Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 14, 2016; 22(38): 8497-8508
Published online Oct 14, 2016. doi: 10.3748/wjg.v22.i38.8497
Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury
Natalia A Osna, Dan Feng, Murali Ganesan, Priya F Maillacheruvu, David J Orlicky, Samuel W French, Dean J Tuma, Kusum K Kharbanda
Natalia A Osna, Dan Feng, Murali Ganesan, Dean J Tuma, Kusum K Kharbanda, Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
Natalia A Osna, Dan Feng, Murali Ganesan, Priya F Maillacheruvu, Dean J Tuma, Kusum K Kharbanda, Department of Internal Medicine, 982000 Nebraska Medical Center, Omaha, NE 68198, United States
Kusum K Kharbanda, Department of Biochemistry and Molecular Biology, 985870 Nebraska Medical Center, Omaha, NE 68198, United States
David J Orlicky, Department of Pathology, University of Colorado Denver, Aurora, CO 80010, United States
Samuel W French, Department of Anatomic Pathology, Harbor UCLA Medical Center, Torrance, CA 90509, United States
Author contributions: Osna NA, Ganesan M and Tuma DJ contributed to this paper with drafting and critical revision, editing, and approval of the final version; Feng D and Maillacheruvu PF were involved in the feeding regimens, data collection, analysis and the approval of the final version; Orlicky DJ contributed to this paper with the histopathological assessments, critical revision, editing and approval of the final version; French SW contributed to this paper with the histopathological assessments and approval of the final version; Kharbanda KK contributed to this paper with conception, literature review, drafting and critical revision, editing, and approval of the final version.
Supported by a Merit Review grant BX001155 (to Kharbanda KK) from the Department of Veterans Affairs, Office of Research and Development (Biomedical Laboratory Research and Development).
Conflict-of-interest statement: No potential conflicts of interest.
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: Kusum K Kharbanda, PhD, Veterans Affairs Nebraska-Western Iowa Health Care System, Research Service (151), 4101 Woolworth Avenue, Omaha, NE 68105, United States. kkharbanda@unmc.edu
Telephone: +1-402-9953752 Fax: +1-402-4490604
Received: June 24, 2016
Peer-review started: June 24, 2016
First decision: August 22, 2016
Revised: August 27, 2016
Accepted: September 8, 2016
Article in press: September 8, 2016
Published online: October 14, 2016
Processing time: 110 Days and 8.3 Hours
Abstract
AIM

To investigate the hypothesis that exposure to guanidinoacetate (GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage.

METHODS

Adult male Wistar rats were fed the control or ethanol Lieber DeCarli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted.

RESULTS

Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macro- and micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol.

CONCLUSION

To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.

Keywords: Methyl balance; S-adenosylmethionine; S-adenosylhomocysteine; Guanidinoacetate; Alcohol

Core tip: We examined the role of a combined exposure to ethanol and guanidinoacetate (GAA) in the pathogenesis of liver injury. Exposure to either treatment lowers the hepatic methylation index which is defined as the ratio of the methyl donor, S-adenosylmethionine to its product S-adenosylhomocysteine. We observed a worsening of liver pathology with prolonged GAA and ethanol treatment compared to either treatment alone. These detrimental consequences were related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol.