Journal
PHARMACOGENOMICS JOURNAL
Volume 10, Issue 3, Pages 165-179Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/tpj.2009.51
Keywords
fenofibrate; lipid catabolism; estrogen receptor-related gamma HDL; phospholipid biosynthesis
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Funding
- National Institutes of Health [HL48739, HL68216]
- European Union [LSHM-CT-2006-0376331, LSHG-CT-2006-037277]
- Biomedical Research Foundation of the Academy of Athens
- Hellenic Cardiological Society
- John F Kostopoulos Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL068216, R01HL048739] Funding Source: NIH RePORTER
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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. The Pharmacogenomics Journal (2010) 10, 165-179; doi:10.1038/tpj.2009.51; published online 1 December 2009
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