Increased methylation demand exacerbates ethanol-induced liver injury.
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 2weeks. 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.
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: kkharbanda@unmc.edu.
Kusum K
KK
Kharbanda
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA.
Sandra L
SL
Todero
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Paul G
PG
Thomes
Department of Pathology, University of Colorado Denver, Aurora, CO 80010, USA.
David J
DJ
Orlicky
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Natalia A
NA
Osna
Department of Anatomic Pathology, Harbor UCLA Medical Center, Torrance, CA 90509, USA.
Samuel W
SW
French
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Dean J
DJ
Tuma
D000428:Alcohol Drinking / Q000378:metabolism; D000579:Amidinotransferases / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D000431:Ethanol / Q000633:toxicity*; D005235:Fatty Liver, Alcoholic / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050937:Guanidinoacetate N-Methyltransferase / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008745:Methylation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D014280:Triglycerides; D006710:Homocysteine; D000431:Ethanol; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; C494508:Gamt protein, rat; D050937:Guanidinoacetate N-Methyltransferase; D000579:Amidinotransferases; C020681:glycine amidinotransferase; C004946:glycocyamine; D005998:Glycine
Guanidinoacetate; Homocysteine; Methyl balance; Methyltransferases; S-adenosylhomocysteine; S-adenosylmethionine