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Regulation of alpha-foetoprotein gene expression by fatty acids and fibrates
B Bois-Joyeux1, K Cailliau, J L Danan
1Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, CNRS, UPR 9078, Meudon, France.
Insights
Fatty acids like ETYA and fibrates, such as clofibric acid, reduce alpha-foetoprotein (AFP) gene expression and transcription. These compounds target the AFP gene promoter, impacting AFP synthesis in fetal development.
Area of Science:
- Biochemistry
- Molecular Biology
- Developmental Biology
Background:
- Alpha-foetoprotein (AFP) is a major fetal plasma protein synthesized by the yolk sac and fetal liver.
- AFP is known to bind polyunsaturated fatty acids, suggesting a role in their metabolism and action.
Purpose of the Study:
- To investigate the effects of specific fatty acids and fibrates on the expression of the alpha-foetoprotein (AFP) gene.
- To identify the regulatory regions of the AFP gene affected by these compounds.
Main Methods:
- Cultured rat yolk sac explants were treated with various fatty acids (ETYA, palmitic acid, oleic acid) and fibrates (clofibric acid, fenofibrate).
- Messenger RNA (mRNA) levels for AFP were quantified.
- HepG2 hepatoma cells were used for transient transfection assays to assess transcriptional activity of the AFP gene regulatory regions.
Main Results:
- 5-8-11-14 eicosatetraynoic acid (ETYA), an arachidonic acid analogue, significantly decreased AFP mRNA levels in cultured rat yolk sac explants.
- Palmitic acid and oleic acid did not affect AFP mRNA levels.
- Clofibric acid and fenofibrate also reduced AFP mRNA levels.
- ETYA and clofibric acid decreased the transcriptional activity of the 7 kb regulatory region of the rat AFP gene.
- The 330 bp AFP promoter was identified as a specific target for the down-regulating effects of ETYA and clofibric acid.
Conclusions:
- Certain fatty acids (ETYA) and fibrates (clofibric acid, fenofibrate) can down-regulate alpha-foetoprotein (AFP) gene expression.
- The transcriptional activity of the AFP gene, particularly its promoter region, is a target for these inhibitory effects.
Abstract:
Alpha-foetoprotein (AFP), the major plasma protein in the foetus, is mainly synthesized by yolk sac and foetal liver. It binds polyunsaturated fatty acids and probably controls their metabolism and action. We investigated the effects of fatty acids and fibrates on expression of the AFP gene using two complementary approaches. Treatment with 5-8-11-14 eicosatetraynoic acid (ETYA), an analogue of arachidonic acid, specifically led to lower AFP mRNA levels in cultured rat yolk sac explants whereas treatment with palmitic or oleic acid did not. Clofibric acid and fenofibrate also gave lower AFP mRNA levels. Transient transfection experiments with HepG2 hepatoma cells showed that ETYA and clofibric acid decreased the transcriptional activity of the 7 kb regulatory region of the rat AFP gene. The 330 bp AFP promoter was identified as a target for these down regulating effects.