The apical sodium-dependent bile acid transporter (ASBT) is the major carrier protein involved in intestinal reclamation of bile salts. Inactivating mutations in humans and mice lead to pathologic bile acid induced diarrhea, while partial inhibition of ASBT-mediated transport can be used to treat hypercholesterolemia and cholestasis. NIH supported investigations in my laboratory have advanced our understanding of the molecular regulation of ASBT, with AP-1 and Farnesoid X-Receptor playing critical regulatory roles. We have recently shown in enterocytes and cholangiocytes that AP-1 and FXR-mediated bile acid regulatory pathways are also influenced by FGF-19 via two newly described membrane signaling proteins, ss-Klotho and Fibroblast Growth Factor Receptor 4 (FGFR4). The biological relevance of regulation by AP-1 is readily apparent in our preliminary analysis of a c-fos null mouse, where ileitis is associated with paradoxical up-regulation of ASBT and more pronounced cellular injury. We propose that the repression of ASBT in the setting of intestinal inflammation is cytoprotective. ASBT expression during normal development is controlled by alterations in mRNA stability, although the precise mechanisms of this aspect of regulation need to be elucidated. Our continued studies of ASBT regulation will be of great significance in light of its crucial role in human health and disease. The proposed studies will focus on elucidating the molecular mechanisms responsible for transcriptional and post-transcriptional regulation of ASBT and translating our in vitro findings to in vivo models. To accomplish these goals the following specific aims are proposed:
Aim 1 : To test the hypothesis that FGF15/19 and FGFR4/ss-klotho mediate regulation of ASBT in enterocytes and cholangiocytes via interrelated and specific signal transduction pathways.
Aim 2 : To test the hypothesis that the RNA binding protein HuR regulates the ontogeny of ASBT via changes in mRNA stability.
Aim 3 : To test the hypothesis that c-fos-mediated regulation of ASBT plays a critical role in the inflammatory reaction to acute ileitis and in response to FGF-19.
SBT, a protein found in the last portion of the small intestine, plays an important role in liver and intestinal function. Regulation of the expression of ASBT can impact on liver disease and cholesterol metabolism. These studies will advance our understanding of the regulation of ASBT and provide new ways to understand and treat intestinal and liver diseases.
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