title: Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.
abstract: Defects in multidrug resistance 3 gene (MDR3), which encodes the canalicular phospholipid flippase, cause a wide spectrum of cholangiopathy phenotypes in humans. Mice deficient in Mdr2 (murine ortholog of MDR3) develop liver diseases that closely reproduce the biochemical, histological, and clinical features of human cholangiopathies such as progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. We hypothesized that modulating bile acid metabolism by the gut hormone fibroblast growth factor 19 (FGF19) may represent a novel approach for treating cholangiopathy and comorbidities. We introduced adeno-associated virus carrying the gene for either the endocrine hormone FGF19 or engineered FGF19 variant M70 to 12-week old Mdr2-deficient mice with fully established disease. Effects on serum levels of liver enzymes, liver histology, and bile acid homeostasis were evaluated. FGF19 and M70 rapidly and effectively reversed liver injury, decreased hepatic inflammation, attenuated biliary fibrosis, and reduced cholecystolithiasis in Mdr2-deficient mice. Mechanistically, FGF19 and M70 significantly inhibited hepatic expression of Cyp7a1 and Cyp27a1, which encode enzymes responsible for the rate-limiting steps in the classic and alternate bile acid synthetic pathways, thereby reducing the hepatic bile acid pool and blood levels of bile acids. Importantly, prolonged exposure to FGF19, but not M70, led to the formation of hepatocellular carcinomas in the Mdr2-deficient mice. Furthermore, M70 ameliorated the hepatosplenomegaly and ductular proliferation that are associated with cholangiopathy.
  
  
  CONCLUSIONS
  These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis.
authors.affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, CA.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhou
authors.affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, CA.
authors.forename: R Marc
authors.initials: RM
authors.lastname: Learned
authors.affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, CA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rossi
authors.affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, CA.
authors.forename: Alex M
authors.initials: AM
authors.lastname: DePaoli
authors.affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, CA.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.affiliation: NGM Biopharmaceuticals, Inc., South San Francisco, CA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ling
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000209:etiology; D015209:Cholangitis, Sclerosing / Q000378:metabolism / Q000628:therapy*; D041761:Cholecystolithiasis / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D015316:Genetic Therapy; D006706:Homeostasis; D050356:Lipid Metabolism; D008113:Liver Neoplasms / Q000209:etiology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data
chemical_list: D001647:Bile Acids and Salts; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors