Limits...
Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice.

Sanoudou D, Duka A, Drosatos K, Hayes KC, Zannis VI - Pharmacogenomics J. (2009)

Bottom Line: The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group.Fenofibrate changed significantly the expression of seven transcription factors.The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens.

ABSTRACT
We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and beta-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.

Show MeSH
Schematic representation of the effect of fenofibrate on genes affecting lipid and lipoprotein metabolism and mitochondrial functions, as well as the role of the transcription factors Esrrg, Pparα, the coactivators Pgc1a and Pgc1b and Arid5b in this process. Direct effects may involve transcriptional activation of the Pparα gene by Esrrg, stabilization of Pparα by ligands, activation by coactivators and synergistic interactions between Esrrg and Pparα on the promoters of fenofibrate-inducible genes. Indirect effects may involve the Esrrg-mediated negative regulation of Arid5b expression, which may influence Pparα gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2875298&req=5

fig6: Schematic representation of the effect of fenofibrate on genes affecting lipid and lipoprotein metabolism and mitochondrial functions, as well as the role of the transcription factors Esrrg, Pparα, the coactivators Pgc1a and Pgc1b and Arid5b in this process. Direct effects may involve transcriptional activation of the Pparα gene by Esrrg, stabilization of Pparα by ligands, activation by coactivators and synergistic interactions between Esrrg and Pparα on the promoters of fenofibrate-inducible genes. Indirect effects may involve the Esrrg-mediated negative regulation of Arid5b expression, which may influence Pparα gene expression.

Mentions: The microarray analysis did not detect significant changes in the hepatic expression of the Pparα gene and showed a 1.5- and 2.03-fold reduction in the expression of Pparα coactivators 1a and 1b (Pgc1a and Pgc1b), respectively (Table 1). The lack of increase in PPARα mRNA level was confirmed by northern blot analysis (Figures 5a and c). However, the protein levels of Pparα were increased in the liver of the fenofibrate-treated mice (Figure 5b). In agreement with our microarray results, RT-PCR analysis of hepatic RNA showed that the Esrrg gene was significantly upregulated in fenofibrate-treated ApoA-I transgenic mice (Figure 5d). The combined effect of fenofibrate on the transcription factors Pparα, Esrrg and Arid5b in mitochondrial and cytosolic genes affecting lipid metabolism and HDL synthesis and remodeling is shown in Figure 6 and explained further in the Discussion section.


Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice.

Sanoudou D, Duka A, Drosatos K, Hayes KC, Zannis VI - Pharmacogenomics J. (2009)

Schematic representation of the effect of fenofibrate on genes affecting lipid and lipoprotein metabolism and mitochondrial functions, as well as the role of the transcription factors Esrrg, Pparα, the coactivators Pgc1a and Pgc1b and Arid5b in this process. Direct effects may involve transcriptional activation of the Pparα gene by Esrrg, stabilization of Pparα by ligands, activation by coactivators and synergistic interactions between Esrrg and Pparα on the promoters of fenofibrate-inducible genes. Indirect effects may involve the Esrrg-mediated negative regulation of Arid5b expression, which may influence Pparα gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2875298&req=5

fig6: Schematic representation of the effect of fenofibrate on genes affecting lipid and lipoprotein metabolism and mitochondrial functions, as well as the role of the transcription factors Esrrg, Pparα, the coactivators Pgc1a and Pgc1b and Arid5b in this process. Direct effects may involve transcriptional activation of the Pparα gene by Esrrg, stabilization of Pparα by ligands, activation by coactivators and synergistic interactions between Esrrg and Pparα on the promoters of fenofibrate-inducible genes. Indirect effects may involve the Esrrg-mediated negative regulation of Arid5b expression, which may influence Pparα gene expression.
Mentions: The microarray analysis did not detect significant changes in the hepatic expression of the Pparα gene and showed a 1.5- and 2.03-fold reduction in the expression of Pparα coactivators 1a and 1b (Pgc1a and Pgc1b), respectively (Table 1). The lack of increase in PPARα mRNA level was confirmed by northern blot analysis (Figures 5a and c). However, the protein levels of Pparα were increased in the liver of the fenofibrate-treated mice (Figure 5b). In agreement with our microarray results, RT-PCR analysis of hepatic RNA showed that the Esrrg gene was significantly upregulated in fenofibrate-treated ApoA-I transgenic mice (Figure 5d). The combined effect of fenofibrate on the transcription factors Pparα, Esrrg and Arid5b in mitochondrial and cytosolic genes affecting lipid metabolism and HDL synthesis and remodeling is shown in Figure 6 and explained further in the Discussion section.

Bottom Line: The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group.Fenofibrate changed significantly the expression of seven transcription factors.The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens.

ABSTRACT
We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and beta-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.

Show MeSH