CCAAT/enhancer-binding protein P is required for activation of genes for ornithine cycle enzymes by glucocorticoids and glucagon in primary-cultured hepatocytes

Transcription of genes for enzymes of the ornithine cycle is activated by hormones such as glucocorticoids and glucagon, Promoters and enhancers of several genes for the enzymes interact with the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors, and C/EBP beta has been suggested to mediate glucocorticoid response of the gene for arginase, the last enzyme of the cycle. To determine the contribution of C/EBP beta to hormonal regulation of genes for ornithine cycle enzymes, we examined mice with targeted disruption of the C/EBP beta gene. Induction of genes for the enzymes by intraperitoneal injection of dexamethasone and glucagon was almost intact in the liver of C/EBP beta -deficient mice. On the other hand, in primary-cultured hepatocytes derived from C/EBP beta -deficient mice, induction of genes for the first enzyme carbamylphosphate synthetase, as well as for arginase, in response to dexamethasone and/or glucagon was severely impaired. Therefore, C/EBP beta is required for hormonal induction of the genes for ornithine cycle enzymes in primary-cultured hepatocytes, while the deficiency of C/EBP beta is compensated for in vivo. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.