Differential regulation of membrane associated-growth hormone binding protein (MA-GHBP) and growth hormone receptor (GHR) expression by growth hormone (GH) in mouse liver

Growth hormone (GH) binding to GH receptor (GHR) is the initial step that leads to the physiological functions of the hormone. Proteolytical cleavage of the GHR in humans and rabbits and alternative processing of the GHR transcript in rodents generates circulating growth hormone binding protein (GHBP). Moreover, other GHR truncated forms that result from alternative processing of the GHR mRNA transcript have been described. These GHR short forms are inserted in the plasma membrane but they are unable to transduce the signal. In rodents, membrane associated-GHBP (MA-GHBP), which accounts for a significant proportion of liver GH binding capacity, represents the main GHR short form found in membranes, and may therefore function as a negative form of the receptor. In the present study, GHR and MA-GHBP content in liver were analyzed using mutant and transgenic mice expressing different concentrations of growth hormone to evaluate the correlation between GH levels, body weight (BW), GHR and MA-GHBP expression. It was found that GH deficiency was associated with diminished BW, GHR and MA-GHBP expression, while increased GH concentration led to increased BW, GHR and MA-GHBP expression, but MA-GHBP upregulation was more pronounced than the observed increase in GHR expression. Since GHR and MA-GHBP both contribute to liver GH binding capacity, GH-induced enrichment of the dominant negative form would represent a compensatory mechanism triggered by high levels of the hormone. This attempt to attenuate the effects of supraphysiological concentrations of GH may be critical to reduce or prevent their plausible damaging effects on the organism.