title: Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.
authors: 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.
authors: Natalia A
authors: NA
authors: Osna
authors: 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.
authors: Dan
authors: D
authors: Feng
authors: 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.
authors: Murali
authors: M
authors: Ganesan
authors: 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.
authors: Priya F
authors: PF
authors: Maillacheruvu
authors: 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.
authors: David J
authors: DJ
authors: Orlicky
authors: 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.
authors: Samuel W
authors: SW
authors: French
authors: 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.
authors: Dean J
authors: DJ
authors: Tuma
authors: 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.
authors: Kusum K
authors: KK
authors: Kharbanda
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000579:Amidinotransferases / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D019587:Dietary Supplements; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005227:Fatty Acids / Q000737:chemistry; D005234:Fatty Liver; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D050937:Guanidinoacetate N-Methyltransferase / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D007249:Inflammation; D007328:Insulin / Q000737:chemistry; D008099:Liver / Q000503:physiopathology; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000080866:Nucleobindins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012435:S-Adenosylhomocysteine / Q000737:chemistry; D012436:S-Adenosylmethionine / Q000737:chemistry; D014280:Triglycerides / Q000737:chemistry
chemical_list: D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D014280:Triglycerides; D006710:Homocysteine; D000431:Ethanol; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D002784:Cholesterol; C494508:Gamt protein, rat; D050937:Guanidinoacetate N-Methyltransferase; D000579:Amidinotransferases; C020681:glycine amidinotransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D046988:Proteasome Endopeptidase Complex; C004946:glycocyamine; D005998:Glycine
keywords: Alcohol; Guanidinoacetate; Methyl balance; S-adenosylhomocysteine; S-adenosylmethionine