Graduate Thesis Or Dissertation
 

The effect of dietary compounds on human cathelicidin antimicrobial peptide gene expression mediated through farnesoid X receptor and its potential role in gastrointestinal health

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  • The human cathelicidin antimicrobial peptide (CAMP) is a broad spectrum microbicidal agent and modulator of both the innate and adaptive immune system. It is induced by 1,25-dihydroxyvitamin D (1,25(OH)₂D₃) through activation of the vitamin D receptor (VDR) and primary bile salts through activation of the xenobiotic nuclear receptor farnesoid X receptor (FXR). Both receptors are expressed by enterohepatic and gastrointestinal (GI) tissues and play important roles in GI immunity and homeostasis. It has been demonstrated by us and others that plant polyphenol xanthohumol (XN) acts as an FXR ligand, but its regulation of CAMP gene expression has not been determined. We hypothesize that plant polyphenols obtained in the diet act as ligands for FXR and regulate expression of the CAMP gene in the GI tract thereby promoting gastrointestinal health through improved barrier defense against infection and inflammation. In this study, we demonstrate that XN induces BSEP (bile acid export pump) and human CAMP promoter activity via FXR. This activation appears to require some combination of the vitamin D response element (VDRE) site in the CAMP promoter and a potential FXR response element (FXRE) located in the third exon of the gene. In addition, XN and its metabolite 8-prenylnaringenin (8-PN) induced the mRNA expression of several FXR target genes including: BSEP, SHP (small heterodimer partner), IBABP (ileal bile acid binding protein), CAMP and FXR in biliary carcinoma cell lines. Combinations of 1,25(OH)₂D₃ and either XN or 8-PN cooperatively induced endogenous CAMP gene expression in cells. We conclude that the plant polyphenol XN and its metabolite 8-PN act as FXR ligands and regulate expression of the human CAMP gene alone or in combination with 1,25(OH)₂D₃. A second distinct project used immunohistochesmitry (IHC), Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) to characterize a transgenic mouse that carries the human CAMP gene. In the transgenic mice fed a normal diet, the human CAMP gene is expressed in immune and epithelial barrier cells and treatment of tissues with 1,25(OH)₂D₃, including those from the GI tract, induced expression of the human, but not the mouse gene. This study advances our understanding of human CAMP gene regulation by FXR and also helps establish the mouse as a reliable model system that can be used in future studies to determine the importance of CAMP gene expression in human health.
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