REGULATION OF THE GASTRIC INHIBITORY PEPTIDE GENE

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Gastric inhibitory peptide (GIP) is a 42-amino acid hormone secreted by the K-cell, a specific intestinal endocrine epithelial cell, and was named for its ability to inhibit acid secretion. Subsequent analysis of its physiological properties has demonstrated that GIP is a potent stimulator of endogenous insulin release and that it plays an important role in maintaining glucose and lipid homeostasis. These studies have established GIP as a physiological modulator of metabolic function, providing a vital link between the alimentary tract and other organs, including the liver and pancreas. Despite its importance in nutrient metabolism, little information regarding GIP gene regulation is available. Because hormone gene expression can be modulated at several different steps along the biosynthetic pathway, a thorough analysis of the molecular mechanisms involved in nutrient-regulated GIP biosynthesis would greatly improve our understanding of the biology of this important peptide. In the present proposal, we will proceed sequentially from an examination of GIP gene expression in vivo, by measuring duodenal GIP mRNA after nutrient administration, to an assessment of nutrient-regulated duodenal GIP gene transcription. Finally, during the last portion of the proposal, the molecular mechanisms governing GIP gene transcription will be investigated. Specifically, the aims of this project are: (1) To study nutrient-dependent regulation of GIP gene expression in the rat duodenum by measuring duodenal mucosal GIP and GIP mRNA levels in response to glucose, lipid, and protein meals. After examining GIP gene regulation at the pretranslational level, (2) To examine GIP gene transcription in the rat duodenum following nutrient administration using in vitro nuclear run-on assays. After demonstrating an effect on nutrient-regulated gene transcription, (3) To isolate and characterize the rat GIP gene, which, along with the next goal, will facilitate the identification of and delineation of putative transcriptional regulatory elements in the gene, and (4) To investigate basal and nutrient-stimulated GIP gene transcription and determine the molecular mechanisms involved in nutrient-dependent and tissue-specific transcriptional regulation of the GIP gene. Collectively, the information gained from this proposal will add a significant new dimension to our understanding of the molecular mechanisms involved in GIP gene regulation by nutrients. Moreover, because of the close structural and functional relationship of GIP to other GI peptides, such studies will advance our general understanding of the molecular mechanisms involved in nutrient-regulated hormone gene expression. Finally, these studies should enable us to explore the possibility of differences in GIP gene regulation that could contribute to the pathogenesis of disorders characterized by abnormalities in gastric acid secretion and glucose and lipid homeostasis.