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PPAR Research
Volume 2010, Article ID 572405, 12 pages
http://dx.doi.org/10.1155/2010/572405
Review Article

Role of PPAR 𝛼 in Hepatic Carbohydrate Metabolism

Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, K.U.Leuven, Campus Gasthuisberg O/N2, 3000 Leuven, Belgium

Received 8 April 2010; Accepted 5 August 2010

Academic Editor: Elisabetta Mueller

Copyright © 2010 Annelies Peeters and Myriam Baes. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. Dreyer, G. Krey, H. Keller, F. Givel, G. Helftenbein, and W. Wahli, “Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors,” Cell, vol. 68, no. 5, pp. 879–887, 1992. View at Publisher · View at Google Scholar · View at Scopus
  2. T. Aoyama, J. M. Peters, N. Iritani et al., “Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α (PPARα),” Journal of Biological Chemistry, vol. 273, no. 10, pp. 5678–5684, 1998. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Kersten, J. Seydoux, J. M. Peters, F. J. Gonzalez, B. Desvergne, and W. Wahli, “Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting,” Journal of Clinical Investigation, vol. 103, no. 11, pp. 1489–1498, 1999. View at Google Scholar · View at Scopus
  4. S. Mandard, M. Müller, and S. Kersten, “Peroxisome proliferator-activated receptor α target genes,” Cellular and Molecular Life Sciences, vol. 61, no. 4, pp. 393–416, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. S. E. Olpin, “Implications of impaired ketogenesis in fatty acid oxidation disorders,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 70, no. 3, pp. 293–308, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. L. M. Sanderson, T. Degenhardt, A. Koppen et al., “Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) but not PPARα serves as a plasma free fatty acid sensor in liver,” Molecular and Cellular Biology, vol. 29, no. 23, pp. 6257–6267, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. M. V. Chakravarthy, Z. Pan, Y. Zhu et al., ““New” hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis,” Cell Metabolism, vol. 1, no. 5, pp. 309–322, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. M. V. Chakravarthy, I. J. Lodhi, L. Yin et al., “Identification of a physiologically relevant endogenous ligand for PPARα in liver,” Cell, vol. 138, no. 3, pp. 476–488, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. D. Patsouris, J. K. Reddy, M. Müller, and S. Kersten, “Peroxisome proliferator-activated receptor α mediates the effects of high-fat diet on hepatic gene expression,” Endocrinology, vol. 147, no. 3, pp. 1508–1516, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. P. G. P. Martin, H. Guillou, F. Lasserre et al., “Novel aspects of PPARα-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study,” Hepatology, vol. 45, no. 3, pp. 767–777, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. L. M. Sanderson, P. J. de Groot, G. J. E. J. Hooiveld et al., “Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics,” PLoS One, vol. 3, no. 2, Article ID e1681, 2008. View at Publisher · View at Google Scholar · View at PubMed
  12. C. N. A. Palmer, M.-H. Hsu, K. J. Griffin, J. L. Raucy, and E. F. Johnson, “Peroxisome proliferator activated receptor-α expression in human liver,” Molecular Pharmacology, vol. 53, no. 1, pp. 14–22, 1998. View at Google Scholar · View at Scopus
  13. M. Rakhshandehroo, G. Hooiveld, M. Müller, and S. Kersten, “Comparative analysis of gene regulation by the transcription factor PPARα between mouse and human,” PLoS One, vol. 4, no. 8, Article ID e6796, 2009. View at Publisher · View at Google Scholar · View at PubMed
  14. F. J. Gonzalez and Y. M. Shah, “PPARα: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators,” Toxicology, vol. 246, no. 1, pp. 2–8, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. M. Fidaleo, “Human health risk assessment for peroxisome proliferators: more than 30 years of research,” Experimental and Toxicologic Pathology, vol. 61, no. 3, pp. 215–221, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. D. H. Wasserman, “Four grams of glucose,” American Journal of Physiology, vol. 296, no. 1, pp. E11–E21, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. M. Stolar, “Glycemic control and complications in type 2 diabetes mellitus,” American Journal of Medicine, vol. 123, no. 3, supplement, pp. S3–S11, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. T. C. Leone, C. J. Weinheimer, and D. P. Kelly, “A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 13, pp. 7473–7478, 1999. View at Publisher · View at Google Scholar · View at Scopus
  19. D. M. Muoio, P. S. MacLean, D. B. Lang et al., “Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) α knock-out mice. Evidence for compensatory regulation by PPARδ,” Journal of Biological Chemistry, vol. 277, no. 29, pp. 26089–26097, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. J. Xu, G. Xiao, C. Tirujillo et al., “Peroxisome proliferator-activated receptor α (PPARα) influences substrate utilization for hepatic glucose production,” Journal of Biological Chemistry, vol. 277, no. 52, pp. 50237–50244, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. R. H. J. Bandsma, T. H. van Dijk, A. ter Harmsel et al., “Hepatic de novo synthesis of glucose 6-phosphate is not affected in peroxisome proliferator-activated receptor α-deficient mice but is preferentially directed toward hepatic glycogen stores after a short term fast,” Journal of Biological Chemistry, vol. 279, no. 10, pp. 8930–8937, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. D. Patsouris, S. Mandard, P. J. Voshol et al., “PPARα governs glycerol metabolism,” Journal of Clinical Investigation, vol. 114, no. 1, pp. 94–103, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. C. Knauf, J. Rieusset, M. Foretz et al., “Peroxisome proliferator-activated receptor-α-null mice have increased white adipose tissue glucose utilization, GLUT4, and fat mass: role in liver and brain,” Endocrinology, vol. 147, no. 9, pp. 4067–4078, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. C. Le May, T. Pineau, K. Bigot, C. Kohl, J. Girard, and J.-P. Pégorier, “Reduced hepatic fatty acid oxidation in fasting PPARα null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression,” FEBS Letters, vol. 475, no. 3, pp. 163–166, 2000. View at Publisher · View at Google Scholar · View at Scopus
  25. T. Hashimoto, W. S. Cook, C. Qi, A. V. Yeldandi, J. K. Reddy, and M. S. Rao, “Defect in peroxisome proliferator-activated receptor α-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting,” Journal of Biological Chemistry, vol. 275, no. 37, pp. 28918–28928, 2000. View at Google Scholar · View at Scopus
  26. T.-H. Kim, H. Kim, J.-M. Park et al., “Interrelationship between liver X receptor α, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor γ, and small heterodimer partner in the transcriptional regulation of glucokinase gene expression in liver,” Journal of Biological Chemistry, vol. 284, no. 22, pp. 15071–15083, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. A. D. Colosia, A. J. Marker, A. J. Lange et al., “Induction of rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase mRNA by refeeding and insulin,” Journal of Biological Chemistry, vol. 263, no. 35, pp. 18669–18677, 1988. View at Google Scholar · View at Scopus
  28. C. Wu, S. A. Khan, and A. J. Lange, “Regulation of glycolysis-role of insulin,” Experimental Gerontology, vol. 40, no. 11, pp. 894–899, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. S. Connaughton, F. Chowdhury, R. R. Attia et al., “Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin,” Molecular and Cellular Endocrinology, vol. 315, no. 1-2, pp. 159–167, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. M. H. Oosterveer, A. Grefhorst, T. H. van Dijk et al., “Fenofibrate simultaneously induces hepatic fatty acid oxidation, synthesis, and elongation in mice,” Journal of Biological Chemistry, vol. 284, no. 49, pp. 34036–34044, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. L. A. Gustafson, F. Kuipers, C. Wiegman, H. P. Sauerwein, J. A. Romijn, and A. J. Meijer, “Clotibrate improves glucose tolerance in fat-fed rats but decreases hepatic glucose consumption capacity,” Journal of Hepatology, vol. 37, no. 4, pp. 425–431, 2002. View at Publisher · View at Google Scholar · View at Scopus
  32. D. A. Pan, M. K. Mater, A. P. Thelen, J. M. Peters, F. J. Gonzalez, and D. B. Jump, “Evidence against the peroxisome proliferator-activated receptor α (PPARα) as the mediator for polyunsaturated fatty acid suppression of hepatic L-pyruvate kinase gene transcription,” Journal of Lipid Research, vol. 41, no. 5, pp. 742–751, 2000. View at Google Scholar · View at Scopus
  33. J. Xu, B. Christian, and D. B. Jump, “Regulation of rat hepatic L-pyruvate kinase promoter composition and activity by glucose, n-3 polyunsaturated fatty acids, and peroxisome proliferator-activated receptor-α agonist,” Journal of Biological Chemistry, vol. 281, no. 27, pp. 18351–18362, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. S.-Y. Kim, H.-I. Kim, S.-K. Park et al., “Liver glucokinase can be activated by peroxisome proliferator-activated receptor-γ,” Diabetes, vol. 53, no. 1, pp. S66–S70, 2004. View at Google Scholar · View at Scopus
  35. J. Xu, V. Chang, S. B. Joseph et al., “Peroxisomal proliferator-activated receptor α deficiency diminishes insulin-responsiveness of gluconeogenic/glycolytic/pentose gene expression and substrate cycle flux,” Endocrinology, vol. 145, no. 3, pp. 1087–1095, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. P. Wu, J. M. Peters, and R. A. Harris, “Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor α,” Biochemical and Biophysical Research Communications, vol. 287, no. 2, pp. 391–396, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. B. Huang, P. Wu, K. M. Popov, and R. A. Harris, “Starvation and diabetes reduce the amount of pyruvate dehydrogenase phosphatase in rat heart and kidney,” Diabetes, vol. 52, no. 6, pp. 1371–1376, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. T. Degenhardt, A. Saramäki, M. Malinen et al., “Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor β/δ,” Journal of Molecular Biology, vol. 372, no. 2, pp. 341–355, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. M. C. Sugden, K. Bulmer, G. F. Gibbons, B. L. Knight, and M. J. Holness, “Peroxisome-proliferator-activated receptor-α (PPARα) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin,” Biochemical Journal, vol. 364, no. 2, pp. 361–368, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. K. Ma, Y. Zhang, M. B. Elam, G. A. Cook, and E. A. Park, “Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter: activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor γ coactivator,” Journal of Biological Chemistry, vol. 280, no. 33, pp. 29525–29532, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. Z. Spolarics, “Endotoxemia, pentose cycle, and the oxidant/antioxidant balance in the hepatic sinusoid,” Journal of Leukocyte Biology, vol. 63, no. 5, pp. 534–541, 1998. View at Google Scholar · View at Scopus
  42. N. J. Hutson, F. T. Brumley, and F. D. Assimacopoulos, “Studies on the α adrenergic activation of hepatic glucose output. I. Studies on the α adrenergic activation of phosphorylase and gluconeogenesis and inactivation of glycogen synthase in isolated rat liver parenchymal cells,” Journal of Biological Chemistry, vol. 251, no. 17, pp. 5200–5208, 1976. View at Google Scholar · View at Scopus
  43. C. Minassian, S. Montano, and G. Mithieux, “Regulatory role of glucose-6 phosphatase in the repletion of liver glycogen during refeeding in fasted rats,” Biochimica et Biophysica Acta, vol. 1452, no. 2, pp. 172–178, 1999. View at Publisher · View at Google Scholar · View at Scopus
  44. S. Mandard, R. Stienstra, P. Escher et al., “Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors,” Cellular and Molecular Life Sciences, vol. 64, no. 9, pp. 1145–1157, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. Y. Cheon, T. Y. Nara, M. R. Band, J. E. Beever, M. A. Wallig, and M. T. Nakamura, “Induction of overlapping genes by fasting and a peroxisome proliferator in pigs: evidence of functional PPARα in nonproliferating species,” American Journal of Physiology, vol. 288, no. 6, pp. R1525–R1535, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. H. Cassuto, A. Aran, H. Cohen, C. L. Eisenberger, and L. Reshef, “Repression and activation of transcription of phosphoenolpyruvate carboxykinase gene during liver development,” FEBS Letters, vol. 457, no. 3, pp. 441–444, 1999. View at Publisher · View at Google Scholar · View at Scopus
  47. C. Xu, K. Chakravarty, X. Kong et al., “Several transcription factors are recruited to the glucose-6-phosphatase gene promoter in response to palmitate in rat hepatocytes and H4IIE cells,” Journal of Nutrition, vol. 137, no. 3, pp. 554–559, 2007. View at Google Scholar · View at Scopus
  48. C. Juge-Aubry, A. Pernin, T. Favez et al., “DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements: importance of the 5'-flanking region,” Journal of Biological Chemistry, vol. 272, no. 40, pp. 25252–25259, 1997. View at Publisher · View at Google Scholar · View at Scopus
  49. P. Tontonoz, E. Hu, J. Devine, E. G. Beale, and B. M. Spiegelman, “PPARγ2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene,” Molecular and Cellular Biology, vol. 15, no. 1, pp. 351–357, 1995. View at Google Scholar · View at Scopus
  50. J. A. Kramer, E. A. G. Blomme, R. T. Bunch et al., “Transcription profiling distinguishes dose-dependent effects in the livers of rats treated with clofibrate,” Toxicologic Pathology, vol. 31, no. 4, pp. 417–431, 2003. View at Publisher · View at Google Scholar · View at Scopus
  51. C. Bernal-Mizrachi, S. Weng, C. Feng et al., “Dexamethasone induction of hypertension and diabetes is PPAR-α dependent in LDL receptor-null mice,” Nature Medicine, vol. 9, no. 8, pp. 1069–1075, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. B. König, A. Koch, K. Giggel, B. Dordschbal, K. Eder, and G. I. Stangl, “Monocarboxylate transporter (MCT)-1 is up-regulated by PPARα,” Biochimica et Biophysica Acta, vol. 1780, no. 6, pp. 899–904, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. B. Konig, S. Fischer, S. Schlotte, G. Wen, K. Eder, and G. I. Stangl, “Monocarboxylate transporter 1 and CD147 are up-regulated by natural and synthetic peroxisome proliferator-activated receptor alpha agonists in livers of rodents and pigs,” Molecular Nutrition & Food Research, vol. 54, pp. 1248–1256, 2010. View at Google Scholar
  54. H. J. Atherton, N. J. Bailey, W. Zhang et al., “A combined 1H-NMR spectroscopy- and mass spectrometry-based metabolomic study of the PPAR-α null mutant mouse defines profound systemic changes in metabolism linked to the metabolic syndrome,” Physiological Genomics, vol. 27, no. 2, pp. 178–186, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. P. Felig, T. Pozefsk, E. Marlis, and G. F. Cahill Jr., “Alanine: key role in gluconeogenesis,” Science, vol. 167, no. 3920, pp. 1003–1004, 1970. View at Google Scholar · View at Scopus
  56. S. Kersten, S. Mandard, P. Escher et al., “The peroxisome proliferator-activated receptor α regulates amino acid metabolism,” FASEB Journal, vol. 15, no. 11, pp. 1971–1978, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. S.-H. Koo, H. Satoh, S. Herzig et al., “PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3,” Nature Medicine, vol. 10, no. 5, pp. 530–534, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. K. Du, S. Herzig, R. N. Kulkarni, and M. Montminy, “TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver,” Science, vol. 300, no. 5625, pp. 1574–1577, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. P. Ferré, M. Foretz, D. Azzout-Marniche, D. Bécard, and F. Foufelle, “Sterol-regulatory-element-binding protein 1c mediates insulin action on hepatic gene expression,” Biochemical Society Transactions, vol. 29, no. 4, pp. 547–552, 2001. View at Publisher · View at Google Scholar · View at Scopus
  60. H. A. Hostetler, H. Huang, A. B. Kier, and F. Schroeder, “Glucose directly links to lipid metabolism through high affinity interaction with peroxisome proliferator-activated receptor α,” Journal of Biological Chemistry, vol. 283, no. 4, pp. 2246–2254, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. H. A. Hostetler, L. R. Syler, L. N. Hall, G. Zhu, F. Schroeder, and A. B. Kier, “A novel high-throughput screening assay for putative antidiabetic agents through PPARα interactions,” Journal of Biomolecular Screening, vol. 13, no. 9, pp. 855–861, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus