title: A nontumorigenic variant of FGF19 treats cholestatic liver diseases.
abstract: Hepatic accumulation of bile acids is central to the pathogenesis of cholestatic liver diseases. Endocrine hormone fibroblast growth factor 19 (FGF19) may reduce hepatic bile acid levels through modulation of bile acid synthesis and prevent subsequent liver damage. However, FGF19 has also been implicated in hepatocellular carcinogenesis, and consequently, the potential risk from prolonged exposure to supraphysiological levels of the hormone represents a major hurdle for developing an FGF19-based therapy. We describe a nontumorigenic FGF19 variant, M70, which regulates bile acid metabolism and, through inhibition of bile acid synthesis and reduction of excess hepatic bile acid accumulation, protects mice from liver injury induced by either extrahepatic or intrahepatic cholestasis. Administration of M70 in healthy human volunteers potently reduces serum levels of 7α-hydroxy-4-cholesten-3-one, a surrogate marker for the hepatic activity of cholesterol 7α-hydroxylase (CYP7A1), the enzyme responsible for catalyzing the first and rate-limiting step in the classical bile acid synthetic pathway. This study provides direct evidence for the regulation of bile acid metabolism by FGF19 pathway in humans. On the basis of these results, the development of nontumorigenic FGF19 variants capable of modulating CYP7A1 expression represents an effective approach for the prevention and treatment of cholestatic liver diseases as well as potentially for other disorders associated with bile acid dysregulation.
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA. lling@ngmbio.com jluo@ngmbio.com.
authors: Jian
authors: J
authors: Luo
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: Brian
authors: B
authors: Ko
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: Michael
authors: M
authors: Elliott
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: Mei
authors: M
authors: Zhou
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: Darrin A
authors: DA
authors: Lindhout
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: Van
authors: V
authors: Phung
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: Carmen
authors: C
authors: To
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: R Marc
authors: RM
authors: Learned
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: Hui
authors: H
authors: Tian
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA.
authors: Alex M
authors: AM
authors: DePaoli
authors: NGM Biopharmaceuticals Inc., 630 Gateway Boulevard, South San Francisco, CA 94080, USA. lling@ngmbio.com jluo@ngmbio.com.
authors: Lei
authors: L
authors: Ling
mesh_terms: D000328:Adult; D000818:Animals; D001315:Australia; D001647:Bile Acids and Salts / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D002756:Cholagogues and Choleretics / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001651:Cholestasis, Extrahepatic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002780:Cholestasis, Intrahepatic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002783:Cholestenones / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004311:Double-Blind Method; D015536:Down-Regulation; D005346:Fibroblast Growth Factors / Q000009:adverse effects / Q000096:biosynthesis / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D014644:Genetic Variation; D064368:Healthy Volunteers; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D002756:Cholagogues and Choleretics; D002783:Cholestenones; C117476:FGF19 protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; C002656:7 alpha-hydroxy-4-cholesten-3-one; D005346:Fibroblast Growth Factors; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse