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Updated: Aug 13, 2026
Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis
Published on: February 10, 2015
Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient
Mei Zhou1, R Marc Learned1, Stephen J Rossi1
1NGM Biopharmaceuticals, Inc., South San Francisco, CA.
Unlabelled:
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.
Conclusion:
These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis.
Insights
Fibroblast growth factor 19 (FGF19) and its variant M70 show promise in treating liver diseases caused by multidrug resistance 3 gene defects. FGF19 biology safely suppresses bile acid synthesis, offering a novel therapeutic avenue for cholangiopathies.
Area of Science:
- Hepatology
- Gastroenterology
- Molecular Biology
Background:
- Defects in the multidrug resistance 3 gene (MDR3) lead to various human cholangiopathies.
- Mdr2-deficient mice models exhibit liver diseases mirroring human conditions like progressive familial intrahepatic cholestasis and primary sclerosing cholangitis.
Purpose of the Study:
- To investigate the therapeutic potential of fibroblast growth factor 19 (FGF19) and its variant M70 in treating Mdr2-deficient mouse models of cholangiopathy.
- To explore the effects of FGF19 and M70 on bile acid metabolism and liver injury.
Main Methods:
- Adeno-associated virus vectors carrying FGF19 or M70 genes were administered to Mdr2-deficient mice.
- Evaluated serum liver enzymes, liver histology, bile acid homeostasis, and tumor formation.
Main Results:
- FGF19 and M70 effectively reversed liver injury, reduced inflammation and fibrosis, and decreased gallstones in Mdr2-deficient mice.
- Both FGF19 and M70 suppressed bile acid synthesis by inhibiting Cyp7a1 and Cyp27a1 expression.
- Prolonged FGF19 exposure induced hepatocellular carcinomas, while M70 ameliorated cholangiopathy-associated hepatosplenomegaly and ductular proliferation.
Conclusions:
- FGF19 biology can be harnessed to suppress bile acid synthesis for cholangiopathy treatment.
- The FGF19 variant M70 demonstrates therapeutic potential with a potentially safer profile regarding tumorigenesis.
