Insulin and heregulin-beta 1 upregulate guanylyl cyclase C expression in rat hepatocytes - Reversal by phosphodiesterase-3 inhibition

Guanylyl cyclase C (GC-C) is the receptor for the hormones guanylin and uro guanylin. Although primarily expressed in the rat intestine, GC-C is also e xpressed in the liver during neonatal or regenerative growth or during the acute phase response. Little is known about the hepatic regulation of GC-C expression. The influence of various hepatic growth or acute phase regulato rs on GC-C expression was evaluated by immunoblot analysis of protein from primary rat hepatocytes grown in a serum-free medium. Insulin and heregulin -beta1 strongly stimulated GC-C expression by 24 h of cell culture. Several different hormones and agents suppressed this action, including transformi ng growth factor beta (TGF-beta), as well as inhibitors of phosphatidylinos itol 3-kinase (PI-3-kinase) and phosphodiesterase 3 (PDE-3, an insulin- and PI-3-kinase-dependent enzyme). The compartmental downregulation of cAMP le vels by PDE-3 may be a critical step in the hormonal action that culminates in GC-C synthesis. (C) 2001 Elsevier Science Inc. All rights reserved.