Peroxisomal-proliferator-activated receptor alpha activates transcription of the rat hepatic malonyl-CoA decarboxylase gene: a key regulation of malonyl-CoA level

Autor: Gha Young Lee, Zheng-Shan Zhao, Bong Soo Cha, Nam Hee Kim, Yu Sam Kim
Rok vydání: 2003
Předmět:
Transcriptional Activation
Carboxy-Lyases
Receptors
Retinoic Acid
Rats
Inbred OLETF
Molecular Sequence Data
Peroxisome proliferator-activated receptor
Receptors
Cytoplasmic and Nuclear
Biology
Response Elements
Biochemistry
Gene Expression Regulation
Enzymologic
Cell Line
Fenofibrate
Cell Line
Tumor
Transcriptional regulation
Animals
RNA
Messenger
Promoter Regions
Genetic
Molecular Biology
Transcription factor
Triglycerides
Regulation of gene expression
chemistry.chemical_classification
Reporter gene
Binding Sites
Retinoid X receptor alpha
Base Sequence
nutritional and metabolic diseases
Promoter
Cell Biology
Malonyl-CoA decarboxylase
Molecular biology
Rats
Malonyl Coenzyme A
Pyrimidines
Retinoid X Receptors
chemistry
Liver
lipids (amino acids
peptides
and proteins)
Transcription Factors
Research Article
Zdroj: The Biochemical journal. 378(Pt 3)
ISSN: 1470-8728
Popis: MCD (malonyl-CoA decarboxylase), which catalyses decarboxylation of malonyl-CoA, is known to play an important role in the regulation of malonyl-CoA concentration. Recently, it has been observed that the expression of MCD is significantly decreased in the hearts of the PPARalpha (peroxisome-proliferator-activated receptor alpha) (-/-) mice, where the rate of fatty-acid oxidation is decreased by the increased malonyl-CoA level [Campbell, Kozak, Wagner, Altarejos, Dyck, Belke, Severson, Kelly and Lopaschuk (2002) J. Biol. Chem. 277, 4098-4103]. This suggests that MCD may be transcriptionally regulated by PPARalpha. To investigate whether PPARalpha is truly responsible for transcriptional regulation of the rat MCD gene, transient reporter assay was performed in CV-1 cells. The promoter activity was increased by 17-fold in CV-1 cells co-transfected with PPARalpha/retinoid X receptor alpha expression plasmid. In sequence analysis of the promoter region, three putative PPREs (PPAR response elements) were identified, and promoter deletion analysis showed that PPRE2 and PPRE3 were functional. Electrophoretic mobility-shift assays revealed that PPARalpha/retinoid X receptor alpha heterodimer indeed bound to the two PPREs, and the binding specificity of PPARalpha on PPRE was also confirmed by experiments with mutated oligonucleotides. These results indicate that the elements behaved as a responsive site to PPARalpha activation. MCD mRNA levels in WY14643-treated rat hepatoma cells as well as in the liver of fenofibrate-fed Otsuka Long-Evans Tokushima fatty rats were also found to be increased, suggesting that PPARalpha can activate the rat hepatic MCD transcription by binding to the PPREs in the promoter. We propose that MCD performs an important role in understanding the regulatory mechanism between activated PPARalpha and fatty-acid oxidation by altering the malonyl-CoA concentration.
Databáze: OpenAIRE
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