Short chain fatty acids (SCFAs), acetate, propionate and butyrate, produced by bacterial fermentation of non-absorbable carbohydrates in the colon are the preferred nutrients for colonocytes. SCFAs have been shown to enhance colonic salt and water absorption, ameliorate intestinal inflammation, act as anti-tumor agents, and are critical for the maintenance of epithelial integrity. SCFA availability in the colonic lumen is known to vary with dietary composition, intestinal disease and antibiotic use. Therefore, it is likely that SCFA absorption is regulated to overcome alterations in luminal SCFA levels. During the last 4 years, extensive studies performed by us provide compelling and novel evidence for both short-term and transcriptional regulation of MCT1 in the human intestine. To date, however, the molecular mechanisms involved in acute and long-term regulation of the human intestinal SCFA absorption via MCT1 are not well understood. Our preliminary studies, utilizing Caco2 cell monolayers as an experimental model for the human intestine, demonstrated differential regulation of MCT1 mediated butyrate uptake by acute treatment with gastrointestinal hormones: serotonin (5-HT) and somatostatin (SST). Our preliminary studies also provide strong evidence for the transcriptional regulation of MCT1 promoter by protein kinase C and luminal butyrate itself. To understand the cellular and molecular mechanisms underlying acute and transcriptional regulation of MCT1, three specific aims have been designed: 1. Examine acute effects of 5-HT and SST on MCT1 activity in Caco2 and NCM460 (model human intestinal monolayer) cells with respect to luminal/serosal treatment, time course, kinetics and the receptor subtypes involved. 2. Elucidate signaling and membrane recycling mechanisms involved in MCT1 regulation by 5-HT and SST utilizing pharmacological and molecular approaches as well as live cell imaging. 3. Investigate mechanisms of transcriptional regulation of MCT1 by protein kinase C and its substrate butyrate with respect to transcription factors, cis-elements and signaling pathways involved. Our planned studies are of great significance for elucidating the molecular mechanisms of SCFA absorption in the human colon for a better understanding of their roles in normal physiology and pathophysiology of colonic disorders e.g. diarrheal and inflammatory diseases. ? ?
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