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Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated
Alejandra Gutierrez1, Eric P Ratliff, Allen M Andres
1Department of Biology and Heart Institute, San Diego State University, San Diego, CA 92182, USA.
Arteriosclerosis, Thrombosis, and Vascular Biology
|November 15, 2005
Summary
Dietary bile acids repress hepatic paraoxonase 1 (PON1) expression through FXR-mediated induction of FGF15. Resistance in some mice involves signaling events downstream of FGF15-FGFR4 interaction.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Paraoxonase 1 (PON1) is crucial for high-density lipoprotein (HDL) function and possesses anti-atherogenic properties.
- Bile acids play a significant role in lipid metabolism and are implicated in various physiological and pathological processes.
- Hepatic PON1 expression is influenced by numerous factors, including diet and hormonal signaling.
Purpose of the Study:
- To elucidate the molecular mechanisms by which dietary bile acids suppress hepatic expression of paraoxonase 1 (PON1).
- To investigate the roles of specific signaling pathways, including FXR and FGFR4, in mediating bile acid-induced repression of PON1.
- To compare the responses of different mouse strains with varying atherosclerosis susceptibility to dietary bile acid challenges.
Main Methods:
- Feeding C57BL/6 and C3H/HeJ mice with chow or atherogenic diets containing taurocholate.
- Analyzing hepatic PON1 and CYP7A1 mRNA expression levels.
- Generating knockout mice for toll receptor 4 (TR4), FXR, and FGFR4.
- Treating human hepatoma cells with FGF19.
- Measuring ileal expression of FGF15.
Main Results:
- C3H/HeJ mice exhibited resistance to taurocholate-induced repression of hepatic PON1 mRNA compared to C57BL/6 mice.
- Deletion of FXR or FGFR4 abolished taurocholate repression of PON1 and CYP7A1.
- FGF19 treatment decreased PON1 and CYP7A1 expression in human hepatoma cells.
- Dietary taurocholate increased ileal FGF15 expression in all studied mice.
Conclusions:
- Hepatic PON1 and CYP7A1 mRNA expression is repressed by bile acids via FXR-mediated induction of FGF15.
- The resistance of C3H/HeJ mice to taurocholate repression is not due to a lack of FGF15 induction but rather downstream signaling events.
- These findings highlight a novel bile acid-FGF15-FGFR4 signaling axis regulating hepatic gene expression with implications for atherosclerosis and HDL metabolism.