The NAD-dependent protein deacetylase Sirt1 is present in the human anterior pituitary gland where it plays a role in GH transcription

Abstract

One of the best known experimental procedures that extend lifespan and resistance to aging-related diseases is caloric restriction. In yeast, C. elegans and Drosophila, Sir2 was shown to mediate the lifespan extending effect of caloric restriction. Sir2 and its mammalian homologue Sirt1 are NAD-dependent protein deacetylases that are sensitive to changes in cellular energy levels. Caloric restriction was shown to decrease plasma GH and IGF-I in rats, but the mechanism has never been understood. In the present study Sirt1 transcript was detected in the human anterior pituitary gland, and Sirt1 protein was found to be widely present in all endocrine cell types, as determined by immunohistochemistry. In order to investigate the effect of Sirt1 on GH expression, the rat mammosomatotrophinoma GH3 cells were transfected with a reporter vector bearing the GH promoter upstream the luciferase gene and Sirt1 was knocked down by RNA interference. Knocking down Sirt1 increased GH relative luciferase activity. GH transcription is under the control of the cAMP pathway. Sirt1 immunoprecipitated with Creb-binding protein (CBP), and was found to block CBP activity. It is possible that this is the mechanism mediating the inhibitory action of Sirt1 on GH transcription. These preliminary data show that Sirt1 is expressed in the anterior pituitary gland, where it can regulate GH synthesis in response to metabolic changes.