glutaminase and Ornithine-Carbamoyltransferase-Deficiency-Disease

Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otc

Topics: Ammonia; Animals; Disease Models, Animal; Glutaminase; Glutamine; Humans; Hyperammonemia; Liver; Mice; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Urea; Urea Cycle Disorders, Inborn

The liver plays a critical role in maintaining ammonia homeostasis. Urea cycle defects, liver injury, or failure and glutamine synthetase (GS) deficiency result in hyperammonemia, serious clinical conditions, and lethality. In this study we used a mouse model with a defect in the urea cycle enzyme ornithine transcarbamylase (Otcspf-ash) to test the hypothesis that glucagon receptor inhibition using a monoclonal blocking antibody will reduce the hyperammonemia and associated lethality induced by a high-protein diet, which exacerbates disease. We found reduced expression of glutaminase, which degrades glutamine and increased expression of GS in livers of Otcspf-ash mice treated with the glucagon receptor blocking antibody. The gene expression changes favor ammonia consumption and were accompanied by increased circulating glutamine levels and diminished hyperammonemia. Otcspf-ash mice treated with the glucagon receptor-blocking antibody gained lean and body mass and had increased survival. These data suggest that glucagon receptor inhibition using a monoclonal antibody could reduce the risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle, liver injury, or failure and GS deficiency.

Topics: Amino Acids; Ammonia; Animals; Antibodies, Monoclonal; Body Weight; Gene Expression Regulation; Glutamate-Ammonia Ligase; Glutaminase; Hyperammonemia; Male; Mice; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Receptors, Glucagon