans Affairs Biomedical Laboratory Research and Development Program, No. BX000849; and National Institutes of Health, NIAAA, No. R01AA015509.
Institutional animal care and use committee statement: All procedures were conducted in accordance with The Guide for the Care and Use of Laboratory Animals, and were approved by the VA Nebraska Western-Iowa Institutional Animal Care and Use Committee.
Conflict-of-interest statement: The authors have no conflicts of interest.
Data sharing statement: No additional data are available.
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: Robert G Bennett, PhD, Professor, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States. rgbennet@unmc.edu
Telephone: +1-402-3468800 Fax: +1-402-4490604
Received: December 28, 2016
Peer-review started: December 29, 2016
First decision: February 10, 2017
Revised: March 30, 2017
Accepted: May 9, 2017
Article in press: May 9, 2017
Published online: June 14, 2017
Abstract
AIM

To determine the effect of combined serelaxin and rosiglitazone treatment on established hepatic fibrosis.

METHODS

Hepatic fibrosis was induced in mice by carbon tetrachloride administration for 6 wk, or vehicle alone (nonfibrotic mice). For the final 2 wk, mice were treated with rosiglitazone, serelaxin, or both rosiglitazone and serelaxin. Serum liver enzymes and relaxin levels were determined by standard methods. The degree of liver collagen content was determined by histology and immunohistochemistry. Expression of type I collagen was determined by quantitative PCR. Activation of hepatic stellate cells was assessed by alpha-smooth muscle actin (SMA) levels. Liver peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC1α) was determined by Western blotting.

RESULTS

Treatment of mice with CCl4 resulted in hepatic fibrosis as evidenced by increased liver enzyme levels (ALT and AST), and increased liver collagen and SMA. Monotherapy with either serelaxin or rosiglitazone for 2 wk was generally without effect. In contrast, the combination of serelaxin and rosiglitazone resulted in significantly improved ALT levels (P < 0.05). Total liver collagen content as determined by Sirius red staining revealed that only combination treatment was effective in reducing total liver collagen (P < 0.05). These results were supported by immunohistochemistry for type I collagen, in which only combination treatment reduced fibrillar collagen levels (P < 0.05). The level of hepatic stellate cell activation was modestly, but significantly, reduced by serelaxin treatment alone, but combination treatment resulted in significantly lower SMA levels. Finally, while hepatic fibrosis reduced liver PGC1α levels, the combination of serelaxin and rosiglitazone resulted in restoration of PGC1α protein levels.

CONCLUSION

The combination of serelaxin and rosiglitazone treatment for 2 wk was effective in significantly reducing established hepatic fibrosis, providing a potential new treatment strategy.

Keywords: Relaxin, Peroxisome proliferator-activated receptors, Liver cirrhosis, Liver diseases, Fibrosis

Core tip: Hepatic fibrosis is a chronic condition that can lead to cirrhosis, but treatment options are limited and ineffective. Agonists of peroxisome proliferator-activated receptor gamma (PPARγ), such as rosiglitazone have shown limited efficacy. The hormone relaxin has antifibrotic effects, and increases the activity of PPARγ, leading to the hypothesis that combination treatment may be more effective. Mice with established hepatic fibrosis were treated with relaxin and rosiglitazone alone or in combination. Combination treatment reduced liver fibrosis, and increased the level of a PPARγ coactivator. These results suggest that relaxin and PPARγ co-therapy could be a more effective treatment for hepatic fibrosis.