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. Conclusion: These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis. (Hepatology 2016;63:914–929)

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

“…Given that both adiponectin and Fgf15 exhibited potent anti-inflammatory properties (15,16,(45)(46)(47), elevation of circulating adiponectin and Fgf15 in the ethanol-fed mNTKO mice might also synergistically or additively trigger an anti-inflammation signaling network and protected mNTKO mice from ethanol-induced liver injury.…”

“…Bile acids are increasingly being recognized as the most sensitive markers of inflammation and liver dysfunction and injury (45,46). Conceivably, the normalized hepatic and serum bile acids in the ethanol-fed mNTKO mice might limit accumulation of toxic bile acids such as deoxycholic acid in liver and ultimately ameliorated ethanolinduced liver damage.…”

“…Hepatic Bile Acid Pool Size and Serum Bile Acid Concentrations-Liver samples were homogenized in 75% ethanol and incubated at 50°C for 2 h (46). After centrifugation at 6000 ϫ g for 10 min, the pellets were extracted again with 50% ethanol.…”

Apical Sodium-Dependent Transporter Inhibitors in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

“…It is noteworthy that although FGF19 downregulates BA synthesis, it induces hepatocyte proliferation and prolonged exposure in animal studies has been shown to cause hepatocellular carcinoma [33] . This potential tumorigenic action of FGF19 is of a concern but circumvented by recent development of engineered FGF19 variants without mitogenic actions [34] . Pre-clinical studies suggest FGF19 analogues have potential in the treatment of PBC and PSC.…”

Bile Acid Uptake Transporters as Targets for Therapy

“…This hormone, when released from the gut, binds to the tyrosine kinase receptor FGF receptor 4/β-Klotho on hepatocytes, which activates the jun N-terminal kinase 1/2 signaling pathway [53]. Intestinal FXR activation [54] and the FGF19 mimetic M70 [55,56] dampen cholestatic liver injury by strongly reducing hepatic bile acid synthesis and the circulating bile acid pool. So, mouse studies clearly show hepatoprotection through (gut-specific) FGF15/19 signaling, primarily by reducing bile acid pools, sharing its mode of action with ASBT-inhibition.…”