Amino acid metabolism in the liver and pancreas

da Silva, Robin (2012) Amino acid metabolism in the liver and pancreas. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

This thesis presents four research papers dealing with the metabolism of creatine and amino acids in the liver and pancreas. Creatine is synthesized in two enzymatic reactions that utilize the amino acids arginine, glycine and methionine. The first step in creatine synthesis is the transfer of the amidino group of arginine onto the amine of glycine resulting in ornithine and guanidinoacetate, catalyzed by the enzyme arginine:glycine amidinotransferase. The guanidinoacetate can then be methylated by the universal methyl donor S-adenosylmethionine to form creatine and S-adenosylhomocysteine. The first two papers investigate the role of the rat liver and pancreas in creatine biosynthesis respectively, using both in vivo and in vitro techniques. I provide evidence that the liver does not perform the first step of creatine synthesis but does perform the second step and has the capacity to methylate all of the guanidinoacetate that is synthesized in the kidney. The third paper examines the effects of creatine-supplementation in high-fat diet fed rat model of non-alcoholic fatty liver disease. This paper shows that dietary creatine-supplementation prevents the accumulation of lipids in the livers of rats fed high-fat diets as well as a number of the negative observations associated with non-alcoholic fatty liver disease. The fourth paper deals with the fate of perivenous hepatocytes in rats that have undergone portacaval shunts. It is known that the expression of hepatic glutamine synthetase is markedly down-regulated in portacaval anastomosis and it has been suggested that there is a loss of the perivenous hepatocytes which contain this enzyme activity. I provide evidence that ornithine aminotransferase activity and the expression of an ammonium transporter RhBG, proteins known to be localized in the perivenous cell population, are increased and unchanged respectively in rats with portacaval anastomosis. The papers presented in this thesis a) show the major role of the liver in creatine synthesis, b) demonstrate a possible role for the pancreas in creatine synthesis, c) introduce creatine as a potential treatment for fatty liver disease, and d) demonstrate that perivenous hepatocytes are not lost during portacaval shunting. These constitute important contributions to the current body of literature relating to creatine metabolism and hepatic zonation.

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