PPARalpha controls the intracellular coenzyme A concentration via regulation of PANK1alpha gene expression

Pantothenate kinase (PanK) is thought to catalyze the first rate-limiting step in CoA biosynthesis. The full-length cDNA encoding the human PanK1alpha protein was isolated, and the complete human PANK1 gene structure was determined. Bezafibrate (BF), a hypolipidemic drug and a peroxisome proliferato...

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Bibliographic Details
Published in:Journal of lipid research 2004-01, Vol.45 (1), p.17-31
Main Authors: Ramaswamy, Gayathri, Karim, Mohammad A, Murti, K Gopal, Jackowski, Suzanne
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Bezafibrate - pharmacology
Cell Line
Coenzyme A - metabolism
DNA, Complementary - genetics
Exons - genetics
Gene Expression Regulation
Half-Life
Haplorhini
Humans
Introns - genetics
Molecular Sequence Data
Organ Specificity
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Promoter Regions, Genetic - genetics
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - metabolism
RNA Stability
RNA, Messenger - genetics
RNA, Messenger - metabolism
Sequence Alignment
Sulfhydryl Compounds - metabolism
Transcription Factors - agonists
Transcription Factors - metabolism
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Summary:Pantothenate kinase (PanK) is thought to catalyze the first rate-limiting step in CoA biosynthesis. The full-length cDNA encoding the human PanK1alpha protein was isolated, and the complete human PANK1 gene structure was determined. Bezafibrate (BF), a hypolipidemic drug and a peroxisome proliferator activator receptor-alpha (PPARalpha) agonist, specifically increased hPANK1alpha mRNA expression in human hepatoblastoma (HepG2) cells as a function of time and dose of the drug, compared with hPANK1beta, hPANK2, and hPANK3, which did not significantly increase. Four putative PPARalpha response elements were identified in the PANKIalpha promoter, and BF stimulated hPANK1alpha promoter activity but did not alter the mRNA half-life. Increased hPANK1alpha mRNA resulted in higher hPanK1 protein, localized in the cytoplasm, and elevated PanK enzyme activity. The enhanced hPANK1alpha gene expression translated into increased activity of the CoA biosynthetic pathway and established a higher steady-state CoA level in HepG2 cells. These data are consistent with a key role for PanK1alpha in the control of cellular CoA content and point to the PPARalpha transcription factor as a major factor governing hepatic CoA levels by specific modulation of PANK1alpha gene expression.
ISSN:0022-2275