1 40 1 Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. URL Address <a href="http://doi.org/10.1093/toxsci/kfy031" target="_blank" rel="noreferrer noopener">http://doi.org/10.1093/toxsci/kfy031</a> Rights Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s). Pages 265-278 Issue 1 Volume 163 Search for Full-text Locate full-text within NEOMED Library's e-journal collections <p>Users with a NEOMED Library login can search for full-text journal articles at the following url: <a href="https://libraryguides.neomed.edu/home">https://libraryguides.neomed.edu/home</a></p> Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Bile Acid Sequestration by Cholestyramine Mitigates FGFR4 Inhibition-Induced ALT Elevation Publisher An entity responsible for making the resource available Toxicological Sciences Date A point or period of time associated with an event in the lifecycle of the resource 2018 2018-05 Subject The topic of the resource 7alpha-hydroxy-4-cholesten-3-one; aminotransferase; aspartate-aminotransferase isozymes; bile acids; Cyp7a1; FGF19; fibroblast-growth-factor; fibroblast-growth-factor; hepatocellular carcinoma; identification; induced liver-injury; Klotho beta; lipophilicity; liver injury; mitigation; nuclear receptor; serum; sinusoidal endothelial-cells; suppression; tgr5; Toxicology Creator An entity primarily responsible for making the resource Schadt H S; Wolf A; Mahl J A; Wuersch K; Couttet P; Schwald M; Fischer A; Lienard M; Emotte C; Teng C H; Skuba E; Richardson T A; Manenti L; Weiss A; Porta D G; Fairhurst R A; Kullak-Ublick G A; Chibout S D; Pognan F; Kluwe W; Kinyamu-Akunda J Description An account of the resource The FGF19- fibroblast growth factor receptor (FGFR4)-beta Klotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1., elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels. Identifier An unambiguous reference to the resource within a given context <a href="http://doi.org/10.1093/toxsci/kfy031" target="_blank" rel="noreferrer noopener">10.1093/toxsci/kfy031</a> Format The file format, physical medium, or dimensions of the resource Journal Article 2018 7alpha-hydroxy-4-cholesten-3-one aminotransferase aspartate-aminotransferase isozymes BILE acids Chibout S D Couttet P CYP7A1 Emotte C Fairhurst R A FGF19 fibroblast-growth-factor Fischer A Hepatocellular carcinoma identification induced liver-injury Journal Article Kinyamu-Akunda J Klotho beta Kluwe W Kullak-Ublick G A Lienard M lipophilicity Liver injury Mahl J A Manenti L mitigation Nuclear Receptor Pognan F Porta D G Richardson T A Schadt H S Schwald M serum sinusoidal endothelial-cells Skuba E suppression Teng C H TGR5 Toxicological Sciences Toxicology Weiss A Wolf A Wuersch K