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Originally published In Press as doi:10.1194/jlr.M300279-JLR200 on October 1, 2003

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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{alpha} controls the intracellular coenzyme A concentration via regulation of PANK1{alpha} gene expression1

Gayathri Ramaswamy*,§, Mohammad A. Karim2,*, K. Gopal Murti{dagger},** and Suzanne Jackowski3,*,§

* Protein Science Division, St. Jude Children's Research Hospital, Memphis, TN 38105-2794
{dagger} 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{alpha} protein was isolated, and the complete human PANK1 gene structure was determined. Bezafibrate (BF), a hypolipidemic drug and a peroxisome proliferator activator receptor-{alpha} (PPAR{alpha}) agonist, specifically increased hPANK1{alpha} 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{alpha} response elements were identified in the PANKI{alpha} promoter, and BF stimulated hPANK1{alpha} promoter activity but did not alter the mRNA half-life. Increased hPANK1{alpha} mRNA resulted in higher hPanK1 protein, localized in the cytoplasm, and elevated PanK enzyme activity. The enhanced hPANK1{alpha} 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{alpha} in the control of cellular CoA content and point to the PPAR{alpha} transcription factor as a major factor governing hepatic CoA levels by specific modulation of PANK1{alpha} 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{alpha}, peroxisome proliferator activator receptor-{alpha}; RACE, rapid amplification of cDNA ends

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


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