Hyperglucagonemia in rats results in decreased plasma homocysteine and increased flux through the transsulfuration pathway in liver.
An elevated plasma level of homocysteine is a risk factor for the development of cardiovascular disease. The purpose of this study was to investigate the effect of glucagon on homocysteine metabolism in the rat. Male Sprague-Dawley rats were treated with 4 mg/kg/day (3 injections per day) glucagon for 2 days while control rats received vehicle injections. Glucagon treatment resulted in a 30% decrease in total plasma homocysteine and increased hepatic activities of glycine N-methyltransferase, cystathionine beta-synthase, and cystathionine gamma-lyase. Enzyme activities of the remethylation pathway were unaffected. The 90% elevation in activity of cystathionine beta-synthase was accompanied by a 2-fold increase in its mRNA level. Hepatocytes prepared from glucagon-injected rats exported less homocysteine, when incubated with methionine, than did hepatocytes of saline-treated rats. Flux through cystathionine beta-synthase was increased 5-fold in hepatocytes isolated from glucagon-treated rats as determined by production of (14)CO(2) and alpha-[1-(14)C]ketobutyrate from l-[1-(14)C]methionine. Methionine transport was elevated 2-fold in hepatocytes isolated from glucagon-treated rats resulting in increased hepatic methionine levels. Hepatic concentrations of S-adenosylmethionine and S-adenosylhomocysteine, allosteric activators of cystathionine beta-synthase, were also increased following glucagon treatment. These results indicate that glucagon can regulate plasma homocysteine through its effects on the hepatic transsulfuration pathway.
Jacobs
R L
RL
Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada.
Stead
L M
LM
Brosnan
M E
ME
Brosnan
J T
JT
D000494:Allosteric Regulation; D000818:Animals; D001692:Biological Transport; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D005934:Glucagon / Q000008:administration & dosage / Q000097:blood*; D006710:Homocysteine / Q000097:blood* / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013455:Sulfur / Q000378:metabolism*
D006710:Homocysteine; D013455:Sulfur; D005934:Glucagon; D008715:Methionine; D003541:Cystathionine beta-Synthase