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The Role of OSTα-OSTβ and Bile Acid Transport in Intestinal Disorders Aand Metabolic Disease

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Over the past 60 years, the study of bile acids has evolved from an esoteric source of fascination for chemists to becoming a field of enormous potential and discovery. Among their important physiological properties, bile acids function as critical detergents to solubilize biliary and dietary lipids. However, these same detergent properties of bile acids also contribute to the pathophysiology and progression of disease. Although bile acids are synthesized in the liver, bile acid transporters located throughout the enterohepatic system (kidneys, liver, gallbladder, intestine) are critical for maintenance of the bile acid pool and for bile acid homeostasis. An essential lynchpin of the EHC of bile acids is the active reabsorption from the distal small intestine, whereby almost 95% of the bile acids are reclaimed and sent back to the liver for secretion into bile. This vital process is facilitated by special transporters, the ASBT and OST-OST. Inherited or acquired defects in hepatic bile acid export, termed cholestasis, results in bile acid accumulation in hepatocytes and is a well-described form of liver injury and disease. In contrast to liver, it was unknown whether bile acid accumulation in intestinal enterocytes can also lead to disease. Blocking ileal export of bile acids by inactivating the basolateral intestinal transporter, OST-OST, results in villus blunting and changes in crypt-villus architecture suggestive of mucosal injury and restitution. To address the underlying molecular mechanisms of this phenotype, the ontogeny of the intestinal phenotype and intestinal bile acid absorption was investigated in OST null mice. As early as postnatal day 5, the ileum of OST null mice exhibits villus blunting, increased crypt depth, with significant increases in cell proliferation, as well as apoptosis. OST null mice also show increase ileal mRNA and protein levels for the ASBT and bile acid-activated FXR target genes such as IBABP, suggesting an increase in ileal enterocyte bile acid accumulation. These changes correlated with increased mRNA levels of NOX1 and Nrf2 target genes, suggesting increased oxidative stress. Inactivation of the ASBT in OST null mice leads to a restoration of a normal ileal crypt-villus architecture, and attenuation of the changes in cell proliferation, apoptosis, and expression of oxidative stress-associated genes. Altogether, the results suggest that loss of OST-OST leads to an early induction of ASBT-mediated bile acid uptake and accumulation of cytotoxic bile acids, which is countered by induction of Nrf2/anti-oxidant response genes and increases in cell proliferation and apoptosis. Overall, this study shows the potential for bile acid cytotoxicity in the intestine and provides insights the mechanisms for cytoprotection and mucosal healing.
Ferrebee, Courtney (author)
Dawson, Paul A (committee chair)
Kock, Nancy (committee member)
Parks, John (committee member)
Rudel, Lawrence (committee member)
Zhu, Xuewei (committee member)
Mensa-Wilmot, Kojo (committee member)
2017-06-15T08:35:52Z (accessioned)
2019-06-14T08:30:11Z (available)
2017 (issued)
Molecular Medicine and Translational Science (discipline)
2019-06-14 (terms)
http://hdl.handle.net/10339/82188 (uri)
en (iso)
Wake Forest University
The Role of OSTα-OSTβ and Bile Acid Transport in Intestinal Disorders Aand Metabolic Disease

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