Alcohol consumption decreases rat hepatic creatine biosynthesis via altered guanidinoacetate methyltransferase activity

Kusum Kharbanda, Sandra L. Todero, Jordan C. Moats, Ryan M. Harris, Natalia A Osna, Paul G Thomes, Dean J. Tuma

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: We have previously shown that decreased S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio generated in livers of alcohol-fed rats can impair the activities of many SAM-dependent methyltransferases. One such methyltransferase is guanidinoacetate methyltransferase (GAMT) that catalyzes the last step of creatine synthesis. As GAMT is the major utilizer of SAM, the purpose of the study was to examine the effects of ethanol (EtOH) on liver creatine levels and GAMT activity. Methods: Male Wistar rats were pair-fed the Lieber-DeCarli control and EtOH diet for 4 to 5 weeks. At the end of the feeding regimen, the liver, kidney, and blood were removed from these rats for subsequent biochemical analyses. Results: We observed ~60% decrease in creatine levels in the livers from EtOH-fed rats as compared to controls. The reduction in creatine levels correlated with lower SAM:SAH ratio observed in the livers of the EtOH-fed rats. Further, in vitro experiments with cell-free system and hepatic cells revealed it is indeed elevated SAH and lower SAM:SAH ratio that directly impairs GAMT activity and significantly reduces creatine synthesis. EtOH intake also slightly decreases the hepatocellular uptake of the creatine precursor, guanidinoacetate (GAA), and the GAMT enzyme expression that could additionally contribute to reduced liver creatine synthesis. The consequences of impaired hepatic creatine synthesis by chronic EtOH consumption include (i) increased toxicity due to GAA accumulation in the liver; (ii) reduced protection due to lower creatine levels in the liver, and (iii) reduced circulating and cardiac creatine levels. Conclusions: Chronic EtOH consumption affects the hepatic creatine biosynthetic pathway leading to detrimental consequences not only in the liver but could also affect distal organs such as the heart that depend on a steady supply of creatine from the liver.

Original languageEnglish (US)
Pages (from-to)641-648
Number of pages8
JournalAlcoholism: Clinical and Experimental Research
Volume38
Issue number3
DOIs
StatePublished - Mar 2014

Fingerprint

Guanidinoacetate N-Methyltransferase
Creatine
Biosynthesis
Alcohol Drinking
Rats
Liver
Alcohols
S-Adenosylmethionine
S-Adenosylhomocysteine
Methyltransferases
Cell-Free System
Biosynthetic Pathways
Nutrition

Keywords

  • Alcohol
  • Guanidinoacetate methyltransferase S-adenosylhomocysteine
  • Hepatic
  • L-arginine:glycine amidinotransferase
  • S-adenosylmethionine
  • S-adenosylmethionine:S-adenosylhomocysteine ratio
  • Tubercidin

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Alcohol consumption decreases rat hepatic creatine biosynthesis via altered guanidinoacetate methyltransferase activity. / Kharbanda, Kusum; Todero, Sandra L.; Moats, Jordan C.; Harris, Ryan M.; Osna, Natalia A; Thomes, Paul G; Tuma, Dean J.

In: Alcoholism: Clinical and Experimental Research, Vol. 38, No. 3, 03.2014, p. 641-648.

Research output: Contribution to journalArticle

@article{0e96ec2a504e4f5ebc258b167b4d2003,
title = "Alcohol consumption decreases rat hepatic creatine biosynthesis via altered guanidinoacetate methyltransferase activity",
abstract = "Background: We have previously shown that decreased S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio generated in livers of alcohol-fed rats can impair the activities of many SAM-dependent methyltransferases. One such methyltransferase is guanidinoacetate methyltransferase (GAMT) that catalyzes the last step of creatine synthesis. As GAMT is the major utilizer of SAM, the purpose of the study was to examine the effects of ethanol (EtOH) on liver creatine levels and GAMT activity. Methods: Male Wistar rats were pair-fed the Lieber-DeCarli control and EtOH diet for 4 to 5 weeks. At the end of the feeding regimen, the liver, kidney, and blood were removed from these rats for subsequent biochemical analyses. Results: We observed ~60{\%} decrease in creatine levels in the livers from EtOH-fed rats as compared to controls. The reduction in creatine levels correlated with lower SAM:SAH ratio observed in the livers of the EtOH-fed rats. Further, in vitro experiments with cell-free system and hepatic cells revealed it is indeed elevated SAH and lower SAM:SAH ratio that directly impairs GAMT activity and significantly reduces creatine synthesis. EtOH intake also slightly decreases the hepatocellular uptake of the creatine precursor, guanidinoacetate (GAA), and the GAMT enzyme expression that could additionally contribute to reduced liver creatine synthesis. The consequences of impaired hepatic creatine synthesis by chronic EtOH consumption include (i) increased toxicity due to GAA accumulation in the liver; (ii) reduced protection due to lower creatine levels in the liver, and (iii) reduced circulating and cardiac creatine levels. Conclusions: Chronic EtOH consumption affects the hepatic creatine biosynthetic pathway leading to detrimental consequences not only in the liver but could also affect distal organs such as the heart that depend on a steady supply of creatine from the liver.",
keywords = "Alcohol, Guanidinoacetate methyltransferase S-adenosylhomocysteine, Hepatic, L-arginine:glycine amidinotransferase, S-adenosylmethionine, S-adenosylmethionine:S-adenosylhomocysteine ratio, Tubercidin",
author = "Kusum Kharbanda and Todero, {Sandra L.} and Moats, {Jordan C.} and Harris, {Ryan M.} and Osna, {Natalia A} and Thomes, {Paul G} and Tuma, {Dean J.}",
year = "2014",
month = "3",
doi = "10.1111/acer.12306",
language = "English (US)",
volume = "38",
pages = "641--648",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Alcohol consumption decreases rat hepatic creatine biosynthesis via altered guanidinoacetate methyltransferase activity

AU - Kharbanda, Kusum

AU - Todero, Sandra L.

AU - Moats, Jordan C.

AU - Harris, Ryan M.

AU - Osna, Natalia A

AU - Thomes, Paul G

AU - Tuma, Dean J.

PY - 2014/3

Y1 - 2014/3

N2 - Background: We have previously shown that decreased S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio generated in livers of alcohol-fed rats can impair the activities of many SAM-dependent methyltransferases. One such methyltransferase is guanidinoacetate methyltransferase (GAMT) that catalyzes the last step of creatine synthesis. As GAMT is the major utilizer of SAM, the purpose of the study was to examine the effects of ethanol (EtOH) on liver creatine levels and GAMT activity. Methods: Male Wistar rats were pair-fed the Lieber-DeCarli control and EtOH diet for 4 to 5 weeks. At the end of the feeding regimen, the liver, kidney, and blood were removed from these rats for subsequent biochemical analyses. Results: We observed ~60% decrease in creatine levels in the livers from EtOH-fed rats as compared to controls. The reduction in creatine levels correlated with lower SAM:SAH ratio observed in the livers of the EtOH-fed rats. Further, in vitro experiments with cell-free system and hepatic cells revealed it is indeed elevated SAH and lower SAM:SAH ratio that directly impairs GAMT activity and significantly reduces creatine synthesis. EtOH intake also slightly decreases the hepatocellular uptake of the creatine precursor, guanidinoacetate (GAA), and the GAMT enzyme expression that could additionally contribute to reduced liver creatine synthesis. The consequences of impaired hepatic creatine synthesis by chronic EtOH consumption include (i) increased toxicity due to GAA accumulation in the liver; (ii) reduced protection due to lower creatine levels in the liver, and (iii) reduced circulating and cardiac creatine levels. Conclusions: Chronic EtOH consumption affects the hepatic creatine biosynthetic pathway leading to detrimental consequences not only in the liver but could also affect distal organs such as the heart that depend on a steady supply of creatine from the liver.

AB - Background: We have previously shown that decreased S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio generated in livers of alcohol-fed rats can impair the activities of many SAM-dependent methyltransferases. One such methyltransferase is guanidinoacetate methyltransferase (GAMT) that catalyzes the last step of creatine synthesis. As GAMT is the major utilizer of SAM, the purpose of the study was to examine the effects of ethanol (EtOH) on liver creatine levels and GAMT activity. Methods: Male Wistar rats were pair-fed the Lieber-DeCarli control and EtOH diet for 4 to 5 weeks. At the end of the feeding regimen, the liver, kidney, and blood were removed from these rats for subsequent biochemical analyses. Results: We observed ~60% decrease in creatine levels in the livers from EtOH-fed rats as compared to controls. The reduction in creatine levels correlated with lower SAM:SAH ratio observed in the livers of the EtOH-fed rats. Further, in vitro experiments with cell-free system and hepatic cells revealed it is indeed elevated SAH and lower SAM:SAH ratio that directly impairs GAMT activity and significantly reduces creatine synthesis. EtOH intake also slightly decreases the hepatocellular uptake of the creatine precursor, guanidinoacetate (GAA), and the GAMT enzyme expression that could additionally contribute to reduced liver creatine synthesis. The consequences of impaired hepatic creatine synthesis by chronic EtOH consumption include (i) increased toxicity due to GAA accumulation in the liver; (ii) reduced protection due to lower creatine levels in the liver, and (iii) reduced circulating and cardiac creatine levels. Conclusions: Chronic EtOH consumption affects the hepatic creatine biosynthetic pathway leading to detrimental consequences not only in the liver but could also affect distal organs such as the heart that depend on a steady supply of creatine from the liver.

KW - Alcohol

KW - Guanidinoacetate methyltransferase S-adenosylhomocysteine

KW - Hepatic

KW - L-arginine:glycine amidinotransferase

KW - S-adenosylmethionine

KW - S-adenosylmethionine:S-adenosylhomocysteine ratio

KW - Tubercidin

UR - http://www.scopus.com/inward/record.url?scp=84896283092&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896283092&partnerID=8YFLogxK

U2 - 10.1111/acer.12306

DO - 10.1111/acer.12306

M3 - Article

C2 - 24256608

AN - SCOPUS:84896283092

VL - 38

SP - 641

EP - 648

JO - Alcoholism: Clinical and Experimental Research

JF - Alcoholism: Clinical and Experimental Research

SN - 0145-6008

IS - 3

ER -