title: Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15.
abstract: Bile acid nuclear receptor farnesoid X receptor (FXR) is a key molecular mediator of many metabolic processes, including the regulation of bile acid, lipid and glucose homeostasis. A significant component of FXR-mediated events essential to its biological activity is attributed to induction of the enteric endocrine hormone fibroblast growth factor (FGF)19 or its rodent ortholog, FGF15. In this report, we compared the properties of human FGF19 and murine FGF15 in the regulation of hepatocarcinogenesis and metabolism in various mouse models of disease.
  
  
  
  Tumorigenicity was assessed in three mouse models (db/db, diet-induced obese, and multi-drug resistance 2 [Mdr2]-deficient) following continuous exposure to FGF19 or FGF15 via adeno-associated viral-mediated gene delivery. Glucose, hemoglobin A1c and β-cell mass were characterized in db/db mice. Oxygen consumption, energy expenditure, and body composition were evaluated in diet-induced obese mice. Serum levels of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase were assessed in Mdr2-deficient mice. Expression profiles of genes encoding key proteins involved in bile acid synthesis and hepatocarcinogenesis were also determined.
  
  
  
  Both FGF15 and FGF19 hormones repressed bile acid synthesis (p<0.001 for both). However, murine FGF15 lacked the protective effects characteristic of human FGF19 in db/db mice with overt diabetes, such as weight-independent HbA1c-lowering and β-cell-protection. Unlike FGF19, FGF15 did not induce hepatocellular carcinomas (HCC) in three mouse models of metabolic diseases (db/db, diet-induced obese, and multi-drug resistance 2 [Mdr2]-deficient mice), even at supra-pharmacological exposure levels.
  
  
  
  Fundamental species-associated differences between FGF19 and FGF15 may restrict the relevance of mouse models for the study of the FXR/FGF19 pathway, and underscore the importance of clinical assessment of this pathway, with respect to both safety and efficacy in humans.
  
  
  
  Activation of the nuclear receptor, FXR, leads to the production of a hormone called fibroblast growth factor 19 (FGF19) and subsequently regulation of multiple metabolic processes. Synthetic activators of FXR have been recently approved or are currently in clinical development for treatment of chronic liver diseases, including primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH). The safety of these activators was partly assessed in mice exposed for prolonged periods of time. However, the results of this study show that mouse FGF15 and human FGF19 exhibit fundamentally different biological activities in mice. This could raise the concern of relying on rodent models for safety assessment of FXR activators. The potential risk of HCC development in patients treated with FXR agonists may need to be monitored.
authors.affiliation: NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhou
authors.affiliation: NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.affiliation: NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: R Marc
authors.initials: RM
authors.lastname: Learned
authors.affiliation: NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Alex M
authors.initials: AM
authors.lastname: DePaoli
authors.affiliation: NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.affiliation: NGM Biopharmaceuticals, Inc., 333 Oyster Point Boulevard, South San Francisco, CA 94080, USA. Electronic address: lling@ngmbio.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Ling
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D063646:Carcinogenesis / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009765:Obesity / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013045:Species Specificity; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D005346:Fibroblast Growth Factors; D006442:Glycated Hemoglobin; D018160:Receptors, Cytoplasmic and Nuclear; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000099150:Receptor, Farnesoid X-Activated; C494087:Stat3 protein, mouse; C108526:fibroblast growth factor 15, mouse; C515447:leptin receptor, mouse
keywords: Bile acids and salts; Body weight; Carcinoma, hepatocellular; Cyp7a1; Diet; FGF15; FGF19; Glucose; Metabolic diseases; Obesity; Receptors, cytoplasmic and nuclear