Published online Oct 14, 2016. doi: 10.3748/wjg.v22.i38.8497
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
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.
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.
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.
To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.
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.