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Journal of Lipid Research, Vol. 45, 17-31, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

PPAR controls the intracellular coenzyme A concentration via regulation of PANK1 gene expression¹

Gayathri Ramaswamy^*,, Mohammad A. Karim^2,*, K. Gopal Murti^,** and Suzanne Jackowski^3,*,

^* Protein Science Division, St. Jude Children's Research Hospital, Memphis, TN 38105-2794
Department of Infectious Diseases, and Scientific Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105-2794
Departments of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163
^** Pathology, University of Tennessee Health Science Center, Memphis, TN 38163

³ To whom correspondence should be addressed. e-mail: suzanne.jackowski{at}stjude.org

Pantothenate kinase (PanK) is thought to catalyze the first rate-limiting step in CoA biosynthesis. The full-length cDNA encoding the human PanK1 protein was isolated, and the complete human PANK1 gene structure was determined. Bezafibrate (BF), a hypolipidemic drug and a peroxisome proliferator activator receptor- (PPAR) agonist, specifically increased hPANK1 mRNA expression in human hepatoblastoma (HepG2) cells as a function of time and dose of the drug, compared with hPANK1ß, hPANK2, and hPANK3, which did not significantly increase. Four putative PPAR response elements were identified in the PANKI promoter, and BF stimulated hPANK1 promoter activity but did not alter the mRNA half-life. Increased hPANK1 mRNA resulted in higher hPanK1 protein, localized in the cytoplasm, and elevated PanK enzyme activity. The enhanced hPANK1 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 PanK1 in the control of cellular CoA content and point to the PPAR transcription factor as a major factor governing hepatic CoA levels by specific modulation of PANK1 gene expression.

Abbreviations: BF, bezafibrate; HSS, Hallervorden-Spatz syndrome; P-Pan, 4'-phosphopantothenate; P-PanSH, 4'-phosphopantetheine; Pan, pantothenate; PanK, pantothenate kinase; PKAN, pantothenate kinase-associated neurodegeneration; PPAR, peroxisome proliferator activator receptor-; RACE, rapid amplification of cDNA ends

Supplementary key words pantothenate • pantothenate kinase • peroxisome proliferator activator receptor- • fatty acid ß-oxidation • liver

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