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File Download Organic Solute Transporter α-β Protects Ileal Enterocytes From Bile Acid–Induced Injury Courtney B. Ferrebee, Emory University Jianing Li, Emory University Jamie Haywood, Wake Forest University Kimberly Pachura, Emory University Brian Robinson, Emory University Benjamin H. Hinrichs, Emory University Rheinallt M Jones, Emory University Anuradha Rao, Emory University Paul A. Dawson, Emory University Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: Volume 5, Number 4 Publisher: Elsevier: Creative Commons Attribution Non-Commercial No-Derivatives License | 2018-01-12, Pages 499-522 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1016/j.jcmgh.2018.01.006 Permanent URL: https://pid.emory.edu/ark:/25593/t0jts Final published version: http://dx.doi.org/10.1016/j.jcmgh.2018.01.006 Copyright information: © 2018 The Authors This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/). Accessed September 29, 2021 5:17 AM EDT ORIGINAL RESEARCH Organic Solute Transporter a-b Protects Ileal Enterocytes From Bile Acid–Induced Injury Courtney B. Ferrebee,1,2 Jianing Li,1 Jamie Haywood,2 Kimberly Pachura,1 Brian S. Robinson,3 Benjamin H. Hinrichs,3 Rheinallt M. Jones,1 Anuradha Rao,1 and Paul A. Dawson1,4 1Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, 3Department of Pathology, Emory University, Atlanta, Georgia; 2Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina; 4Children’s Healthcare of Atlanta, Atlanta, Georgia – SUMMARY acid activated farnesoid X receptor target genes in neonatal Osta-/- mice. Expression of reduced nicotinamide adenine – Enterocyte bile acid stasis in early postnatal life results in bile dinucleotide phosphate oxidase-1 and Nrf2 anti-oxidant fi acid–induced cytotoxicity, oxidative stress, and a restitution responsive genes were increased signi cantly in neonatal a-/- response. Blocking enterocyte apical membrane bile acid Ost mice at these postnatal time points. Bile acids also uptake protects against ileal epithelial injury. activated Nrf2 in Drosophila enterocytes and enterocyte- specific knockdown of Nrf2 increased sensitivity of flies to bile acid–induced toxicity. Inactivation of the Asbt prevented BACKGROUND & AIMS: Ileal bile acid absorption is mediated the changes in ileal morphology and induction of anti-oxidant a-/- by uptake via the apical sodium-dependent bile acid trans- response genes in Ost mice. porter (ASBT), and export via the basolateral heteromeric CONCLUSIONS: Early in postnatal development, loss of Osta a b a b organic solute transporter - (OST -OST ). In this study, we leads to bile acid accumulation, oxidative stress, and a resti- investigated the cytotoxic effects of enterocyte bile acid stasis tution response in ileum. In addition to its essential role in a-/- in Ost mice, including the temporal relationship between maintaining bile acid homeostasis, Osta-Ostb functions to intestinal injury and initiation of the enterohepatic circulation protect the ileal epithelium against bile acid–induced injury. of bile acids. NCBI Gene Expression Omnibus: GSE99579. (Cell Mol Gastro- – METHODS: Ileal tissue morphometry, histology, markers of cell enterol Hepatol 2018;5:499 522; https://doi.org/10.1016/ proliferation, gene, and protein expression were analyzed in j.jcmgh.2018.01.006) male and female wild-type and Osta-/- mice at postnatal days 5, 10, 15, 20, and 30. Osta-/-Asbt-/- mice were generated and Keywords: Ileum; Reactive Oxygen Species; Nuclear Factor analyzed. Bile acid activation of intestinal Nrf2-activated path- Erythroid-Derived 2-Like 2; Neonate; Drosophila. ways was investigated in Drosophila. RESULTS: As early as day 5, Osta-/- mice showed significantly n the hepatocyte, bile acids are synthesized from increased ileal weight per length, decreased villus height, and I cholesterol, conjugated to taurine or glycine, and then increased epithelial cell proliferation. This correlated with secreted into bile for storage in the gallbladder or passage premature expression of the Asbt and induction of bile into the small intestine. During a meal, bile acids are present 500 Ferrebee et al Cellular and Molecular Gastroenterology and Hepatology Vol. 5, No. 4 in high concentration in the small intestine where they act hepatocyte injury include induction of endoplasmic reticu- as detergents to facilitate absorption of fats, fat-soluble vi- lum stress and mitochondrial damage.14,17–20 However, tamins, and cholesterol. After reaching the distal small in- more recent studies have suggested that intracellular testine, bile acids are almost quantitatively reabsorbed by conjugated bile acids indirectly stimulate hepatocyte che- ileal enterocytes, and carried back to the liver in the portal mokine expression and induce liver injury via a hepatocyte- circulation for uptake and resecretion into bile.1 This initiated inflammatory response.15,21 Beyond the liver and enterohepatic circulation functions to safely store and then biliary tract, there is a substantial flux of bile acids across promptly deliver bile acids to the intestinal lumen, while the ileal epithelium. Surprisingly little is known regarding limiting the systemic distribution and potential cytotoxicity how the ileal enterocyte is protected against bile acid of these amphipathic molecules. The major membrane car- cytotoxicity.22–24 In Osta-/- mice, we hypothesize that riers that maintain the enterohepatic circulation of bile acids continued ileal enterocyte Asbt-mediated bile acid uptake in are known and include specific transporters expressed on the absence of a mechanism for efficient export will in- the sinusoidal and canalicular membranes of the hepatocyte, crease intracellular bile acid levels. This in turn can pro- and on the apical brush border and basolateral membranes mote bile acid–induced injury and drive the apparent of the ileal enterocyte.2 In ileum, the apical sodium- epithelial damage observed. The ontogeny of bile acid dependent bile acid transporter (ASBT) (gene symbol: synthesis and transport has been carefully described in rats SLC10A2) and the heteromeric organic solute transporter and mice, with an abrupt induction of ileal Asbt expression a-b (OSTa-OSTb) (gene symbols: SLC51A-SLC51B) mediate coinciding with concentrative bile acid uptake between these steps, respectively.3,4 ASBT mutations in human be- postnatal days 17 and 21.25–28 If bile acids are important ings or inactivation of the Asbt in mice yields a primary bile for the morphologic changes observed in Osta-/- mice, then acid malabsorption phenotype that is characterized by Asbt-mediated bile acid uptake into the ileal enterocytes impaired intestinal bile absorption, induction of hepatic bile should precede or coincide with the intestinal injury. To acid synthesis, and increased fecal loss of bile acids in the test this hypothesis, we investigated the temporal rela- absence of ileal histologic or ultrastructural changes.5–7 tionship in Osta-/- mice between the intestinal adaptive Inactivation of Osta in mice also impairs intestinal bile response and initiation of active ileal bile acid absorption, acid absorption. However, unlike Asbt-/- mice or patients and whether inactivation of the Asbt is protective in Osta-/- with ASBT mutations, Osta-/- mice show a complex pheno- mice. The potential mechanisms underlying the postulated type that includes a paradoxic reduction in hepatic bile acid bile acid–induced injury also were explored with a reduc- synthesis and ileal hypertrophy.8,9 The changes in bile tionist approach using the Drosophila model organism. acid metabolism are associated with altered gut-liver bile acid signaling through the farnesoid X receptor (FXR)- Materials and Methods fibroblast growth factor (FGF)15/19-FGF receptor 4 Animals, Treatments, and Tissue Collection pathway, and inactivation of FXR in Osta-/- mice reverses the The Institutional Animal Care and Use Committees at the reductions in hepatic Cyp7a1 expression and bile acid syn- – Wake Forest School of Medicine and Emory University thesis.8 10 By contrast, the altered ileal morphology in approved these experiments. The Osta-/- and Asbt-/- mice Osta-/- mice is not affected by inactivation of FXR.11 The ileal were generated as previously described.7,8 The mice were changes observed in Osta-/- mice, which include villous backcrossed onto a C57BL/6J background for 8 generations blunting, are typically associated with epithelial damage and and compared with wild-type (WT) littermates on the same subsequent healing.12 Although adult Osta-/- mice do not background. The Osta-/-Asbt-/- mice were generated by show overt symptoms of intestinal injury, such as increased cross-breeding the corresponding null mice and compared inflammatory gene expression in ileum, bleeding, or diar- with lines generated from WT, Osta-/-, and Asbt-/- littermates rhea, newborn Osta-/- mice show a small postnatal growth as controls. The mice were group-housed in ventilated cages deficiency, and this may coincide with the onset of injury or initiation of an adaptive response.8,9 The cause of the altered ileal morphology in Osta-/- mice Abbreviations used in this paper: ARE, anti-oxidant response element; Asbt, apical sodium-dependent bile acid transporter; CDCA, cheno- is unclear, but may involve bile acids. Conjugated bile acids deoxycholic acid; cRNA, complementary RNA; FGF, fibroblast
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