HYPOGLYCEMIA-ASSOCIATED HYPERAMMONEMIA CAUSED BY IMPAIRED EXPRESSION OF ORNITHINE CYCLE ENZYME GENES IN C EBP-ALPHA KNOCKOUT MICE/

Ammonia produced by amino acid metabolism is detoxified through conver sion into urea by the ornithine cycle in the Liver, whereas carbon ske letons of amino acids are converted to glucose by gluconeogenic enzyme s. Promoter and enhancer sequences of several genes for ornithine cycl e enzymes interact with members of the CCAAT/enhancer-binding protein (C/EBP) transcription factor family. Disruption of the C/EBP alpha gen e in mice causes hypoglycemia associated with the impaired expression of gluconeogenic enzymes. Here we examined the expression of ornithine cycle enzyme genes in the livers of C/EBP alpha-deficient mice. mRNA levels for the first, third, fourth, and fifth enzymes of five enzymes in the cycle were decreased in C/EBP alpha-deficient mice. Protein le vels for the first, second, fourth, and fifth enzymes were also decrea sed. In situ hybridization analysis revealed that the enzyme mRNAs wer e distributed normally in the periportal region but were disordered in C/EBP alpha-deficient mice with relatively higher mRNA levels in the midlobular region. Blood ammonia concentrations in the mutant mice wer e severalfold higher than in wild-type mice. Thus, C/EBP alpha is cruc ial for ammonia detoxification by ornithine cycle enzymes and for coor dination of gluconeogenesis and urea synthesis.