Logo of biochemjBJ Latest papers and much more!
Biochem J. 2003 Feb 1; 369(Pt 3): 721–729.
PMCID: PMC1223125

Control of human carnitine palmitoyltransferase II gene transcription by peroxisome proliferator-activated receptor through a partially conserved peroxisome proliferator-responsive element.


The expression of several genes involved in fatty acid metabolism is regulated by peroxisome proliferator-activated receptors (PPARs). To gain more insight into the control of carnitine palmitoyltransferase (CPT) gene expression, we examined the transcriptional regulation of the human CPT II gene. We show that the 5'-flanking region of this gene is transcriptionally active and binds PPARalpha in vivo in a chromatin immunoprecipitation assay. In addition, we characterized the peroxisome proliferator-responsive element (PPRE) in the proximal promoter of the CPT II gene, which appears to be a novel PPRE. The sequence of this PPRE contains one half-site which is a perfect consensus sequence (TGACCT) but no clearly recognizable second half-site (CAGCAC); this part of the sequence contains only one match to the consensus, which seems to be irrelevant for the binding of PPARalpha. As expected, other members of the nuclear receptor superfamily also bind to this element and repress the activation mediated by PPARalpha, thus showing that the interplay between several nuclear receptors may regulate the entry of fatty acids into the mitochondria, a crucial step in their metabolism.

Full Text

The Full Text of this article is available as a PDF (244K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997 Feb 15;244(1):1–14. [PubMed]
  • Hashimoto T, Cook WS, Qi C, Yeldandi AV, Reddy JK, Rao MS. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem. 2000 Sep 15;275(37):28918–28928. [PubMed]
  • Asins G, Serra D, Hegardt FG. The effect of etomoxir on the mRNA levels of enzymes involved in ketogenesis and cholesterogenesis in rat liver. Biochem Pharmacol. 1994 Apr 20;47(8):1373–1379. [PubMed]
  • Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem. 1998 Mar 6;273(10):5678–5684. [PubMed]
  • Hashimoto T, Fujita T, Usuda N, Cook W, Qi C, Peters JM, Gonzalez FJ, Yeldandi AV, Rao MS, Reddy JK. Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype. J Biol Chem. 1999 Jul 2;274(27):19228–19236. [PubMed]
  • Chatelain F, Kohl C, Esser V, McGarry JD, Girard J, Pegorier JP. Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene transcription in cultured fetal rat hepatocytes. Eur J Biochem. 1996 Feb 1;235(3):789–798. [PubMed]
  • Asins G, Serra D, Arias G, Hegardt FG. Developmental changes in carnitine palmitoyltransferases I and II gene expression in intestine and liver of suckling rats. Biochem J. 1995 Mar 1;306(Pt 2):379–384. [PMC free article] [PubMed]
  • Thumelin S, Esser V, Charvy D, Kolodziej M, Zammit VA, McGarry D, Girard J, Pegorier JP. Expression of liver carnitine palmitoyltransferase I and II genes during development in the rat. Biochem J. 1994 Jun 1;300(Pt 2):583–587. [PMC free article] [PubMed]
  • Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996 May;37(5):907–925. [PubMed]
  • Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312–4317. [PMC free article] [PubMed]
  • Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4318–4323. [PMC free article] [PubMed]
  • Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995 Jun 2;270(22):12953–12956. [PubMed]
  • Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995 Dec 1;83(5):803–812. [PubMed]
  • Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 1996 Nov 7;384(6604):39–43. [PubMed]
  • Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995 Dec 15;83(6):841–850. [PubMed]
  • Palmer CN, Hsu MH, Griffin HJ, Johnson EF. Novel sequence determinants in peroxisome proliferator signaling. J Biol Chem. 1995 Jul 7;270(27):16114–16121. [PubMed]
  • IJpenberg A, Jeannin E, Wahli W, Desvergne B. Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA. A functional analysis of the malic enzyme gene PPAR response element. J Biol Chem. 1997 Aug 8;272(32):20108–20117. [PubMed]
  • Juge-Aubry C, Pernin A, Favez T, Burger AG, Wahli W, Meier CA, Desvergne B. DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5'-flanking region. J Biol Chem. 1997 Oct 3;272(40):25252–25259. [PubMed]
  • Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999 Oct;20(5):649–688. [PubMed]
  • Carter ME, Gulick T, Moore DD, Kelly DP. A pleiotropic element in the medium-chain acyl coenzyme A dehydrogenase gene promoter mediates transcriptional regulation by multiple nuclear receptor transcription factors and defines novel receptor-DNA binding motifs. Mol Cell Biol. 1994 Jul;14(7):4360–4372. [PMC free article] [PubMed]
  • Gulick T, Cresci S, Caira T, Moore DD, Kelly DP. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11012–11016. [PMC free article] [PubMed]
  • Raisher BD, Gulick T, Zhang Z, Strauss AW, Moore DD, Kelly DP. Identification of a novel retinoid-responsive element in the promoter region of the medium chain acyl-coenzyme A dehydrogenase gene. J Biol Chem. 1992 Oct 5;267(28):20264–20269. [PubMed]
  • Carter ME, Gulick T, Raisher BD, Caira T, Ladias JA, Moore DD, Kelly DP. Hepatocyte nuclear factor-4 activates medium chain acyl-CoA dehydrogenase gene transcription by interacting with a complex regulatory element. J Biol Chem. 1993 Jul 5;268(19):13805–13810. [PubMed]
  • Sladek R, Bader JA, Giguère V. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol. 1997 Sep;17(9):5400–5409. [PMC free article] [PubMed]
  • Sack MN, Disch DL, Rockman HA, Kelly DP. A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6438–6443. [PMC free article] [PubMed]
  • Schoonjans K, Watanabe M, Suzuki H, Mahfoudi A, Krey G, Wahli W, Grimaldi P, Staels B, Yamamoto T, Auwerx J. Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J Biol Chem. 1995 Aug 18;270(33):19269–19276. [PubMed]
  • Yu GS, Lu YC, Gulick T. Co-regulation of tissue-specific alternative human carnitine palmitoyltransferase Ibeta gene promoters by fatty acid enzyme substrate. J Biol Chem. 1998 Dec 4;273(49):32901–32909. [PubMed]
  • Rodríguez JC, Gil-Gómez G, Hegardt FG, Haro D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem. 1994 Jul 22;269(29):18767–18772. [PubMed]
  • Rodríguez JC, Ortiz JA, Hegardt FG, Haro D. Chicken ovalbumin upstream-promoter transcription factor (COUP-TF) could act as a transcriptional activator or repressor of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene. Biochem J. 1997 Sep 1;326(Pt 2):587–592. [PMC free article] [PubMed]
  • Rodríguez JC, Ortiz JA, Hegardt FG, Haro D. The hepatocyte nuclear factor 4 (HNF-4) represses the mitochondrial HMG-CoA synthase gene. Biochem Biophys Res Commun. 1998 Jan 26;242(3):692–696. [PubMed]
  • Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995 Jun;15(6):3012–3022. [PMC free article] [PubMed]
  • Montermini L, Wang H, Verderio E, Taroni F, DiDonato S, Finocchiaro G. Identification of 5' regulatory regions of the human carnitine palmitoyltransferase II gene. Biochim Biophys Acta. 1994 Sep 13;1219(1):237–240. [PubMed]
  • Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989 Apr 15;77(1):51–59. [PubMed]
  • Serra D, Bellido D, Asins G, Arias G, Vilaró S, Hegardt FG. The expression of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A synthase in neonatal rat intestine and liver is under transcriptional control. Eur J Biochem. 1996 Apr 1;237(1):16–24. [PubMed]
  • Elbrecht A, Chen Y, Adams A, Berger J, Griffin P, Klatt T, Zhang B, Menke J, Zhou G, Smith RG, et al. L-764406 is a partial agonist of human peroxisome proliferator-activated receptor gamma. The role of Cys313 in ligand binding. J Biol Chem. 1999 Mar 19;274(12):7913–7922. [PubMed]
  • Braunstein M, Rose AB, Holmes SG, Allis CD, Broach JR. Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 1993 Apr;7(4):592–604. [PubMed]
  • Laffitte BA, Kast HR, Nguyen CM, Zavacki AM, Moore DD, Edwards PA. Identification of the DNA binding specificity and potential target genes for the farnesoid X-activated receptor. J Biol Chem. 2000 Apr 7;275(14):10638–10647. [PubMed]
  • Watanabe K, Fujii H, Takahashi T, Kodama M, Aizawa Y, Ohta Y, Ono T, Hasegawa G, Naito M, Nakajima T, et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity. J Biol Chem. 2000 Jul 21;275(29):22293–22299. [PubMed]
  • Hsu MH, Savas U, Griffin KJ, Johnson EF. Identification of peroxisome proliferator-responsive human genes by elevated expression of the peroxisome proliferator-activated receptor alpha in HepG2 cells. J Biol Chem. 2001 Jul 27;276(30):27950–27958. [PubMed]
  • Johnston SD, Liu X, Zuo F, Eisenbraun TL, Wiley SR, Kraus RJ, Mertz JE. Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements. Mol Endocrinol. 1997 Mar;11(3):342–352. [PubMed]
  • Louet JF, Chatelain F, Decaux JF, Park EA, Kohl C, Pineau T, Girard J, Pegorier JP. Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway. Biochem J. 2001 Feb 15;354(Pt 1):189–197. [PMC free article] [PubMed]
  • Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7473–7478. [PMC free article] [PubMed]
  • Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999 Jun;103(11):1489–1498. [PMC free article] [PubMed]
  • Le May C, Pineau T, Bigot K, Kohl C, Girard J, Pégorier JP. Reduced hepatic fatty acid oxidation in fasting PPARalpha null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression. FEBS Lett. 2000 Jun 23;475(3):163–166. [PubMed]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...