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 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.
Ramaswamy
Gayathri
G
Protein Science Division, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Karim
Mohammad A
MA
Murti
K Gopal
KG
Jackowski
Suzanne
S
D000595:Amino Acid Sequence; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D002460:Cell Line; D003065:Coenzyme A / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D016415:Sequence Alignment; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*
D018076:DNA, Complementary; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A; D001629:Bezafibrate