Abstract
MCD (malonyl-CoA decarboxylase), which catalyses decarboxylation of malonyl-CoA, is known to play an important role in the regulation of malonyl-CoA concentration. Recently, it has been observed that the expression of MCD is significantly decreased in the hearts of the PPARalpha (peroxisome-proliferator-activated receptor alpha) (-/-) mice, where the rate of fatty-acid oxidation is decreased by the increased malonyl-CoA level [Campbell, Kozak, Wagner, Altarejos, Dyck, Belke, Severson, Kelly and Lopaschuk (2002) J. Biol. Chem. 277, 4098-4103]. This suggests that MCD may be transcriptionally regulated by PPARalpha. To investigate whether PPARalpha is truly responsible for transcriptional regulation of the rat MCD gene, transient reporter assay was performed in CV-1 cells. The promoter activity was increased by 17-fold in CV-1 cells co-transfected with PPARalpha/retinoid X receptor alpha expression plasmid. In sequence analysis of the promoter region, three putative PPREs (PPAR response elements) were identified, and promoter deletion analysis showed that PPRE2 and PPRE3 were functional. Electrophoretic mobility-shift assays revealed that PPARalpha/retinoid X receptor alpha heterodimer indeed bound to the two PPREs, and the binding specificity of PPARalpha on PPRE was also confirmed by experiments with mutated oligonucleotides. These results indicate that the elements behaved as a responsive site to PPARalpha activation. MCD mRNA levels in WY14643-treated rat hepatoma cells as well as in the liver of fenofibrate-fed Otsuka Long-Evans Tokushima fatty rats were also found to be increased, suggesting that PPARalpha can activate the rat hepatic MCD transcription by binding to the PPREs in the promoter. We propose that MCD performs an important role in understanding the regulatory mechanism between activated PPARalpha and fatty-acid oxidation by altering the malonyl-CoA concentration.
Full Text
The Full Text of this article is available as a PDF (271.7 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alam N., Saggerson E. D. Malonyl-CoA and the regulation of fatty acid oxidation in soleus muscle. Biochem J. 1998 Aug 15;334(Pt 1):233–241. doi: 10.1042/bj3340233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Braissant O., Wahli W. Differential expression of peroxisome proliferator-activated receptor-alpha, -beta, and -gamma during rat embryonic development. Endocrinology. 1998 Jun;139(6):2748–2754. doi: 10.1210/endo.139.6.6049. [DOI] [PubMed] [Google Scholar]
- Campbell Fiona M., Kozak Ray, Wagner Alese, Altarejos Judith Y., Dyck Jason R. B., Belke Darrell D., Severson David L., Kelly Daniel P., Lopaschuk Gary D. A role for peroxisome proliferator-activated receptor alpha (PPARalpha ) in the control of cardiac malonyl-CoA levels: reduced fatty acid oxidation rates and increased glucose oxidation rates in the hearts of mice lacking PPARalpha are associated with higher concentrations of malonyl-CoA and reduced expression of malonyl-CoA decarboxylase. J Biol Chem. 2001 Dec 4;277(6):4098–4103. doi: 10.1074/jbc.M106054200. [DOI] [PubMed] [Google Scholar]
- Chaput E., Saladin R., Silvestre M., Edgar A. D. Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight. Biochem Biophys Res Commun. 2000 May 10;271(2):445–450. doi: 10.1006/bbrc.2000.2647. [DOI] [PubMed] [Google Scholar]
- Chien D., Dean D., Saha A. K., Flatt J. P., Ruderman N. B. Malonyl-CoA content and fatty acid oxidation in rat muscle and liver in vivo. Am J Physiol Endocrinol Metab. 2000 Aug;279(2):E259–E265. doi: 10.1152/ajpendo.2000.279.2.E259. [DOI] [PubMed] [Google Scholar]
- Chu R., Lin Y., Rao M. S., Reddy J. K. Cooperative formation of higher order peroxisome proliferator-activated receptor and retinoid X receptor complexes on the peroxisome proliferator responsive element of the rat hydratase-dehydrogenase gene. J Biol Chem. 1995 Dec 15;270(50):29636–29639. doi: 10.1074/jbc.270.50.29636. [DOI] [PubMed] [Google Scholar]
- Cook W. S., Yeldandi A. V., Rao M. S., Hashimoto T., Reddy J. K. Less extrahepatic induction of fatty acid beta-oxidation enzymes by PPAR alpha. Biochem Biophys Res Commun. 2000 Nov 11;278(1):250–257. doi: 10.1006/bbrc.2000.3739. [DOI] [PubMed] [Google Scholar]
- Dana S. L., Hoener P. A., Bilakovics J. M., Crombie D. L., Ogilvie K. M., Kauffman R. F., Mukherjee R., Paterniti J. R., Jr Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Metabolism. 2001 Aug;50(8):963–971. doi: 10.1053/meta.2001.24870. [DOI] [PubMed] [Google Scholar]
- Desvergne B., Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999 Oct;20(5):649–688. doi: 10.1210/edrv.20.5.0380. [DOI] [PubMed] [Google Scholar]
- Dyck J. R., Berthiaume L. G., Thomas P. D., Kantor P. F., Barr A. J., Barr R., Singh D., Hopkins T. A., Voilley N., Prentki M. Characterization of rat liver malonyl-CoA decarboxylase and the study of its role in regulating fatty acid metabolism. Biochem J. 2000 Sep 1;350(Pt 2):599–608. [PMC free article] [PubMed] [Google Scholar]
- Dyck J. R., Kudo N., Barr A. J., Davies S. P., Hardie D. G., Lopaschuk G. D. Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5'-AMP activated protein kinase. Eur J Biochem. 1999 May;262(1):184–190. doi: 10.1046/j.1432-1327.1999.00371.x. [DOI] [PubMed] [Google Scholar]
- Hamilton C., Saggerson E. D. Malonyl-CoA metabolism in cardiac myocytes. Biochem J. 2000 Aug 15;350(Pt 1):61–67. [PMC free article] [PubMed] [Google Scholar]
- Issemann I., Prince R. A., Tugwood J. D., Green S. The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J Mol Endocrinol. 1993 Aug;11(1):37–47. doi: 10.1677/jme.0.0110037. [DOI] [PubMed] [Google Scholar]
- Jang S. H., Cheesbrough T. M., Kolattukudy P. E. Molecular cloning, nucleotide sequence, and tissue distribution of malonyl-CoA decarboxylase. J Biol Chem. 1989 Feb 25;264(6):3500–3505. [PubMed] [Google Scholar]
- Kalderon B., Hertz R., Bar-Tana J. Tissue selective modulation of redox and phosphate potentials by beta,beta'-methyl-substituted hexadecanedioic acid. Endocrinology. 1992 Oct;131(4):1629–1635. doi: 10.1210/endo.131.4.1396307. [DOI] [PubMed] [Google Scholar]
- Kaushik V. K., Young M. E., Dean D. J., Kurowski T. G., Saha A. K., Ruderman N. B. Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR. Am J Physiol Endocrinol Metab. 2001 Aug;281(2):E335–E340. doi: 10.1152/ajpendo.2001.281.2.E335. [DOI] [PubMed] [Google Scholar]
- Kersten Sander. Peroxisome proliferator activated receptors and obesity. Eur J Pharmacol. 2002 Apr 12;440(2-3):223–234. doi: 10.1016/s0014-2999(02)01431-0. [DOI] [PubMed] [Google Scholar]
- Kim K. H., López-Casillas F., Bai D. H., Luo X., Pape M. E. Role of reversible phosphorylation of acetyl-CoA carboxylase in long-chain fatty acid synthesis. FASEB J. 1989 Sep;3(11):2250–2256. doi: 10.1096/fasebj.3.11.2570725. [DOI] [PubMed] [Google Scholar]
- Kim K. H. Regulation of mammalian acetyl-coenzyme A carboxylase. Annu Rev Nutr. 1997;17:77–99. doi: 10.1146/annurev.nutr.17.1.77. [DOI] [PubMed] [Google Scholar]
- Kim Y. S., Kolattukudy P. E., Boos A. Dual sites of occurrence of malonyl-CoA decarboxylase and their possible functional significance in avian tissues. Comp Biochem Physiol B. 1979;62(4):443–447. doi: 10.1016/0305-0491(79)90115-9. [DOI] [PubMed] [Google Scholar]
- Kim Y. S., Kolattukudy P. E., Boos A. Malonyl-CoA decarboxylase in rat brain mitochondria. Int J Biochem. 1979;10(6):551–555. doi: 10.1016/0020-711x(79)90013-2. [DOI] [PubMed] [Google Scholar]
- Kim Y. S., Kolattukudy P. E. Malonyl-CoA decarboxylase from the uropygial gland of waterfowl: purification, properties, immunological comparison, and role in regulating the synthesis of multimethyl-branched fatty acids. Arch Biochem Biophys. 1978 Oct;190(2):585–597. doi: 10.1016/0003-9861(78)90314-4. [DOI] [PubMed] [Google Scholar]
- Kim Y. S., Kolattukudy P. E. Purification and properties of malonyl-CoA decarboxylase from rat liver mitochondria and its immunological comparison with the enzymes from rat brain, heart, and mammary gland. Arch Biochem Biophys. 1978 Sep;190(1):234–246. doi: 10.1016/0003-9861(78)90273-4. [DOI] [PubMed] [Google Scholar]
- Kuriyama H., Yamashita S., Shimomura I., Funahashi T., Ishigami M., Aragane K., Miyaoka K., Nakamura T., Takemura K., Man Z. Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation. Hepatology. 1998 Feb;27(2):557–562. doi: 10.1002/hep.510270233. [DOI] [PubMed] [Google Scholar]
- Kurowski T. G., Saha A. K., Cunningham B. A., Holbert R. I., Colca J. R., Corkey B. E., Ruderman N. B. Malonyl coenzyme A and adiposity in the Dahl salt-sensitive rat: effects of pioglitazone. Metabolism. 1996 Apr;45(4):519–525. doi: 10.1016/s0026-0495(96)90230-9. [DOI] [PubMed] [Google Scholar]
- Lee Gha Young, Cho Jin Won, Lee Hyun Chul, Kim Yu Sam. Genomic organization and characterization of the promoter of rat malonyl-CoA decarboxylase gene. Biochim Biophys Acta. 2002 Aug 19;1577(1):133–138. doi: 10.1016/s0167-4781(02)00398-6. [DOI] [PubMed] [Google Scholar]
- Lee H. J., Choi S. S., Park M. K., An Y. J., Seo S. Y., Kim M. C., Hong S. H., Hwang T. H., Kang D. Y., Garber A. J. Fenofibrate lowers abdominal and skeletal adiposity and improves insulin sensitivity in OLETF rats. Biochem Biophys Res Commun. 2002 Aug 16;296(2):293–299. doi: 10.1016/s0006-291x(02)00822-7. [DOI] [PubMed] [Google Scholar]
- McGarry J. D., Brown N. F. Reconstitution of purified, active and malonyl-CoA-sensitive rat liver carnitine palmitoyltransferase I: relationship between membrane environment and malonyl-CoA sensitivity. Biochem J. 2000 Jul 1;349(Pt 1):179–187. doi: 10.1042/0264-6021:3490179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McGarry J. D., Brown N. F. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 1997 Feb 15;244(1):1–14. doi: 10.1111/j.1432-1033.1997.00001.x. [DOI] [PubMed] [Google Scholar]
- McGarry J. D., Leatherman G. F., Foster D. W. Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J Biol Chem. 1978 Jun 25;253(12):4128–4136. [PubMed] [Google Scholar]
- McGarry J. D., Takabayashi Y., Foster D. W. The role of malonyl-coa in the coordination of fatty acid synthesis and oxidation in isolated rat hepatocytes. J Biol Chem. 1978 Nov 25;253(22):8294–8300. [PubMed] [Google Scholar]
- Moir A. M., Zammit V. A. Insulin-independent and extremely rapid switch in the partitioning of hepatic fatty acids from oxidation to esterification in starved-refed diabetic rats. Possible roles for changes in cell pH and volume. Biochem J. 1995 Feb 1;305(Pt 3):953–958. doi: 10.1042/bj3050953. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Muoio Deborah M., Way James M., Tanner Charles J., Winegar Deborah A., Kliewer Steven A., Houmard Joseph A., Kraus William E., Dohm G. Lynis. Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells. Diabetes. 2002 Apr;51(4):901–909. doi: 10.2337/diabetes.51.4.901. [DOI] [PubMed] [Google Scholar]
- Park Haejoe, Kaushik Virendar K., Constant Scarlet, Prentki Marc, Przybytkowski Ewa, Ruderman Neil B., Saha Asish K. Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J Biol Chem. 2002 Jun 13;277(36):32571–32577. doi: 10.1074/jbc.M201692200. [DOI] [PubMed] [Google Scholar]
- Rasmussen Blake B., Holmbäck Ulf C., Volpi Elena, Morio-Liondore Beatrice, Paddon-Jones Douglas, Wolfe Robert R. Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. J Clin Invest. 2002 Dec;110(11):1687–1693. doi: 10.1172/JCI15715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rustan A. C., Christiansen E. N., Drevon C. A. Serum lipids, hepatic glycerolipid metabolism and peroxisomal fatty acid oxidation in rats fed omega-3 and omega-6 fatty acids. Biochem J. 1992 Apr 15;283(Pt 2):333–339. doi: 10.1042/bj2830333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sacksteder K. A., Morrell J. C., Wanders R. J., Matalon R., Gould S. J. MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency. J Biol Chem. 1999 Aug 27;274(35):24461–24468. doi: 10.1074/jbc.274.35.24461. [DOI] [PubMed] [Google Scholar]
- Saha A. K., Laybutt D. R., Dean D., Vavvas D., Sebokova E., Ellis B., Klimes I., Kraegen E. W., Shafrir E., Ruderman N. B. Cytosolic citrate and malonyl-CoA regulation in rat muscle in vivo. Am J Physiol. 1999 Jun;276(6 Pt 1):E1030–E1037. doi: 10.1152/ajpendo.1999.276.6.E1030. [DOI] [PubMed] [Google Scholar]
- Saha A. K., Schwarsin A. J., Roduit R., Masse F., Kaushik V., Tornheim K., Prentki M., Ruderman N. B. Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-beta -D-ribofuranoside. J Biol Chem. 2000 Aug 11;275(32):24279–24283. doi: 10.1074/jbc.C000291200. [DOI] [PubMed] [Google Scholar]
- Sakamoto J., Barr R. L., Kavanagh K. M., Lopaschuk G. D. Contribution of malonyl-CoA decarboxylase to the high fatty acid oxidation rates seen in the diabetic heart. Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1196–H1204. doi: 10.1152/ajpheart.2000.278.4.H1196. [DOI] [PubMed] [Google Scholar]
- Skrede S., Bremer J., Berge R. K., Rustan A. C. Stimulation of fatty acid oxidation by a 3-thia fatty acid reduces triacylglycerol secretion in cultured rat hepatocytes. J Lipid Res. 1994 Aug;35(8):1395–1404. [PubMed] [Google Scholar]
- Stephens T. J., Chen Z-P, Canny B. J., Michell B. J., Kemp B. E., McConell G. K. Progressive increase in human skeletal muscle AMPKalpha2 activity and ACC phosphorylation during exercise. Am J Physiol Endocrinol Metab. 2002 Mar;282(3):E688–E694. doi: 10.1152/ajpendo.00101.2001. [DOI] [PubMed] [Google Scholar]
- Swenson T. L., Porter J. W. Mechanism of glucagon inhibition of liver acetyl-CoA carboxylase. Interrelationship of the effects of phosphorylation, polymer-protomer transition, and citrate on enzyme activity. J Biol Chem. 1985 Mar 25;260(6):3791–3797. [PubMed] [Google Scholar]
- Yeh L. A., Kim K. H. Regulation of acetyl-coA carboxylase: properties of coA activation of acetyl-coA carboxylase. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3351–3355. doi: 10.1073/pnas.77.6.3351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Young M. E., Goodwin G. W., Ying J., Guthrie P., Wilson C. R., Laws F. A., Taegtmeyer H. Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids. Am J Physiol Endocrinol Metab. 2001 Mar;280(3):E471–E479. doi: 10.1152/ajpendo.2001.280.3.E471. [DOI] [PubMed] [Google Scholar]