Increased methylation demand exacerbates ethanol-induced liver injury

Kusum K. Kharbanda, Sandra L. Todero, Paul G. Thomes, David J. Orlicky, Natalia A. Osna, Samuel W. French, Dean J. Tuma

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


We previously reported that chronic ethanol intake lowers hepatocellular S-adenosylmethionine to S-adenosylhomocysteine ratio and significantly impairs many liver methylation reactions. One such reaction, catalyzed by guanidinoacetate methyltransferase (GAMT), is a major consumer of methyl groups and utilizes as much as 40% of the SAM-derived groups to convert guanidinoacetate (GAA) to creatine. The exposure to methyl-group consuming compounds has substantially increased over the past decade that puts additional stresses on the cellular methylation potential. The purpose of our study was to investigate whether increased ingestion of a methyl-group consumer (GAA) either alone or combined with ethanol intake, plays a role in the pathogenesis of liver injury. Adult male Wistar rats were pair-fed the Lieber DeCarli control or ethanol diet in the presence or absence of GAA for 2. weeks. At the end of the feeding regimen, biochemical and histological analyses were conducted. We observed that 2. weeks of GAA- or ethanol-alone treatment increases hepatic triglyceride accumulation by 4.5 and 7-fold, respectively as compared with the pair-fed controls. However, supplementing GAA in the ethanol diet produced panlobular macro- and micro-vesicular steatosis, a marked decrease in the methylation potential and a 28-fold increased triglyceride accumulation. These GAA-supplemented ethanol diet-fed rats displayed inflammatory changes and significantly increased liver toxicity compared to the other groups. In conclusion, increased methylation demand superimposed on chronic ethanol consumption causes more pronounced liver injury. Thus, alcoholic patients should be cautioned for increased dietary intake of methyl-group consuming compounds even for a short period of time.

Original languageEnglish (US)
Pages (from-to)49-56
Number of pages8
JournalExperimental and Molecular Pathology
Issue number1
StatePublished - Aug 2014


  • Guanidinoacetate
  • Homocysteine
  • Methyl balance
  • Methyltransferases
  • S-adenosylhomocysteine
  • S-adenosylmethionine

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Clinical Biochemistry


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