A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids
Paraoxonase-1 (PON1), an enzyme that metabolizes organophosphate insecticides, is secreted by the liver and transported in the blood complexed to HDL. In humans and mice, low plasma levels of PON1 have also been linked to the development of atherosclerosis. We previously reported that hepatic Pon1 e...
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| Format: | Article |
| Language: | English |
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Elsevier
2006-02-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520336397 |
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| author | Diana M. Shih Heidi R. Kast-Woelbern Jack Wong Yu-Rong Xia Peter A. Edwards Aldons J. Lusis |
| author_facet | Diana M. Shih Heidi R. Kast-Woelbern Jack Wong Yu-Rong Xia Peter A. Edwards Aldons J. Lusis |
| author_sort | Diana M. Shih |
| collection | DOAJ |
| description | Paraoxonase-1 (PON1), an enzyme that metabolizes organophosphate insecticides, is secreted by the liver and transported in the blood complexed to HDL. In humans and mice, low plasma levels of PON1 have also been linked to the development of atherosclerosis. We previously reported that hepatic Pon1 expression was decreased when C57BL/6J mice were fed a high-fat, high-cholesterol diet supplemented with cholic acid (CA). In the current study, we used wild-type and farnesoid X receptor (FXR) null mice to demonstrate that this repression is dependent upon CA and FXR. PON1 mRNA levels were also repressed when HepG2 cells, derived from a human hepatoma, were incubated with natural or highly specific synthetic FXR agonists. In contrast, fibroblast growth factor-19 (FGF-19) mRNA levels were greatly induced by these same FXR agonists. Furthermore, treatment of HepG2 cells with recombinant human FGF-19 significantly decreased PON1 mRNA levels. Finally, deletion studies revealed that the proximal −230 to −96 bp region of the PON1 promoter contains regulatory element(s) necessary for promoter activity and bile acid repression. These data demonstrate that human PON1 expression is repressed by bile acids through the actions of FXR and FGF-19. |
| first_indexed | 2024-12-17T22:27:47Z |
| format | Article |
| id | doaj.art-9185cf015fe94d64abdeaa15f04fb047 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T22:27:47Z |
| publishDate | 2006-02-01 |
| publisher | Elsevier |
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| series | Journal of Lipid Research |
| spelling | doaj.art-9185cf015fe94d64abdeaa15f04fb0472022-12-21T21:30:19ZengElsevierJournal of Lipid Research0022-22752006-02-01472384392A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acidsDiana M. Shih0Heidi R. Kast-Woelbern1Jack Wong2Yu-Rong Xia3Peter A. Edwards4Aldons J. Lusis5Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095; Department of Human Genetics and Department of Molecular Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095; Department of Human Genetics and Department of Molecular Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095; Department of Human Genetics and Department of Molecular Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095; Department of Human Genetics and Department of Molecular Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095; Department of Human Genetics and Department of Molecular Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095; Department of Human Genetics and Department of Molecular Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095Paraoxonase-1 (PON1), an enzyme that metabolizes organophosphate insecticides, is secreted by the liver and transported in the blood complexed to HDL. In humans and mice, low plasma levels of PON1 have also been linked to the development of atherosclerosis. We previously reported that hepatic Pon1 expression was decreased when C57BL/6J mice were fed a high-fat, high-cholesterol diet supplemented with cholic acid (CA). In the current study, we used wild-type and farnesoid X receptor (FXR) null mice to demonstrate that this repression is dependent upon CA and FXR. PON1 mRNA levels were also repressed when HepG2 cells, derived from a human hepatoma, were incubated with natural or highly specific synthetic FXR agonists. In contrast, fibroblast growth factor-19 (FGF-19) mRNA levels were greatly induced by these same FXR agonists. Furthermore, treatment of HepG2 cells with recombinant human FGF-19 significantly decreased PON1 mRNA levels. Finally, deletion studies revealed that the proximal −230 to −96 bp region of the PON1 promoter contains regulatory element(s) necessary for promoter activity and bile acid repression. These data demonstrate that human PON1 expression is repressed by bile acids through the actions of FXR and FGF-19.http://www.sciencedirect.com/science/article/pii/S0022227520336397gene regulationhigh density lipoproteinatherosclerosismousec-Jun N-terminal kinasefarnesoid X receptor |
| spellingShingle | Diana M. Shih Heidi R. Kast-Woelbern Jack Wong Yu-Rong Xia Peter A. Edwards Aldons J. Lusis A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids Journal of Lipid Research gene regulation high density lipoprotein atherosclerosis mouse c-Jun N-terminal kinase farnesoid X receptor |
| title | A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids |
| title_full | A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids |
| title_fullStr | A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids |
| title_full_unstemmed | A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids |
| title_short | A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids |
| title_sort | role for fxr and human fgf 19 in the repression of paraoxonase 1 gene expression by bile acids |
| topic | gene regulation high density lipoprotein atherosclerosis mouse c-Jun N-terminal kinase farnesoid X receptor |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520336397 |
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