PPAR alpha controls the intracellular coenzyme A concentration via regulation of PANK1 alpha 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 PPARa. response elements were identified in the PANK1alpha 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.