Antibody-Mediated Inhibition of Fibroblast Growth Factor 19 Results in Increased Bile Acids Synthesis and Ileal Malabsorption of Bile Acids in Cynomolgus Monkeys
Open Access
- 19 January 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 126 (2), 446-456
- https://doi.org/10.1093/toxsci/kfs011
Abstract
Fibroblast growth factor 19 (FGF19) represses cholesterol 7α-hydroxylase (Cyp7α1) and inhibits bile acid synthesis in vitro and in vivo. Previous studies have shown that anti-FGF19 antibody treatment reduces growth of colon tumor xenografts and prevents hepatocellular carcinomas in FGF19 transgenic mice and thus may be a useful cancer target. In a repeat dose safety study in cynomolgus monkeys, anti-FGF19 treatment (3–100 mg/kg) demonstrated dose-related liver toxicity accompanied by severe diarrhea and low food consumption. The mechanism of anti-FGF19 toxicity was investigated using in vitro and in vivo approaches. Our results show that anti-FGF19 antibody had no direct cytotoxic effect on monkey hepatocytes. Anti-FGF19 increased Cyp7α1, as expected, but also increased bile acid efflux transporter gene (bile salt export pump, multidrug resistant protein 2 [MRP2], and MRP3) expression and reduced sodium taurocholate cotransporting polypeptide and organic anion transporter 2 expression in liver tissues from treated monkeys and in primary hepatocytes. In addition, anti-FGF19 treatment increased solute transporter gene (ileal bile acid–binding protein, organic solute transporter α [OST-α], and OST-β) expression in ileal tissues from treated monkeys but not in Caco-2 cells. However, deoxycholic acid (a secondary bile acid) increased expression of FGF19 and these solute transporter genes in Caco-2 cells. Gas chromatography-mass spectrometry analysis of monkey feces showed an increase in total bile acids and cholic acid derivatives. These findings suggest that high doses of anti-FGF19 increase Cyp7α1 expression and bile acid synthesis and alter the expression of bile transporters in the liver resulting in enhanced bile acid efflux and reduced uptake. Increased bile acids alter expression of solute transporters in the ileum causing diarrhea and the enhanced enterohepatic recirculation of bile acids leading to liver toxicity.Keywords
This publication has 44 references indexed in Scilit:
- Bile acids: regulation of synthesisJournal of Lipid Research, 2009
- Bile Acid Sulfation: A Pathway of Bile Acid Elimination and DetoxificationToxicological Sciences, 2009
- Ostα-Ostβ is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liverAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2008
- Bile Acid Transporters: Structure, Function, Regulation and Pathophysiological ImplicationsPharmaceutical Research, 2007
- Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: A resource for investigations into drug dispositionXenobiotica, 2006
- OSTα-OSTβ: A major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epitheliaHepatology, 2005
- The bile salt export pump: molecular properties, function and regulationPflügers Archiv - European Journal of Physiology, 2004
- Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanismsJournal of Hepatology, 2004
- Cellular regulation of hepatic bile acid transport in health and cholestasisHepatology, 2004
- Human Bile Salt Export Pump Promoter Is Transactivated by the Farnesoid X Receptor/Bile Acid ReceptorJournal of Biological Chemistry, 2001