Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, and an association between altered bile acid (BA) metabolism, down‐regulation of farnesoid X receptor (FXR), which is a master regulator of BA metabolism, and hepatocarcinogenesis has been documented. While global FXR defi...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2018-12-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1263 |
| _version_ | 1797761607430832128 |
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| author | Shogo Takahashi Naoki Tanaka Tatsuki Fukami Cen Xie Tomoki Yagai Donghwan Kim Thomas J. Velenosi Tingting Yan Kristopher W. Krausz Moshe Levi Frank J. Gonzalez |
| author_facet | Shogo Takahashi Naoki Tanaka Tatsuki Fukami Cen Xie Tomoki Yagai Donghwan Kim Thomas J. Velenosi Tingting Yan Kristopher W. Krausz Moshe Levi Frank J. Gonzalez |
| author_sort | Shogo Takahashi |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, and an association between altered bile acid (BA) metabolism, down‐regulation of farnesoid X receptor (FXR), which is a master regulator of BA metabolism, and hepatocarcinogenesis has been documented. While global FXR deficiency in mice results in spontaneous HCC with aging, the contribution of tissue‐specific FXR deficiency to hepatocarcinogenesis remains unclear. In this study, the prevalence of hepatic tumors, expression of genes related to tumorigenesis, and serum/liver BA levels were compared among male whole‐body Fxr‐null, hepatocyte‐specific Fxr‐null (Fxr∆Hep), and enterocyte‐specific Fxr‐null (Fxr∆IE) mice at the age of 3, 14, and 20 months. More than 90% of 20‐month‐old whole‐body Fxr‐null mice had hepatic tumors with enhanced hepatic expression of myelocytomatosis oncogene (Myc) and cyclin‐dependent kinase 4 (Cdk4) messenger RNAs (mRNAs) and elevated serum taurocholate (TCA) and tauromuricholate (TMCA) and their respective unconjugated derivatives. The incidence of hepatic tumors was significantly lower in Fxr∆Hep and Fxr∆IE mice (20% and 5%, respectively), and the increases in Myc and Cdk4 mRNA or serum BA concentrations were not detected in these mice compared to Fxrfloxed [fl]/fl mice; a similar tendency was observed in 14‐month‐old mice. However, increased hepatic c‐Myc protein expression was found only in Fxr‐null mice at the age of 3, 14, and 20 months. Treatment with TCA induced Myc expression in Fxr‐null cultured primary mouse hepatocytes but not in wild‐type (WT) mouse hepatocytes, demonstrating that the combination of hepatocyte FXR disruption with elevated TCA is required for Myc induction and ensuing age‐dependent hepatocarcinogenesis in Fxr‐null mice. Conclusion: There is a relatively low risk of hepatic tumors by inhibition of FXR in enterocytes, likely due to the lack of increased TCA and Myc induction. |
| first_indexed | 2024-03-12T19:15:28Z |
| format | Article |
| id | doaj.art-dfa052a0f4e946dfaf779f784ef1f2a2 |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T19:15:28Z |
| publishDate | 2018-12-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-dfa052a0f4e946dfaf779f784ef1f2a22023-08-02T05:35:40ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2018-12-012121567158210.1002/hep4.1263Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor DevelopmentShogo Takahashi0Naoki Tanaka1Tatsuki Fukami2Cen Xie3Tomoki Yagai4Donghwan Kim5Thomas J. Velenosi6Tingting Yan7Kristopher W. Krausz8Moshe Levi9Frank J. Gonzalez10Laboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDDepartment of Metabolic Regulation Shinshu University School of Medicine Matsumoto JapanLaboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDLaboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDLaboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDLaboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDLaboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDLaboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDLaboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDDepartment of Biochemistry and Molecular and Cellular Biology Georgetown University Washington DCLaboratory of Metabolism National Cancer Institute, National Institutes of Health Bethesda MDHepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, and an association between altered bile acid (BA) metabolism, down‐regulation of farnesoid X receptor (FXR), which is a master regulator of BA metabolism, and hepatocarcinogenesis has been documented. While global FXR deficiency in mice results in spontaneous HCC with aging, the contribution of tissue‐specific FXR deficiency to hepatocarcinogenesis remains unclear. In this study, the prevalence of hepatic tumors, expression of genes related to tumorigenesis, and serum/liver BA levels were compared among male whole‐body Fxr‐null, hepatocyte‐specific Fxr‐null (Fxr∆Hep), and enterocyte‐specific Fxr‐null (Fxr∆IE) mice at the age of 3, 14, and 20 months. More than 90% of 20‐month‐old whole‐body Fxr‐null mice had hepatic tumors with enhanced hepatic expression of myelocytomatosis oncogene (Myc) and cyclin‐dependent kinase 4 (Cdk4) messenger RNAs (mRNAs) and elevated serum taurocholate (TCA) and tauromuricholate (TMCA) and their respective unconjugated derivatives. The incidence of hepatic tumors was significantly lower in Fxr∆Hep and Fxr∆IE mice (20% and 5%, respectively), and the increases in Myc and Cdk4 mRNA or serum BA concentrations were not detected in these mice compared to Fxrfloxed [fl]/fl mice; a similar tendency was observed in 14‐month‐old mice. However, increased hepatic c‐Myc protein expression was found only in Fxr‐null mice at the age of 3, 14, and 20 months. Treatment with TCA induced Myc expression in Fxr‐null cultured primary mouse hepatocytes but not in wild‐type (WT) mouse hepatocytes, demonstrating that the combination of hepatocyte FXR disruption with elevated TCA is required for Myc induction and ensuing age‐dependent hepatocarcinogenesis in Fxr‐null mice. Conclusion: There is a relatively low risk of hepatic tumors by inhibition of FXR in enterocytes, likely due to the lack of increased TCA and Myc induction.https://doi.org/10.1002/hep4.1263 |
| spellingShingle | Shogo Takahashi Naoki Tanaka Tatsuki Fukami Cen Xie Tomoki Yagai Donghwan Kim Thomas J. Velenosi Tingting Yan Kristopher W. Krausz Moshe Levi Frank J. Gonzalez Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development Hepatology Communications |
| title | Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development |
| title_full | Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development |
| title_fullStr | Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development |
| title_full_unstemmed | Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development |
| title_short | Role of Farnesoid X Receptor and Bile Acids in Hepatic Tumor Development |
| title_sort | role of farnesoid x receptor and bile acids in hepatic tumor development |
| url | https://doi.org/10.1002/hep4.1263 |
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