| International Session（Symposium）1(JSH・JSGE) |
| Thu. November 21st 9:30 - 12:00 Room 11: Portopia Hotel South Wing Topaz |
| Role of Farnesoid X Receptor and Bile Acids in Liver Tumorigenesis | |||
| Naoki Tanaka1, Shogo Takahashi2,3, Frank J. Gonzalez3 | |||
| 1Department of Metabolic Regulation, Shinshu University, 2Biochemistry and Molecular & Cellular Biology, Georgetown University, 3Laboratory of Metabolism, National Institutes of Health | |||
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| [Background and Aim] Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis, and Fxr-null mice exhibit spontaneous hepatocellular carcinoma (HCC) with aging. This study aimed to examine the contribution of hepatocyte/enterocyte FXR deficiency to age-dependent liver tumorigenesis. [Methods] The prevalence of hepatic tumors and tumor-associated gene expression were measured in male whole-body, hepatocyte- and enterocyte-specific Fxr-null mice (Fxr-null, FxrΔHep, and FxrΔIE). [Results] More than 90% of 20-month-old Fxr-null had hepatic tumors with enhanced expression of myelocytomatosis oncogene (c-Myc) and elevated taurocholate (TCA) levels. The tumor incidence was significantly lower in FxrΔHep and FxrΔIE mice (20% and 5%) and increased c-Myc expression and TCA concentrations were not detected. Additional experiment revealed that c-Myc was induced only by TCA treatment to Fxr-null hepatocytes. [Conclusion] The combination of hepatocyte FXR disruption with elevated TCA is required for c-Myc induction, leading to age-dependent liver tumorigenesis in Fxr-null mice. FXR disruption/antagonism in enterocytes only may not increase the risk of hepatic tumors. |
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Index Term 1: FXR Index Term 2: Liver tumor |
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