Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2016, Article ID 7403230, 18 pages
http://dx.doi.org/10.1155/2016/7403230
Review Article

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

1Clinical Gastroenterology Unit, Department of Biomedical Clinical and Experimental Sciences “Mario Serio”, University of Florence, Viale Pieraccini 6, 50129 Florence, Italy
2Careggi University Hospital, Florence, Italy

Received 22 July 2016; Revised 8 November 2016; Accepted 10 November 2016

Academic Editor: Daniele Fanale

Copyright © 2016 Tommaso Mello et al. 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. J. Ferlay, I. Soerjomataram, M. Ervik et al., GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide, IARC CancerBase no. 11, International Agency for Research on Cancer, 2013, http://globocan.iarc.fr.
  2. H. B. El-Serag, “Hepatocellular carcinoma,” New England Journal of Medicine, vol. 365, no. 12, pp. 1118–1127, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. Z. M. Younossi, A. B. Koenig, D. Abdelatif, Y. Fazel, L. Henry, and M. Wymer, “Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes,” Hepatology, vol. 64, no. 1, pp. 73–84, 2016. View at Publisher · View at Google Scholar
  4. B. Q. Starley, C. J. Calcagno, and S. A. Harrison, “Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection,” Hepatology, vol. 51, no. 5, pp. 1820–1832, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. H. B. El-Serag, T. Tran, and J. E. Everhart, “Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma,” Gastroenterology, vol. 126, no. 2, pp. 460–468, 2004. View at Publisher · View at Google Scholar · View at Scopus
  6. N. Chalasani, Z. Younossi, J. E. Lavine et al., “The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association,” Hepatology, vol. 55, no. 6, pp. 2005–2023, 2012. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Masarone, A. Federico, L. Abenavoli, C. Loguercio, and M. Persico, “Non alcoholic fatty liver: epidemiology and natural history,” Reviews on Recent Clinical Trials, vol. 9, no. 3, pp. 126–133, 2014. View at Google Scholar · View at Scopus
  8. N. Kawada, K. Imanaka, T. Kawaguchi et al., “Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis,” Journal of Gastroenterology, vol. 44, no. 12, pp. 1190–1194, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. O. Warburg, “On the origin of cancer cells,” Science, vol. 123, no. 3191, pp. 309–314, 1956. View at Publisher · View at Google Scholar · View at Scopus
  10. O. warburg, “On respiratory impairment in cancer cells,” Science, vol. 124, no. 3215, pp. 269–270, 1956. View at Google Scholar · View at Scopus
  11. C. S. Ahn and C. M. Metallo, “Mitochondria as biosynthetic factories for cancer proliferation,” Cancer & Metabolism, vol. 3, no. 1, article 1, 2015. View at Publisher · View at Google Scholar
  12. A. W. F. Janssen, B. Betzel, G. Stoopen et al., “The impact of PPARα activation on whole genome gene expression in human precision cut liver slices,” BMC Genomics, vol. 16, no. 1, article 760, 2015. View at Publisher · 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 Scopus
  14. W. Wahli and L. Michalik, “PPARs at the crossroads of lipid signaling and inflammation,” Trends in Endocrinology and Metabolism, vol. 23, no. 7, pp. 351–363, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. 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 Scopus
  16. 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 Scopus
  17. 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 Scopus
  18. 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 Scopus
  19. 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 Publisher · View at Google Scholar · View at Scopus
  20. A. Montagner, A. Polizzi, E. Fouche et al., “Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD,” Gut, vol. 65, no. 7, pp. 1202–1214, 2016. View at Publisher · View at Google Scholar
  21. 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 Scopus
  22. T. Yamauchi, J. Kamon, Y. Ito et al., “Cloning of adiponectin receptors that mediate antidiabetic metabolic effects,” Nature, vol. 423, no. 6941, pp. 762–769, 2003. View at Publisher · View at Google Scholar · View at Scopus
  23. P. Iglesias, R. Selgas, S. Romero, and J. J. Díez, “Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21,” European Journal of Endocrinology, vol. 167, no. 3, pp. 301–309, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. F. M. Fisher, P. C. Chui, I. A. Nasser et al., “Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets,” Gastroenterology, vol. 147, no. 5, pp. 1073.e6–1083.e6, 2014. View at Publisher · View at Google Scholar · View at Scopus
  25. E. Szalowska, H. A. Tesfay, S. A. van Hijum, and S. Kersten, “Transcriptomic signatures of peroxisome proliferator-activated receptor α (PPARα) in different mouse liver models identify novel aspects of its biology,” BMC Genomics, vol. 15, no. 1, article 1106, 2014. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Kersten, M. Rakhshandehroo, B. Knoch, and M. Müller, “Peroxisome proliferator-activated receptor alpha target genes,” PPAR Research, Article ID 612089, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. D. G. Cotter, B. Ercal, X. Huang et al., “Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia,” The Journal of Clinical Investigation, vol. 124, no. 12, pp. 5175–5190, 2014. View at Publisher · View at Google Scholar · View at Scopus
  28. Y. Wang, A.-W. Mohsen, S. J. Mihalik, E. S. Goetzman, and J. Vockley, “Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes,” Journal of Biological Chemistry, vol. 285, no. 39, pp. 29834–29841, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. F. Villarroya, R. Iglesias, and M. Giralt, “PPARs in the control of uncoupling proteins gene expression,” PPAR Research, vol. 2007, Article ID 74364, 12 pages, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. L. J. Kelly, P. P. Vicario, G. M. Thompson et al., “Peroxisome proliferator-activated receptors γ and α mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression,” Endocrinology, vol. 139, no. 12, pp. 4920–4927, 1998. View at Google Scholar · View at Scopus
  31. G. Y. Lee, N. H. Kim, Z.-S. Zhao, B. S. Cha, and Y. S. Kim, “Peroxisomal-proliferator-activated receptor α activates transcription of the rat hepatic malonyl-CoA decarboxylase gene: a key regulation of malonyl-CoA level,” Biochemical Journal, vol. 378, no. 3, pp. 983–990, 2004. View at Publisher · View at Google Scholar · View at Scopus
  32. L. Cheng, G. Ding, Q. Qin et al., “Cardiomyocyte-restricted peroxisome proliferator-activated receptor-δ deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy,” Nature Medicine, vol. 10, no. 11, pp. 1245–1250, 2004. View at Publisher · View at Google Scholar · View at Scopus
  33. 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 Scopus
  34. U. Dressel, T. L. Allen, J. B. Pippal, P. R. Rohde, P. Lau, and G. E. O. Muscat, “The peroxisome proliferator-activated receptor β/δ agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells,” Molecular Endocrinology, vol. 17, no. 12, pp. 2477–2493, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. B. Brunmair, K. Staniek, J. Dörig et al., “Activation of PPAR-delta in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids,” Diabetologia, vol. 49, no. 11, pp. 2713–2722, 2006. View at Publisher · View at Google Scholar · View at Scopus
  36. L. Jiang, J. Wan, L.-Q. Ke, Q.-G. Lü, and N.-W. Tong, “Activation of PPARδ promotes mitochondrial energy metabolism and decreases basal insulin secretion in palmitate-treated β-cells,” Molecular and Cellular Biochemistry, vol. 343, no. 1-2, pp. 249–256, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. M. C. Manio, K. Inoue, M. Fujitani, S. Matsumura, and T. Fushiki, “Combined pharmacological activation of AMPK and PPARδ potentiates the effects of exercise in trained mice,” Physiological Reports, vol. 4, no. 5, Article ID e12625, 2016. View at Publisher · View at Google Scholar
  38. S. Liu, B. Hatano, M. Zhao et al., “Role of peroxisome proliferator-activated receptor δ/β in hepatic metabolic regulation,” Journal of Biological Chemistry, vol. 286, no. 2, pp. 1237–1247, 2011. View at Publisher · View at Google Scholar · View at Scopus
  39. L. M. Sanderson, M. V. Boekschoten, B. Desvergne, M. Müller, and S. Kersten, “Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver,” Physiological Genomics, vol. 41, no. 1, pp. 42–52, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Liu, J. D. Brown, K. J. Stanya et al., “A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use,” Nature, vol. 502, no. 7472, pp. 550–554, 2013. View at Publisher · View at Google Scholar · View at Scopus
  41. D.-Y. Zhu, J.-Y. Wu, H. Li et al., “PPAR-β facilitating maturation of hepatic-like tissue derived from mouse embryonic stem cells accompanied by mitochondriogenesis and membrane potential retention,” Journal of Cellular Biochemistry, vol. 109, no. 3, pp. 498–508, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. E. Hondares, M. Rosell, J. Díaz-Delfín et al., “Peroxisome proliferator-activated receptor α (PPARα) induces PPARγ coactivator 1α (PGC-1α) gene expression and contributes to thermogenic activation of brown fat: involvement of PRDM16,” Journal of Biological Chemistry, vol. 286, no. 50, pp. 43112–43122, 2011. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Schuler, F. Ali, C. Chambon et al., “PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type switching, obesity, and type 2 diabetes,” Cell Metabolism, vol. 4, no. 5, pp. 407–414, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. E. Hondares, I. Pineda-Torra, R. Iglesias, B. Staels, F. Villarroya, and M. Giralt, “PPARδ, but not PPARα, activates PGC-1α gene transcription in muscle,” Biochemical and Biophysical Research Communications, vol. 354, no. 4, pp. 1021–1027, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. S. Herzig, F. Long, U. S. Jhala et al., “CREB regulates hepatic gluconeogenesis through the coactivator PGC-1,” Nature, vol. 413, no. 6852, pp. 179–183, 2001. View at Publisher · View at Google Scholar · View at Scopus
  46. M. T. Nakamura, B. E. Yudell, and J. J. Loor, “Regulation of energy metabolism by long-chain fatty acids,” Progress in Lipid Research, vol. 53, no. 1, pp. 124–144, 2014. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998. View at Publisher · View at Google Scholar · View at Scopus
  48. R. E. Soccio, E. R. Chen, and M. A. Lazar, “Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes,” Cell Metabolism, vol. 20, no. 4, pp. 573–591, 2014. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Ahmadian, J. M. Suh, N. Hah et al., “PPARγ signaling and metabolism: the good, the bad and the future,” Nature Medicine, vol. 19, no. 5, pp. 557–566, 2013. View at Publisher · View at Google Scholar · View at Scopus
  50. O. Gavrilova, M. Haluzik, K. Matsusue et al., “Liver peroxisome proliferator-activated receptor γ contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass,” Journal of Biological Chemistry, vol. 278, no. 36, pp. 34268–34276, 2003. View at Publisher · View at Google Scholar · View at Scopus
  51. K. Matsusue, M. Haluzik, G. Lambert et al., “Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes,” The Journal of Clinical Investigation, vol. 111, no. 5, pp. 737–747, 2003. View at Publisher · View at Google Scholar · View at Scopus
  52. P. Puigserver, Z. Wu, C. W. Park, R. Graves, M. Wright, and B. M. Spiegelman, “A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis,” Cell, vol. 92, no. 6, pp. 829–839, 1998. View at Publisher · View at Google Scholar · View at Scopus
  53. J. St-Pierre, J. Lin, S. Krauss et al., “Bioenergetic analysis of peroxisome proliferator-activated receptor γ coactivators 1α and 1β (PGC-1α and PGC-1β) in muscle cells,” The Journal of Biological Chemistry, vol. 278, no. 29, pp. 26597–26603, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. W. Fan and R. Evans, “PPARs and ERRs: molecular mediators of mitochondrial metabolism,” Current Opinion in Cell Biology, vol. 33, pp. 49–54, 2015. View at Publisher · View at Google Scholar · View at Scopus
  55. E. Hondares, O. Mora, P. Yubero et al., “Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-1α gene transcription: an autoregulatory loop controls PGC-1α expression in adipocytes via peroxisome proliferator-activated receptor-γ coactivation,” Endocrinology, vol. 147, no. 6, pp. 2829–2838, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. H. Maruyama, S. Kiyono, T. Kondo, T. Sekimoto, and O. Yokosuka, “Palmitate-induced regulation of PPARγ via PGC1α: a mechanism for lipid accumulation in the liver in nonalcoholic fatty liver disease,” International Journal of Medical Sciences, vol. 13, no. 3, pp. 169–178, 2016. View at Publisher · View at Google Scholar
  57. P. D. Ray, B.-W. Huang, and Y. Tsuji, “Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling,” Cellular Signalling, vol. 24, no. 5, pp. 981–990, 2012. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Schieber and N. S. Chandel, “ROS function in redox signaling and oxidative stress,” Current Biology, vol. 24, no. 10, pp. R453–R462, 2014. View at Publisher · View at Google Scholar · View at Scopus
  59. L. Zeng, W. J. Tang, J. J. Yin, and B. J. Zhou, “Signal transductions and nonalcoholic fatty liver: a mini-review,” International Journal of Clinical and Experimental Medicine, vol. 7, no. 7, pp. 1624–1631, 2014. View at Google Scholar · View at Scopus
  60. I. Afanas'ev, “Signaling of reactive oxygen and nitrogen species in diabetes mellitus,” Oxidative Medicine and Cellular Longevity, vol. 3, no. 6, pp. 361–373, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. I. Afanas'ev, “Reactive oxygen species signaling in cancer: comparison with aging,” Aging and Disease, vol. 2, no. 3, pp. 219–230, 2011. View at Google Scholar · View at Scopus
  62. J. St-Pierre, J. A. Buckingham, S. J. Roebuck, and M. D. Brand, “Topology of superoxide production from different sites in the mitochondrial electron transport chain,” The Journal of Biological Chemistry, vol. 277, no. 47, pp. 44784–44790, 2002. View at Publisher · View at Google Scholar · View at Scopus
  63. E. B. Tahara, F. D. T. Navarete, and A. J. Kowaltowski, “Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation,” Free Radical Biology and Medicine, vol. 46, no. 9, pp. 1283–1297, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. T. Mello, F. Zanieri, E. Ceni, and A. Galli, “Oxidative stress in the healthy and wounded hepatocyte: a cellular organelles perspective,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 8327410, 15 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  65. C. Ricci, V. Pastukh, J. Leonard et al., “Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis,” American Journal of Physiology—Cell Physiology, vol. 294, no. 2, pp. C413–C422, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. H. Kawahara, M. Fukura, M. Tsuchishima, and S. Takase, “Mutation of mitochondrial DNA in livers from patients with alcoholic hepatitis and nonalcoholic steatohepatitis,” Alcoholism: Clinical and Experimental Research, vol. 31, supplement 1, pp. S54–S60, 2007. View at Publisher · View at Google Scholar · View at Scopus
  67. L. Llacuna, A. Fernández, C. V. Montfort et al., “Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury,” Journal of Hepatology, vol. 54, no. 5, pp. 1002–1010, 2011. View at Publisher · View at Google Scholar · View at Scopus
  68. L. A. Videla, R. Rodrigo, M. Orellana et al., “Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients,” Clinical Science, vol. 106, no. 3, pp. 261–268, 2004. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Xiao and G. L. Tipoe, “Inflammasomes in non-alcoholic fatty liver disease,” Frontiers in Bioscience, vol. 21, pp. 683–695, 2016. View at Publisher · View at Google Scholar
  70. D. Sharma and T. Kanneganti, “The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation,” The Journal of Cell Biology, vol. 213, no. 6, pp. 617–629, 2016. View at Publisher · View at Google Scholar
  71. M. Y. Lee, R. Choi, H. M. Kim et al., “Peroxisome proliferator-activated receptor delta agonist attenuates hepatic steatosis by anti-inflammatory mechanism,” Experimental & Molecular Medicine, vol. 44, no. 10, pp. 578–585, 2012. View at Google Scholar
  72. S. Seki, T. Kitada, T. Yamada, H. Sakaguchi, K. Nakatani, and K. Wakasa, “In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases,” Journal of Hepatology, vol. 37, no. 1, pp. 56–62, 2002. View at Publisher · View at Google Scholar · View at Scopus
  73. S. H. Caldwell, R. H. Swerdlow, E. M. Khan et al., “Mitochondrial abnormalities in non-alcoholic steatohepatitis,” Journal of Hepatology, vol. 31, no. 3, pp. 430–434, 1999. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Pérez-Carreras, P. Del Hoyo, M. A. Martín et al., “Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis,” Hepatology, vol. 38, no. 4, pp. 999–1007, 2003. View at Publisher · View at Google Scholar · View at Scopus
  75. R. Gambino, G. Musso, and M. Cassader, “Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities,” Antioxidants and Redox Signaling, vol. 15, no. 5, pp. 1325–1365, 2011. View at Publisher · View at Google Scholar · View at Scopus
  76. Y. Ikura, M. Ohsawa, T. Suekane et al., “Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: impact on disease progression,” Hepatology, vol. 43, no. 3, pp. 506–514, 2006. View at Publisher · View at Google Scholar · View at Scopus
  77. S. Li, X.-Y. Zeng, X. Zhou et al., “Dietary cholesterol induces hepatic inflammation and blunts mitochondrial function in the liver of high-fat-fed mice,” Journal of Nutritional Biochemistry, vol. 27, pp. 96–103, 2016. View at Publisher · View at Google Scholar · View at Scopus
  78. V. Ribas, C. García-Ruiz, and J. C. Fernández-Checa, “Mitochondria, cholesterol and cancer cell metabolism,” Clinical and Translational Medicine, vol. 5, article 22, 2016. View at Publisher · View at Google Scholar
  79. E. Ip, G. C. Farrell, G. Robertson, P. Hall, R. Kirsch, and I. Leclercq, “Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice,” Hepatology, vol. 38, no. 1, pp. 123–132, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. E. Ip, G. Farrell, P. Hall, G. Robertson, and I. Leclercq, “Administration of the potent PPARα agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice,” Hepatology, vol. 39, no. 5, pp. 1286–1296, 2004. View at Publisher · View at Google Scholar · View at Scopus
  81. P. Costet, C. Legendre, J. Moré, A. Edgar, P. Galtier, and T. Pineau, “Peroxisome proliferator-activated receptor α-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis,” The Journal of Biological Chemistry, vol. 273, no. 45, pp. 29577–29585, 1998. View at Publisher · View at Google Scholar · View at Scopus
  82. M. A. Abdelmegeed, S.-H. Yoo, L. E. Henderson, F. J. Gonzalez, K. J. Woodcroft, and B.-J. Song, “PPARα expression protects male mice from high fat-induced nonalcoholic fatty liver,” The Journal of Nutrition, vol. 141, no. 4, pp. 603–610, 2011. View at Publisher · View at Google Scholar · View at Scopus
  83. K. Begriche, J. Massart, M.-A. Robin, F. Bonnet, and B. Fromenty, “Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease,” Hepatology, vol. 58, no. 4, pp. 1497–1507, 2013. View at Publisher · View at Google Scholar · View at Scopus
  84. M. Monetti, M. C. Levin, M. J. Watt et al., “Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver,” Cell Metabolism, vol. 6, no. 1, pp. 69–78, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. W. Liao, T. Y. Hui, S. G. Young, and R. A. Davis, “Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER,” Journal of Lipid Research, vol. 44, no. 5, pp. 978–985, 2003. View at Publisher · View at Google Scholar · View at Scopus
  86. Z. Z. Li, M. Berk, T. M. McIntyre, and A. E. Feldstein, “Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-Coa desaturase,” Journal of Biological Chemistry, vol. 284, no. 9, pp. 5637–5644, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. M. Sharma, S. Mitnala, R. K. Vishnubhotla, R. Mukherjee, D. N. Reddy, and P. N. Rao, “The riddle of nonalcoholic fatty liver disease: progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis,” Journal of Clinical and Experimental Hepatology, vol. 5, no. 2, pp. 147–158, 2015. View at Publisher · View at Google Scholar · View at Scopus
  88. K. Beier, A. Völkl, and D. Fahimi, “TNF-α downregulates the peroxisome proliferator activated receptor-α and the mRNAs encoding peroxisomal proteins in rat liver,” FEBS Letters, vol. 412, no. 2, pp. 385–387, 1997. View at Publisher · View at Google Scholar · View at Scopus
  89. V. G. Giby and T. A. Ajith, “Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease,” World Journal of Hepatology, vol. 6, no. 8, pp. 570–579, 2014. View at Publisher · View at Google Scholar · View at Scopus
  90. S. R. Ande, K. H. Nguyen, B. L. Grégoire Nyomba, and S. Mishra, “Prohibitin-induced, obesity-associated insulin resistance and accompanying low-grade inflammation causes NASH and HCC,” Scientific Reports, vol. 6, Article ID 23608, 2016. View at Publisher · View at Google Scholar
  91. S. Francque, A. Verrijken, S. Caron et al., “PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis,” Journal of Hepatology, vol. 63, no. 1, pp. 164–173, 2015. View at Publisher · View at Google Scholar · View at Scopus
  92. Y. M. Shah, K. Morimura, Q. Yang, T. Tanabe, M. Takagi, and F. J. Gonzalez, “Peroxisome proliferator-activated receptor α regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation,” Molecular and Cellular Biology, vol. 27, no. 12, pp. 4238–4247, 2007. View at Publisher · View at Google Scholar · View at Scopus
  93. N. Tanaka, K. Moriya, K. Kiyosawa, K. Koike, F. J. Gonzalez, and T. Aoyama, “PPARα activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice,” The Journal of Clinical Investigation, vol. 118, no. 2, pp. 683–694, 2008. View at Publisher · View at Google Scholar · View at Scopus
  94. 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 Scopus
  95. S. Bonovas, G. K. Nikolopoulos, and P. G. Bagos, “Use of fibrates and cancer risk: a systematic review and meta-analysis of 17 long-term randomized placebo-controlled trials,” PLoS ONE, vol. 7, no. 9, Article ID 0045259, 2012. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Zhang, E. S. H. Chu, J. Zhang et al., “Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway,” Oncotarget, vol. 5, no. 18, pp. 8330–8340, 2014. View at Publisher · View at Google Scholar · View at Scopus
  97. M. C. Sugden and M. J. Holness, “Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases,” Archives of Physiology and Biochemistry, vol. 112, no. 3, pp. 139–149, 2006. View at Publisher · View at Google Scholar · View at Scopus
  98. M. Grabacka, M. Pierzchalska, and K. Reiss, “Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitochondrial metabolism,” Current Pharmaceutical Biotechnology, vol. 14, no. 3, pp. 342–356, 2013. View at Publisher · View at Google Scholar · View at Scopus
  99. S. Oka, R. Alcendor, P. Zhai et al., “PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway,” Cell Metabolism, vol. 14, no. 5, pp. 598–611, 2011. View at Publisher · View at Google Scholar · View at Scopus
  100. M. Pawlak, E. Baugé, W. Bourguet et al., “The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice,” Hepatology, vol. 60, no. 5, pp. 1593–1606, 2014. View at Publisher · View at Google Scholar · View at Scopus
  101. S. Kamarajugadda, J. R. Becker, E. A. Hanse et al., “Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation,” Oncotarget, vol. 7, no. 30, pp. 47674–47686, 2016. View at Publisher · View at Google Scholar
  102. X. Qin, X. Xie, Y. Fan et al., “Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice,” Hepatology, vol. 48, no. 2, pp. 432–441, 2008. View at Publisher · View at Google Scholar · View at Scopus
  103. M. Goudarzi, T. Koga, C. Khozoie et al., “PPARβ/δ modulates ethanol-induced hepatic effects by decreasing pyridoxal kinase activity,” Toxicology, vol. 311, no. 3, pp. 87–98, 2013. View at Publisher · View at Google Scholar · View at Scopus
  104. C.-H. Lee, P. Olson, A. Hevener et al., “PPARδ regulates glucose metabolism and insulin sensitivity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 9, pp. 3444–3449, 2006. View at Publisher · View at Google Scholar · View at Scopus
  105. M. Zarei, E. Barroso, R. Leiva et al., “Heme-regulated eIF2α kinase modulates hepatic FGF21 and is activated by PPARβ/δ deficiency,” Diabetes, vol. 65, no. 10, pp. 3185–3199, 2016. View at Publisher · View at Google Scholar
  106. Y. Zhang, T. Lei, J. F. Huang et al., “The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes,” Molecular and Cellular Endocrinology, vol. 342, no. 1-2, pp. 41–47, 2011. View at Publisher · View at Google Scholar · View at Scopus
  107. J. Xu, D. J. Lloyd, C. Hale et al., “Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice,” Diabetes, vol. 58, no. 1, pp. 250–259, 2009. View at Publisher · View at Google Scholar · View at Scopus
  108. L. Serrano-Marco, R. Rodríguez-Calvo, I. El Kochairi et al., “Activation of peroxisome proliferator—activated receptor-β/-δ (PPAR-β/-δ) ameliorates insulin signaling and reduces SOCS3 levels by inhibiting STAT3 in interleukin-6-stimulated adipocytes,” Diabetes, vol. 60, no. 7, pp. 1990–1999, 2011. View at Publisher · View at Google Scholar · View at Scopus
  109. X. Li, J. Li, X. Lu et al., “Treatment with PPARδ agonist alleviates non-alcoholic fatty liver disease by modulating glucose and fatty acid metabolic enzymes in a rat model,” International Journal of Molecular Medicine, vol. 36, no. 3, pp. 767–775, 2015. View at Publisher · View at Google Scholar · View at Scopus
  110. H. J. Lee, J. E. Yeon, E. J. Ko et al., “Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease,” World Journal of Gastroenterology, vol. 21, no. 45, pp. 12787–12799, 2015. View at Publisher · View at Google Scholar · View at Scopus
  111. L. A. Bojic, D. E. Telford, M. D. Fullerton et al., “PPARδ activation attenuates hepatic steatosis in Ldlr−/− mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity,” Journal of Lipid Research, vol. 55, no. 7, pp. 1254–1266, 2014. View at Publisher · View at Google Scholar · View at Scopus
  112. U. Risérus, D. Sprecher, T. Johnson et al., “Activation of peroxisome proliferator-activated receptor (PPAR)δ promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men,” Diabetes, vol. 57, no. 2, pp. 332–339, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. H. E. Bays, S. Schwartz, T. Littlejohn III et al., “MBX-8025, a novel peroxisome proliferator receptor-δ agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 9, pp. 2889–2897, 2011. View at Publisher · View at Google Scholar · View at Scopus
  114. H.-X. Liu, Y. Fang, Y. Hu, F. J. Gonzalez, J. Fang, and Y.-J. Y. Wan, “PPARβ regulates liver regeneration by modulating Akt and E2f signaling,” PLoS ONE, vol. 8, no. 6, Article ID e65644, 2013. View at Publisher · View at Google Scholar · View at Scopus
  115. M. Vacca, S. D'Amore, G. Graziano et al., “Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma,” PLoS ONE, vol. 9, no. 8, Article ID e104449, 2014. View at Publisher · View at Google Scholar · View at Scopus
  116. H. E. Hollingshead, R. L. Killins, M. G. Borland et al., “Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands do not potentiate growth of human cancer cell lines,” Carcinogenesis, vol. 28, no. 12, pp. 2641–2649, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. L. Xu, C. Han, K. Lim, and T. Wu, “Cross-talk between peroxisome proliferator-activated receptor δ and cytosolic phospholipase A2α/cyclooxygenase-2/prostaglandin E2 signaling pathways in human hepatocellular carcinoma cells,” Cancer Research, vol. 66, no. 24, pp. 11859–11868, 2006. View at Publisher · View at Google Scholar · View at Scopus
  118. S. Handeli and J. A. Simon, “A small-molecule inhibitor of Tcf/β-catenin signaling down-regulates PPARγ and PPARδ activities,” Molecular Cancer Therapeutics, vol. 7, no. 3, pp. 521–529, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. C. Y. Cao, S. W.-F. Mok, V. W.-S. Cheng, and S. K.-W. Tsui, “The FHL2 regulation in the transcriptional circuitry of human cancers,” Gene, vol. 572, no. 1, pp. 1–7, 2015. View at Publisher · View at Google Scholar · View at Scopus
  120. C.-F. Ng, P. K.-S. Ng, V. W.-Y. Lui et al., “FHL2 exhibits anti-proliferative and anti-apoptotic activities in liver cancer cells,” Cancer Letters, vol. 304, no. 2, pp. 97–106, 2011. View at Publisher · View at Google Scholar · View at Scopus
  121. H. Yau, K. Rivera, R. Lomonaco, and K. Cusi, “The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus,” Current Diabetes Reports, vol. 13, no. 3, pp. 329–341, 2013. View at Publisher · View at Google Scholar · View at Scopus
  122. D. M. Torres, C. D. Williams, and S. A. Harrison, “Features, diagnosis, and treatment of nonalcoholic fatty liver disease,” Clinical Gastroenterology and Hepatology, vol. 10, no. 8, pp. 837–858, 2012. View at Publisher · View at Google Scholar · View at Scopus
  123. E. Boettcher, G. Csako, F. Pucino, R. Wesley, and R. Loomba, “Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis,” Alimentary Pharmacology and Therapeutics, vol. 35, no. 1, pp. 66–75, 2012. View at Publisher · View at Google Scholar · View at Scopus
  124. V. Ratziu, P. Giral, S. Jacqueminet et al., “Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement With Rosiglitazone Therapy (FLIRT) trial,” Gastroenterology, vol. 135, no. 1, pp. 100–110, 2008. View at Publisher · View at Google Scholar · View at Scopus
  125. V. Ratziu, F. Charlotte, C. Bernhardt et al., “Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the Fatty Liver Improvement by Rosiglitazone Therapy (FLIRT 2) extension trial,” Hepatology, vol. 51, no. 2, pp. 445–453, 2010. View at Publisher · View at Google Scholar · View at Scopus
  126. D. M. Torres, F. J. Jones, J. C. Shaw, C. D. Williams, J. A. Ward, and S. A. Harrison, “Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial,” Hepatology, vol. 54, no. 5, pp. 1631–1639, 2011. View at Publisher · View at Google Scholar · View at Scopus
  127. M. Gao, Y. Ma, M. Alsaggar, and D. Liu, “Dual outcomes of rosiglitazone treatment on fatty liver,” The AAPS Journal, vol. 18, no. 4, pp. 1023–1031, 2016. View at Publisher · View at Google Scholar
  128. P. Pettinelli and L. A. Videla, “Up-regulation of PPAR-γ mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 5, pp. 1424–1430, 2011. View at Publisher · View at Google Scholar · View at Scopus
  129. M. Inoue, T. Ohtake, W. Motomura et al., “Increased expression of PPARγ in high fat diet-induced liver steatosis in mice,” Biochemical and Biophysical Research Communications, vol. 336, no. 1, pp. 215–222, 2005. View at Publisher · View at Google Scholar · View at Scopus
  130. Y.-L. Zhang, A. Hernandez-Ono, P. Siri et al., “Aberrant hepatic expression of PPARγ2 stimulates hepatic lipogenesis in a mouse model of obesity, insulin resistance, dyslipidemia, and hepatic steatosis,” Journal of Biological Chemistry, vol. 281, no. 49, pp. 37603–37615, 2006. View at Publisher · View at Google Scholar · View at Scopus
  131. A. Vidal-Puig, M. Jimenez-Liñan, B. B. Lowell et al., “Regulation of PPAR γ gene expression by nutrition and obesity in rodents,” The Journal of Clinical Investigation, vol. 97, no. 11, pp. 2553–2561, 1996. View at Publisher · View at Google Scholar · View at Scopus
  132. G. P. Ables, “Update on Pparγ and nonalcoholic fatty liver disease,” PPAR Research, vol. 2012, Article ID 912351, 5 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  133. J. Sakamoto, H. Kimura, S. Moriyama et al., “Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone,” Biochemical and Biophysical Research Communications, vol. 278, no. 3, pp. 704–711, 2000. View at Publisher · View at Google Scholar · View at Scopus
  134. E. Xu, M.-P. Forest, M. Schwab et al., “Hepatocyte-specific Ptpn6 deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: potential role of PPARγ,” Hepatology, vol. 59, no. 5, pp. 1803–1815, 2014. View at Publisher · View at Google Scholar · View at Scopus
  135. C. W. Wu, E. S. H. Chu, C. N. Y. Lam et al., “PPARγ is essential for protection against nonalcoholic steatohepatitis,” Gene Therapy, vol. 17, no. 6, pp. 790–798, 2010. View at Publisher · View at Google Scholar · View at Scopus
  136. E. Morán-Salvador, M. López-Parra, V. García-Alonso et al., “Role for PPARγ in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts,” FASEB Journal, vol. 25, no. 8, pp. 2538–2550, 2011. View at Publisher · View at Google Scholar · View at Scopus
  137. S. Kuntz, S. Mazerbourg, M. Boisbrun et al., “Energy restriction mimetic agents to target cancer cells: comparison between 2-deoxyglucose and thiazolidinediones,” Biochemical Pharmacology, vol. 92, no. 1, pp. 102–111, 2014. View at Publisher · View at Google Scholar · View at Scopus
  138. A. Galli, T. Mello, E. Ceni, E. Surrenti, and C. Surrenti, “The potential of antidiabetic thiazolidinediones for anticancer therapy,” Expert Opinion on Investigational Drugs, vol. 15, no. 9, pp. 1039–1049, 2006. View at Publisher · View at Google Scholar · View at Scopus
  139. C.-W. Wu, G. C. Farrell, and J. Yu, “Functional role of peroxisome-proliferator-activated receptor γ in hepatocellular carcinoma,” Journal of Gastroenterology and Hepatology, vol. 27, no. 11, pp. 1665–1669, 2012. View at Publisher · View at Google Scholar · View at Scopus
  140. A. Laganà, S. Vitale, A. Nigro et al., “Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in dysregulated metabolic homeostasis, inflammation and cancer: current evidence and future perspectives,” International Journal of Molecular Sciences, vol. 17, no. 7, p. 999, 2016. View at Publisher · View at Google Scholar
  141. J. Yu, B. Shen, E. S. H. Chu et al., “Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro,” Hepatology, vol. 51, no. 6, pp. 2008–2019, 2010. View at Publisher · View at Google Scholar · View at Scopus
  142. A. Galli, E. Ceni, T. Mello et al., “Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor γ-independent regulation of nucleophosmin,” Hepatology, vol. 52, no. 2, pp. 493–505, 2010. View at Publisher · View at Google Scholar · View at Scopus
  143. E. Ceni, T. Mello, M. Tarocchi et al., “Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells,” World Journal of Gastroenterology, vol. 11, no. 8, pp. 1122–1130, 2005. View at Publisher · View at Google Scholar · View at Scopus
  144. X. Ren, D. Zheng, F. Guo et al., “PPARγ suppressed Wnt/β-catenin signaling pathway and its downstream effector SOX9 expression in gastric cancer cells,” Medical Oncology, vol. 32, no. 4, 2015. View at Publisher · View at Google Scholar · View at Scopus
  145. K. Wu, Y. Yang, D. Liu et al., “Activation of PPARγ suppresses proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway,” Oncotarget, 2016. View at Publisher · View at Google Scholar
  146. S. Dionne, E. Levy, D. Levesque, and E. G. Seidman, “PPARγ ligand 15-deoxy-delta 12,14-prostaglandin J2 sensitizes human colon carcinoma cells to TWEAK-induced apoptosis,” Anticancer Research, vol. 30, no. 1, pp. 157–166, 2010. View at Google Scholar · View at Scopus
  147. O. Pellerito, A. Notaro, S. Sabella et al., “WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARγ down-regulation,” Apoptosis, vol. 19, no. 6, pp. 1029–1042, 2014. View at Publisher · View at Google Scholar · View at Scopus
  148. D. M. Ray, S. H. Bernstein, and R. P. Phipps, “Human multiple myeloma cells express peroxisome proliferator-activated receptor γ and undergo apoptosis upon exposure to PPARγ ligands,” Clinical Immunology, vol. 113, no. 2, pp. 203–213, 2004. View at Publisher · View at Google Scholar · View at Scopus
  149. A. Galli, E. Ceni, D. W. Crabb et al., “Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARγ independent mechanisms,” Gut, vol. 53, no. 11, pp. 1688–1697, 2004. View at Publisher · View at Google Scholar · View at Scopus
  150. L.-Q. Cao, Z.-L. Shao, H.-H. Liang et al., “Activation of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits hepatoma cell growth via downregulation of SEPT2 expression,” Cancer Letters, vol. 359, no. 1, pp. 127–135, 2015. View at Publisher · View at Google Scholar · View at Scopus
  151. I. Cellai, G. Petrangolini, M. Tortoreto et al., “In vivo effects of rosiglitazone in a human neuroblastoma xenograft,” British Journal of Cancer, vol. 102, no. 4, pp. 685–692, 2010. View at Publisher · View at Google Scholar · View at Scopus
  152. B. Shen, E. S. H. Chu, G. Zhao et al., “PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice,” British Journal of Cancer, vol. 106, no. 9, pp. 1486–1494, 2012. View at Publisher · View at Google Scholar · View at Scopus
  153. P. Avena, W. Anselmo, D. Whitaker-Menezes et al., “Compartment-specific activation of PPARγ governs breast cancer tumor growth, via metabolic reprogramming and symbiosis,” Cell Cycle, vol. 12, no. 9, pp. 1360–1370, 2013. View at Publisher · View at Google Scholar · View at Scopus
  154. J. A. Menendez, “Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives,” Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids, vol. 1801, no. 3, pp. 381–391, 2010. View at Publisher · View at Google Scholar · View at Scopus
  155. D. F. Calvisi, C. Wang, C. Ho et al., “Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma,” Gastroenterology, vol. 140, no. 3, pp. 1071–1083, 2011. View at Publisher · View at Google Scholar · View at Scopus
  156. J. Hu, L. Che, L. Li et al., “Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice,” Scientific Reports, vol. 6, Article ID 20484, 2016. View at Publisher · View at Google Scholar · View at Scopus
  157. L. Li, L. Che, K. M. Tharp et al., “Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans,” Hepatology, vol. 63, no. 6, pp. 1900–1913, 2016. View at Publisher · View at Google Scholar
  158. L. Li, G. M. Pilo, X. Li et al., “Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans,” Journal of Hepatology, vol. 64, no. 2, pp. 333–341, 2016. View at Publisher · View at Google Scholar · View at Scopus
  159. D. Cao, X. Song, L. Che et al., “Both de novo synthetized and exogenous fatty acids support the growth of hepatocellular carcinoma cells,” Liver International, 2016. View at Publisher · View at Google Scholar
  160. J. Samarin, V. Laketa, M. Malz et al., “PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells,” Hepatology, vol. 63, no. 3, pp. 813–826, 2016. View at Publisher · View at Google Scholar · View at Scopus
  161. C. Wang, L. Che, J. Hu et al., “Activated mutant forms of PIK3CA cooperate with RasV12 or c-Met to induce liver tumour formation in mice via AKT2/mTORC1 cascade,” Liver International, vol. 36, no. 8, pp. 1176–1186, 2016. View at Publisher · View at Google Scholar
  162. M. Laplante and D. M. Sabatini, “Regulation of mTORC1 and its impact on gene expression at a glance,” Journal of Cell Science, vol. 126, pp. 1713–1719, 2013. View at Publisher · View at Google Scholar · View at Scopus
  163. G. Panasyuk, C. Espeillac, C. Chauvin et al., “PPARγ contributes to PKM2 and HK2 expression in fatty liver,” Nature Communications, vol. 3, article 672, 2012. View at Publisher · View at Google Scholar · View at Scopus
  164. D. P. King and J. S. Takahashi, “Molecular genetics of circadian rhythms in mammals,” Annual Review of Neuroscience, vol. 23, pp. 713–742, 2000. View at Publisher · View at Google Scholar · View at Scopus
  165. U. Schibler and P. Sassone-Corsi, “A web of circadian pacemakers,” Cell, vol. 111, no. 7, pp. 919–922, 2002. View at Publisher · View at Google Scholar · View at Scopus
  166. D. Feng and M. A. Lazar, “Clocks, metabolism, and the epigenome,” Molecular Cell, vol. 47, no. 2, pp. 158–167, 2012. View at Publisher · View at Google Scholar · View at Scopus
  167. N. Koike, S.-H. Yoo, H.-C. Huang et al., “Transcriptional architecture and chromatin landscape of the core circadian clock in mammals,” Science, vol. 338, no. 6105, pp. 349–354, 2012. View at Publisher · View at Google Scholar · View at Scopus
  168. J. Morf, G. Rey, K. Schneider et al., “Cold-inducible RNA-binding protein modulates circadian gene expression posttranscriptionally,” Science, vol. 338, no. 6105, pp. 379–383, 2012. View at Publisher · View at Google Scholar · View at Scopus
  169. G. Rey, F. Cesbron, J. Rougemont, H. Reinke, M. Brunner, and F. Naef, “Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver,” PLoS Biology, vol. 9, no. 2, Article ID e1000595, 2011. View at Publisher · View at Google Scholar · View at Scopus
  170. H. Yoshitane, H. Ozaki, H. Terajima et al., “CLOCK-controlled polyphonic regulation of circadian rhythms through canonical and noncanonical E-boxes,” Molecular and Cellular Biology, vol. 34, no. 10, pp. 1776–1787, 2014. View at Publisher · View at Google Scholar · View at Scopus
  171. Y. Tahara and S. Shibata, “Circadian rhythms of liver physiology and disease: experimental and clinical evidence,” Nature Reviews Gastroenterology and Hepatology, vol. 13, no. 4, pp. 217–226, 2016. View at Publisher · View at Google Scholar
  172. X. Tong and L. Yin, “Circadian rhythms in liver physiology and liver diseases,” Comprehensive Physiology, vol. 3, no. 2, pp. 917–940, 2013. View at Publisher · View at Google Scholar · View at Scopus
  173. S. Sahar and P. Sassone-Corsi, “Metabolism and cancer: the circadian clock connection,” Nature Reviews Cancer, vol. 9, no. 12, pp. 886–896, 2009. View at Publisher · View at Google Scholar · View at Scopus
  174. C. B. Peek, A. H. Affinati, K. M. Ramsey et al., “Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice,” Science, vol. 342, no. 6158, Article ID 1243417, 2013. View at Publisher · View at Google Scholar · View at Scopus
  175. M. D. Hirschey, T. Shimazu, J.-Y. Huang, B. Schwer, and E. Verdin, “SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 76, pp. 267–277, 2011. View at Publisher · View at Google Scholar · View at Scopus
  176. G. F. Gibbons, D. Patel, D. Wiggins, and B. L. Knight, “The functional efficiency of lipogenic and cholesterogenic gene expression in normal mice and in mice lacking the peroxisomal proliferator-activated receptor-alpha (PPAR-α),” Advances in Enzyme Regulation, vol. 42, pp. 227–247, 2002. View at Publisher · View at Google Scholar · View at Scopus
  177. D. D. Patel, B. L. Knight, D. Wiggins, S. M. Humphreys, and G. F. Gibbons, “Disturbances in the normal regulation of SREBP-sensitive genes in PPARα-deficient mice,” Journal of Lipid Research, vol. 42, no. 3, pp. 328–337, 2001. View at Google Scholar · View at Scopus
  178. K. Oishi, H. Shirai, and N. Ishida, “CLOCK is involved in the circadian transactivation of peroxisome-proliferator-activated receptor α (PPARα) in mice,” Biochemical Journal, vol. 386, no. 3, pp. 575–581, 2005. View at Publisher · View at Google Scholar · View at Scopus
  179. P. Gervois, S. Chopin-Delannoy, A. Fadel et al., “Fibrates increase human REV-ERBα expression in liver via a novel peroxisome proliferator-activated receptor response element,” Molecular Endocrinology, vol. 13, no. 3, pp. 400–409, 1999. View at Google Scholar · View at Scopus
  180. L. Canaple, J. Rambaud, O. Dkhissi-Benyahya et al., “Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor α defines a novel positive feedback loop in the rodent liver circadian clock,” Molecular Endocrinology, vol. 20, no. 8, pp. 1715–1727, 2006. View at Publisher · View at Google Scholar · View at Scopus
  181. L. Chen and G. Yang, “PPARs integrate the mammalian clock and energy metabolism,” PPAR Research, vol. 2014, Article ID 653017, 6 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  182. F. Gachon, N. Leuenberger, T. Claudel et al., “Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor α (PPARα) activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 12, pp. 4794–4799, 2011. View at Publisher · View at Google Scholar · View at Scopus
  183. A. Benavides, M. Siches, and M. Llobera, “Circadian rhythms of lipoprotein lipase and hepatic lipase activities in intermediate metabolism of adult rat,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 275, no. 3, part 2, pp. R811–R817, 1998. View at Google Scholar · View at Scopus
  184. M. C. Hunt, P. J. G. Lindquist, J. M. Peters, F. J. Gonzalez, U. Diczfalusy, and S. E. H. Alexson, “Involvement of the peroxisome proliferator-activated receptor α in regulating long-chain acyl-CoA thioesterases,” Journal of Lipid Research, vol. 41, no. 5, pp. 814–823, 2000. View at Google Scholar · View at Scopus
  185. M. C. Hunt, K. Solaas, B. Frode Kase, and S. E. H. Alexson, “Characterization of an acyl-CoA thioesterase that functions as a major regulator of peroxisomal lipid metabolism,” Journal of Biological Chemistry, vol. 277, no. 2, pp. 1128–1138, 2002. View at Publisher · View at Google Scholar · View at Scopus
  186. K. Schoonjans, J. Peinado-Onsurbe, A.-M. Lefebvre et al., “PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene,” The EMBO Journal, vol. 15, no. 19, pp. 5336–5348, 1996. View at Google Scholar · View at Scopus
  187. M. Kawai, C. B. Green, B. Lecka-Czernik et al., “A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-γ nuclear translocation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 23, pp. 10508–10513, 2010. View at Publisher · View at Google Scholar · View at Scopus
  188. G. Yang, Z. Jia, T. Aoyagi, D. McClain, R. M. Mortensen, and T. Yang, “Systemic pparγ deletion impairs circadian rhythms of behavior and metabolism,” PLoS ONE, vol. 7, no. 8, Article ID e38117, 2012. View at Publisher · View at Google Scholar · View at Scopus
  189. C. Liu, S. Li, T. Liu, J. Borjigin, and J. D. Lin, “Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism,” Nature, vol. 447, no. 7143, pp. 477–481, 2007. View at Publisher · View at Google Scholar · View at Scopus
  190. J. Sonoda, I. R. Mehl, L.-W. Chong, R. R. Nofsinger, and R. M. Evans, “PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 12, pp. 5223–5228, 2007. View at Publisher · View at Google Scholar · View at Scopus
  191. H. R. Ueda, W. Chen, A. Adachi et al., “A transcription factor response element for gene expression during circadian night,” Nature, vol. 418, no. 6897, pp. 534–539, 2002. View at Publisher · View at Google Scholar · View at Scopus
  192. C. Esau, S. Davis, S. F. Murray et al., “miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting,” Cell Metabolism, vol. 3, no. 2, pp. 87–98, 2006. View at Publisher · View at Google Scholar · View at Scopus
  193. D. Gatfield, G. Le Martelot, C. E. Vejnar et al., “Integration of microRNA miR-122 in hepatic circadian gene expression,” Genes and Development, vol. 23, no. 11, pp. 1313–1326, 2009. View at Publisher · View at Google Scholar · View at Scopus
  194. A. Neufeld-Cohen, M. S. Robles, R. Aviram et al., “Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 12, pp. E1673–E1682, 2016. View at Publisher · View at Google Scholar
  195. E. Filipski, P. F. Innominato, M. W. Wu et al., “Effects of light and food schedules on liver and tumor molecular clocks in mice,” Journal of the National Cancer Institute, vol. 97, no. 7, pp. 507–517, 2005. View at Publisher · View at Google Scholar · View at Scopus
  196. E. Filipski, P. Subramanian, J. Carrière, C. Guettier, H. Barbason, and F. Lévi, “Circadian disruption accelerates liver carcinogenesis in mice,” Mutation Research—Genetic Toxicology and Environmental Mutagenesis, vol. 680, no. 1-2, pp. 95–105, 2009. View at Publisher · View at Google Scholar · View at Scopus
  197. K. D. Bruce, D. Szczepankiewicz, K. K. Sihota et al., “Altered cellular redox status, sirtuin abundance and clock gene expression in a mouse model of developmentally primed NASH,” Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, vol. 1861, no. 7, pp. 584–593, 2016. View at Publisher · View at Google Scholar
  198. U. S. Udoh, J. A. Valcin, K. L. Gamble, and S. M. Bailey, “The molecular circadian clock and alcohol-induced liver injury,” Biomolecules, vol. 5, no. 4, pp. 2504–2537, 2015. View at Publisher · View at Google Scholar
  199. K. Honma, M. Hikosaka, K. Mochizuki, and T. Goda, “Loss of circadian rhythm of circulating insulin concentration induced by high-fat diet intake is associated with disrupted rhythmic expression of circadian clock genes in the liver,” Metabolism, vol. 65, no. 4, pp. 482–491, 2016. View at Publisher · View at Google Scholar
  200. F. W. Turek, C. Joshu, A. Kohsaka et al., “Obesity and metabolic syndrome in circadian Clock mutant mice,” Science, vol. 308, no. 5724, pp. 1043–1045, 2005. View at Publisher · View at Google Scholar · View at Scopus
  201. K. L. Eckel-Mahan, V. R. Patel, S. de Mateo et al., “Reprogramming of the circadian clock by nutritional challenge,” Cell, vol. 155, no. 7, pp. 1464–1478, 2013. View at Publisher · View at Google Scholar · View at Scopus
  202. K. Matsusue, T. Kusakabe, T. Noguchi et al., “Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene Fsp27,” Cell Metabolism, vol. 7, no. 4, pp. 302–311, 2008. View at Publisher · View at Google Scholar · View at Scopus
  203. C. B. Green, N. Douris, S. Kojima et al., “Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 23, pp. 9888–9893, 2007. View at Publisher · View at Google Scholar · View at Scopus
  204. Y.-M. Lin, J. H. Chang, K.-T. Yeh et al., “Disturbance of circadian gene expression in hepatocellular carcinoma,” Molecular Carcinogenesis, vol. 47, no. 12, pp. 925–933, 2008. View at Publisher · View at Google Scholar · View at Scopus
  205. B. Zhao, J. Lu, J. Yin et al., “A functional polymorphism in PER3 gene is associated with prognosis in hepatocellular carcinoma,” Liver International, vol. 32, no. 9, pp. 1451–1459, 2012. View at Publisher · View at Google Scholar · View at Scopus
  206. S. Ishibashi, S. Yamashita, H. Arai et al., “Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: a randomized, double blind, active- and placebo-controlled, phase 2 trial,” Atherosclerosis, vol. 249, pp. 36–43, 2016. View at Publisher · View at Google Scholar
  207. S. Raza-Iqbal, T. Tanaka, M. Anai et al., “Transcriptome analysis of K-877 (A novel selective PPARα modulator (SPPARMα))-regulated genes in primary human hepatocytes and the mouse liver,” Journal of Atherosclerosis and Thrombosis, vol. 22, no. 8, pp. 754–772, 2015. View at Publisher · View at Google Scholar · View at Scopus
  208. J. P. Taygerly, L. R. McGee, S. M. Rubenstein et al., “Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity,” Bioorganic and Medicinal Chemistry, vol. 21, no. 4, pp. 979–992, 2013. View at Publisher · View at Google Scholar · View at Scopus
  209. B. Cariou, R. Hanf, S. Lambert-Porcheron et al., “Dual peroxisome proliferator-activated receptor α/δ agonist gft505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects,” Diabetes Care, vol. 36, no. 10, pp. 2923–2930, 2013. View at Publisher · View at Google Scholar · View at Scopus
  210. B. Cariou, Y. Zaïr, B. Staels, and E. Bruckert, “Effects of the new dual PPARα/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism,” Diabetes Care, vol. 34, no. 9, pp. 2008–2014, 2011. View at Publisher · View at Google Scholar · View at Scopus
  211. B. Staels, A. Rubenstrunk, B. Noel et al., “Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis,” Hepatology, vol. 58, no. 6, pp. 1941–1952, 2013. View at Publisher · View at Google Scholar · View at Scopus
  212. V. Ratziu, S. A. Harrison, S. Francque et al., “Elafibranor, an agonist of the peroxisome proliferator−activated receptor−α and −δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening,” Gastroenterology, vol. 150, no. 5, pp. 1147.e5–1159.e5, 2016. View at Publisher · View at Google Scholar