Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of B...Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of BA homeostasis worsens ALD.BA synthesis is critically regulated by fibroblast growthfactor(FGF)15 in mice and FGF19 in humans.FGF15/19 are mainly produced in the ileum and their mainfunction is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4(FGFR4)on hepatocytes.The effects of intestine-specific Fgf15 deficiency on the development ofALD were determined in the current study.Methods:Enterocyte-specific Fgf15 knockout mice(Fgf15intint^(-/-))and the established mouse model bychronic and binge ethanol feeding(NIAAA model)were adapted in this study.Results:The Fgf15intint^(-/-)mice had increased BA pool size,consistent with negative effects of FGF15-FGFR4signaling on BA synthesis.There were not obviously physical and hepatic histological abnormalitiespresented in Fgf15intint^(-/-)mice compared to wild-type mice.Following alcohol treatment,the Fgf15intint^(-/-)mice exhibited a higher degree of liver injury,increased hepatic expression of Cd14,a receptor forlipopolysaccharide expressed in the liver,and increased hepatic lipid levels.We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis,regardless ofgenotypes or following the alcohol treatment.Conclusions:FGF15 may prevent hepatic steatosis in the development of ALD in mice,and maintainingFGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in thefuture.展开更多
基金the USA National Institutes of Health(NIH)(grant number:GM135258,ES029258)the Vet-erans Affair(grant number:BX002741).
文摘Background and aims:Alcoholic liver disease(ALD)is an important and growing cause for the development of chronic liver diseases in the world.Bile acid(BA)levels are increased in patients with ALD anddysregulation of BA homeostasis worsens ALD.BA synthesis is critically regulated by fibroblast growthfactor(FGF)15 in mice and FGF19 in humans.FGF15/19 are mainly produced in the ileum and their mainfunction is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4(FGFR4)on hepatocytes.The effects of intestine-specific Fgf15 deficiency on the development ofALD were determined in the current study.Methods:Enterocyte-specific Fgf15 knockout mice(Fgf15intint^(-/-))and the established mouse model bychronic and binge ethanol feeding(NIAAA model)were adapted in this study.Results:The Fgf15intint^(-/-)mice had increased BA pool size,consistent with negative effects of FGF15-FGFR4signaling on BA synthesis.There were not obviously physical and hepatic histological abnormalitiespresented in Fgf15intint^(-/-)mice compared to wild-type mice.Following alcohol treatment,the Fgf15intint^(-/-)mice exhibited a higher degree of liver injury,increased hepatic expression of Cd14,a receptor forlipopolysaccharide expressed in the liver,and increased hepatic lipid levels.We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis,regardless ofgenotypes or following the alcohol treatment.Conclusions:FGF15 may prevent hepatic steatosis in the development of ALD in mice,and maintainingFGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in thefuture.
