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Metabolic aspects in NAFLD, NASH and hepatocellular carcinoma: the role of PGC1 coactivators

Nature Reviews Gastroenterology & Hepatology (2018) | Download Citation


Alterations of hepatic metabolism are critical to the development of liver disease. The peroxisome proliferator-activated receptor-γ coactivators (PGC1s) are able to orchestrate, on a transcriptional level, different aspects of liver metabolism, such as mitochondrial oxidative phosphorylation, gluconeogenesis and fatty acid synthesis. As modifications affecting both mitochondrial and lipid metabolism contribute to the initiation and/or progression of liver steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), a link between disrupted PGC1 pathways and onset of these pathological conditions has been postulated. However, despite the large quantity of studies, the scenario is still not completely understood, and some issues remain controversial. Here, we discuss the roles of PGC1s in healthy liver and explore their contribution to the pathogenesis and future therapy of NASH and HCC.

Key points

  • Peroxisome proliferator-activated receptor-γ coactivators (PGC1s) have a key role in liver metabolism and contribute to energy homeostasis.

  • PGC1α and PGC1β exert divergent functions on liver metabolism and regulate different pathways.

  • Although the hepatic expression of both PGC1α and PGC1β negatively correlates with nonalcoholic fatty liver disease (NAFLD) severity, hepatocellular carcinoma (HCC) development is inhibited by PGC1α and promoted by PGC1β.

  • Although direct coactivator targeting is problematic, pharmacological modulation of transcriptional and post-transcriptional activators of PGC1s is an appealing therapeutic avenue.

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  1. 1.

    Miller, L. L., Bly, C. G., Watson, M. L. & Bale, W. F. The dominant role of the liver in plasma protein synthesis; a direct study of the isolated perfused rat liver with the aid of lysine-epsilon-C14. J. Exp. Med. 94, 431–453 (1951).

  2. 2.

    Klaassen, C. D. & Aleksunes, L. M. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol. Rev. 62, 1–96 (2010).

  3. 3.

    Haussinger, D. Nitrogen metabolism in liver: structural and functional organization and physiological relevance. Biochem. J. 267, 281–290 (1990).

  4. 4.

    Andreyev, A. Y., Kushnareva, Y. E. & Starkov, A. A. Mitochondrial metabolism of reactive oxygen species. Biochemistry 70, 200–214 (2005).

  5. 5.

    Pieczenik, S. R. & Neustadt, J. Mitochondrial dysfunction and molecular pathways of disease. Exp. Mol. Pathol. 83, 84–92 (2007).

  6. 6.

    Michelotti, G. A., Machado, M. V. & Diehl, A. M. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656–665 (2013).

  7. 7.

    Baffy, G., Brunt, E. M. & Caldwell, S. H. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J. Hepatol. 56, 1384–1391 (2012).

  8. 8.

    Ertle, J. et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int. J. Cancer 128, 2436–2443 (2011).

  9. 9.

    Stickel, F. & Hellerbrand, C. Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut 59, 1303–1307 (2010).

  10. 10.

    McKenna, N. J. & O’Malley, B. W. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108, 465–474 (2002).

  11. 11.

    Puigserver, P. et al. Activation of PPARgamma coactivator-1 through transcription factor docking. Science 286, 1368–1371 (1999).

  12. 12.

    Spiegelman, B. M. & Heinrich, R. Biological control through regulated transcriptional coactivators. Cell 119, 157–167 (2004).

  13. 13.

    Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

  14. 14.

    Kressler, D., Schreiber, S. N., Knutti, D. & Kralli, A. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha. J. Biol. Chem. 277, 13918–13925 (2002).

  15. 15.

    Andersson, U. & Scarpulla, R. C. PGC-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol. Cell. Biol. 21, 3738–3749 (2001).

  16. 16.

    Nemoto, S., Fergusson, M. M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456–16460 (2005).

  17. 17.

    Lerin, C. et al. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 3, 429–438 (2006).

  18. 18.

    Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

  19. 19.

    Lin, J., Puigserver, P., Donovan, J., Tarr, P. & Spiegelman, B. M. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem. 277, 1645–1648 (2002).

  20. 20.

    Meirhaeghe, A. et al. Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo. Biochem. J. 373, 155–165 (2003).

  21. 21.

    Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

  22. 22.

    Lin, J. et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).

  23. 23.

    Gleyzer, N. & Scarpulla, R. C. PGC-1-related coactivator (PRC), a sensor of metabolic stress, orchestrates a redox-sensitive program of inflammatory gene expression. J. Biol. Chem. 286, 39715–39725 (2011).

  24. 24.

    Herzig, R. P., Scacco, S. & Scarpulla, R. C. Sequential serum-dependent activation of CREB and NRF-1 leads to enhanced mitochondrial respiration through the induction of cytochrome c. J. Biol. Chem. 275, 13134–13141 (2000).

  25. 25.

    Vercauteren, K., Gleyzer, N. & Scarpulla, R. C. Short hairpin RNA-mediated silencing of PRC (PGC-1-related coactivator) results in a severe respiratory chain deficiency associated with the proliferation of aberrant mitochondria. J. Biol. Chem. 284, 2307–2319 (2009).

  26. 26.

    Finck, B. N. & Kelly, D. P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 116, 615–622 (2006).

  27. 27.

    Lin, J. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119, 121–135 (2004).

  28. 28.

    Leone, T. C. et al. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLOS Biol. 3, e101 (2005).

  29. 29.

    Yoon, J. C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001).

  30. 30.

    Herzig, S. et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179–183 (2001).

  31. 31.

    Lin, J. et al. PGC-1beta in the regulation of hepatic glucose and energy metabolism. J. Biol. Chem. 278, 30843–30848 (2003).

  32. 32.

    Schreiber, S. N. et al. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc. Natl Acad. Sci. USA 101, 6472–6477 (2004).

  33. 33.

    Scarpulla, R. C. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann. NY Acad. Sci. 1147, 321–334 (2008).

  34. 34.

    Larsson, N. G. et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet. 18, 231–236 (1998).

  35. 35.

    Scarpulla, R. C. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim.  Biophys. Acta 1576, 1–14 (2002).

  36. 36.

    Scarpulla, R. C. Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene 286, 81–89 (2002).

  37. 37.

    Wolfrum, C. & Stoffel, M. Coactivation of Foxa2 through Pgc-1beta promotes liver fatty acid oxidation and triglyceride/VLDL secretion. Cell Metab. 3, 99–110 (2006).

  38. 38.

    Morris, E. M. et al. PGC-1alpha overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G979–G992 (2012).

  39. 39.

    Burgess, S. C. et al. Diminished hepatic gluconeogenesis via defects in tricarboxylic acid cycle flux in peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)-deficient mice. J. Biol. Chem. 281, 19000–19008 (2006).

  40. 40.

    St-Pierre, J. et al. Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells. J. Biol. Chem. 278, 26597–26603 (2003).

  41. 41.

    Lin, J. et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell 120, 261–273 (2005).

  42. 42.

    Bellafante, E. et al. Hepatic-specific activation of peroxisome proliferator-activated receptor gamma coactivator-1beta protects against steatohepatitis. Hepatology 57, 1343–1356 (2013).

  43. 43.

    Bernal-Mizrachi, C. et al. Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice. Nat. Med. 9, 1069–1075 (2003).

  44. 44.

    Finck, B. N. et al. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab. 4, 199–210 (2006).

  45. 45.

    Knutti, D., Kaul, A. & Kralli, A. A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen. Mol. Cell. Biol. 20, 2411–2422 (2000).

  46. 46.

    Psarra, A. M. & Sekeris, C. E. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim. Biophys. Acta 1813, 1814–1821 (2011).

  47. 47.

    Menconi, M. J. et al. Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1beta in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 299, E533–E543 (2010).

  48. 48.

    Adeva-Andany, M. M., Carneiro-Freire, N., Seco-Filgueira, M., Fernandez-Fernandez, C. & Mourino-Bayolo, D. Mitochondrial beta-oxidation of saturated fatty acids in humans. Mitochondrion (2018).

  49. 49.

    Koo, S. H. et al. PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat. Med. 10, 530–534 (2004).

  50. 50.

    Lelliott, C. J. et al. Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLOS Biol. 4, e369 (2006).

  51. 51.

    Sonoda, J., Mehl, I. R., Chong, L. W., Nofsinger, R. R. & Evans, R. M. PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc. Natl Acad. Sci. USA 104, 5223–5228 (2007).

  52. 52.

    Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423, 550–555 (2003).

  53. 53.

    Rhee, J. et al. Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc. Natl Acad. Sci. USA 100, 4012–4017 (2003).

  54. 54.

    Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434, 113–118 (2005).

  55. 55.

    Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127, 1109–1122 (2006).

  56. 56.

    Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429, 771–776 (2004).

  57. 57.

    Perez-Schindler, J. et al. The corepressor NCoR1 antagonizes PGC-1alpha and estrogen-related receptor alpha in the regulation of skeletal muscle function and oxidative metabolism. Mol. Cell. Biol. 32, 4913–4924 (2012).

  58. 58.

    Lustig, Y. et al. Separation of the gluconeogenic and mitochondrial functions of PGC-1α through S6 kinase. Genes Dev. 25, 1232–1244 (2011).

  59. 59.

    Li, X., Monks, B., Ge, Q. & Birnbaum, M. J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature 447, 1012–1016 (2007).

  60. 60.

    Zhang, Y., Castellani, L. W., Sinal, C. J., Gonzalez, F. J. & Edwards, P. A. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 18, 157–169 (2004).

  61. 61.

    Yamamoto, T. et al. SREBP-1 interacts with hepatocyte nuclear factor-4 alpha and interferes with PGC-1 recruitment to suppress hepatic gluconeogenic genes. J. Biol. Chem. 279, 12027–12035 (2004).

  62. 62.

    Hernandez, C., Molusky, M., Li, Y., Li, S. & Lin, J. D. Regulation of hepatic ApoC3 expression by PGC-1beta mediates hypolipidemic effect of nicotinic acid. Cell Metab. 12, 411–419 (2010).

  63. 63.

    Dowman, J. K., Tomlinson, J. W. & Newsome, P. N. Pathogenesis of non-alcoholic fatty liver disease. QJM 103, 71–83 (2010).

  64. 64.

    Chalasani, N. 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 55, 2005–2023 (2012).

  65. 65.

    Marrero, J. A. et al. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 36, 1349–1354 (2002).

  66. 66.

    Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).

  67. 67.

    Paradis, V. et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49, 851–859 (2009).

  68. 68.

    Day, C. P. & James, O. F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114, 842–845 (1998).

  69. 69.

    Birkenfeld, A. L. & Shulman, G. I. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 59, 713–723 (2014).

  70. 70.

    Peverill, W., Powell, L. W. & Skoien, R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int. J. Mol. Sci. 15, 8591–8638 (2014).

  71. 71.

    Buzzetti, E., Pinzani, M. & Tsochatzis, E. A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65, 1038–1048 (2016).

  72. 72.

    George, J. & Liddle, C. Nonalcoholic fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets. Mol. Pharm. 5, 49–59 (2008).

  73. 73.

    Yamaguchi, K. et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45, 1366–1374 (2007).

  74. 74.

    Zhang, X. Q., Xu, C. F., Yu, C. H., Chen, W. X. & Li, Y. M. Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J. Gastroenterol. 20, 1768–1776 (2014).

  75. 75.

    Begriche, K., Massart, J., Robin, M. A., Bonnet, F. & Fromenty, B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 58, 1497–1507 (2013).

  76. 76.

    Tilg, H. & Moschen, A. R. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52, 1836–1846 (2010).

  77. 77.

    Kern, P. A. et al. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest. 95, 2111–2119 (1995).

  78. 78.

    Fernandez-Real, J. M. et al. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J. Clin. Endocrinol. Metab. 86, 1154–1159 (2001).

  79. 79.

    Mridha, A. R. et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66, 1037–1046 (2017).

  80. 80.

    Miura, K. et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139, 323–334 (2010).

  81. 81.

    Nobili, V. et al. Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology 56, 2142–2153 (2012).

  82. 82.

    Katz, N. & Jungermann, K. Autoregulatory shift from fructolysis to lactate gluconeogenisis in rat hepatocyte suspensions. The problem of metabolic zonation of liver parenchyma. Hoppe Seylers Z. Physiol. Chem. 357, 359–375 (1976).

  83. 83.

    Jungermann, K. Metabolic zonation of liver parenchyma. Semin. Liver Dis. 8, 329–341 (1988).

  84. 84.

    Jungermann, K. & Kietzmann, T. Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology 31, 255–260 (2000).

  85. 85.

    Halpern, K. B. et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. Nature 542, 352–356 (2017).

  86. 86.

    Lamers, W. H. et al. Hepatic enzymic zonation: a reevaluation of the concept of the liver acinus. Hepatology 10, 72–76 (1989).

  87. 87.

    Gebhardt, R. Metabolic zonation of the liver: regulation and implications for liver function. Pharmacol. Ther. 53, 275–354 (1992).

  88. 88.

    Hall, Z. et al. Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hepatology 65, 1165–1180 (2017).

  89. 89.

    Brunt, E. M. Pathology of fatty liver disease. Mod. Pathol. 20, S40–S48 (2007).

  90. 90.

    Chalasani, N. et al. Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease. J. Hepatol. 48, 829–834 (2008).

  91. 91.

    Carter-Kent, C. et al. Relations of steatosis type, grade, and zonality to histological features in pediatric nonalcoholic fatty liver disease. J. Pediatr. Gastroenterol. Nutr. 52, 190–197 (2011).

  92. 92.

    Koliaki, C. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 21, 739–746 (2015).

  93. 93.

    Collins, P., Jones, C., Choudhury, S., Damelin, L. & Hodgson, H. Increased expression of uncoupling protein 2 in HepG2 cells attenuates oxidative damage and apoptosis. Liver Int. 25, 880–887 (2005).

  94. 94.

    Serviddio, G. et al. Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut 57, 957–965 (2008).

  95. 95.

    Chavin, K. D. et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J. Biol. Chem. 274, 5692–5700 (1999).

  96. 96.

    Satapati, S. et al. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J. Clin. Invest. 126, 1605 (2016).

  97. 97.

    Perez-Carreras, M. et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38, 999–1007 (2003).

  98. 98.

    Wang, L. et al. ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis. Hepatology 61, 486–496 (2015).

  99. 99.

    Gual, P. & Postic, C. Therapeutic potential of nicotinamide adenine dinucleotide for nonalcoholic fatty liver disease. Hepatology 63, 1074–1077 (2016).

  100. 100.

    Gariani, K. et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 63, 1190–1204 (2016).

  101. 101.

    Shimomura, I. et al. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol. Cell 6, 77–86 (2000).

  102. 102.

    Schwarz, J. M., Linfoot, P., Dare, D. & Aghajanian, K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am. J. Clin. Nutr. 77, 43–50 (2003).

  103. 103.

    Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005).

  104. 104.

    Ducheix, S. et al. Is hepatic lipogenesis fundamental for NAFLD/NASH? A focus on the nuclear receptor coactivator PGC-1beta. Cell. Mol. Life Sci. 73, 3809–3822 (2016).

  105. 105.

    Li, Z. Z., Berk, M., McIntyre, T. M. & Feldstein, A. E. Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J. Biol. Chem. 284, 5637–5644 (2009).

  106. 106.

    Chambers, K. T. et al. PGC-1beta and ChREBP partner to cooperatively regulate hepatic lipogenesis in a glucose concentration-dependent manner. Mol. Metab. 2, 194–204 (2013).

  107. 107.

    Oropeza, D. et al. PGC-1 coactivators in beta-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids. Mol. Metab. 4, 811–822 (2015).

  108. 108.

    Rehnmark, S., Giometti, C. S., Slavin, B. G., Doolittle, M. H. & Reue, K. The fatty liver dystrophy mutant mouse: microvesicular steatosis associated with altered expression levels of peroxisome proliferator-regulated proteins. J. Lipid Res. 39, 2209–2217 (1998).

  109. 109.

    Estall, J. L. et al. Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression. Diabetes 58, 1499–1508 (2009).

  110. 110.

    Sanchez-Ramos, C. et al. PGC-1alpha downregulation in steatotic liver enhances ischemia-reperfusion injury and impairs ischemic preconditioning. Antioxid. Redox. Signal. 27, 1332–1346 (2017).

  111. 111.

    Aharoni-Simon, M., Hann-Obercyger, M., Pen, S., Madar, Z. & Tirosh, O. Fatty liver is associated with impaired activity of PPARgamma-coactivator 1alpha (PGC1alpha) and mitochondrial biogenesis in mice. Lab Invest. 91, 1018–1028 (2011).

  112. 112.

    Lee, M. Y. et al. Peroxisome proliferator-activated receptor delta agonist attenuates hepatic steatosis by anti-inflammatory mechanism. Exp. Mol. Med. 44, 578–585 (2012).

  113. 113.

    Barroso, W. A. et al. High-fat diet inhibits PGC-1alpha suppressive effect on NFkappaB signaling in hepatocytes. Eur. J. Nutr. 57, 1891–1900 (2017).

  114. 114.

    Buler, M. et al. Energy-sensing factors coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and AMP-activated protein kinase control expression of inflammatory mediators in liver: induction of interleukin 1 receptor antagonist. J. Biol. Chem. 287, 1847–1860 (2012).

  115. 115.

    Eisele, P. S., Salatino, S., Sobek, J., Hottiger, M. O. & Handschin, C. The peroxisome proliferator-activated receptor gamma coactivator 1alpha/beta (PGC-1) coactivators repress the transcriptional activity of NF-kappaB in skeletal muscle cells. J. Biol. Chem. 288, 2246–2260 (2013).

  116. 116.

    Eisele, P. S., Furrer, R., Beer, M. & Handschin, C. The PGC-1 coactivators promote an anti-inflammatory environment in skeletal muscle in vivo. Biochem. Biophys. Res. Commun. 464, 692–697 (2015).

  117. 117.

    Sica, A., Invernizzi, P. & Mantovani, A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 59, 2034–2042 (2014).

  118. 118.

    Tan, H. Y. et al. The reactive oxygen species in macrophage polarization: reflecting its dual role in progression and treatment of human diseases. Oxid. Med. Cell. Longev. 2016, 2795090 (2016).

  119. 119.

    Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).

  120. 120.

    Vats, D. et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab. 4, 13–24 (2006).

  121. 121.

    Yoneda, M. et al. Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol. 8, 27 (2008).

  122. 122.

    Lin, Y. C., Chang, P. F., Chang, M. H. & Ni, Y. H. A common variant in the peroxisome proliferator-activated receptor-gamma coactivator-1alpha gene is associated with nonalcoholic fatty liver disease in obese children. Am. J. Clin. Nutr. 97, 326–331 (2013).

  123. 123.

    Hirschey, M. D. et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 44, 177–190 (2011).

  124. 124.

    Crunkhorn, S. et al. Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. J. Biol. Chem. 282, 15439–15450 (2007).

  125. 125.

    Besse-Patin, A. et al. Estrogen signals through peroxisome proliferator-activated receptor-gamma coactivator 1alpha to reduce oxidative damage associated with diet-induced fatty liver disease. Gastroenterology 152, 243–256 (2017).

  126. 126.

    Lonardo, A., Carani, C., Carulli, N. & Loria, P. ‘Endocrine NAFLD’ a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis. J. Hepatol. 44, 1196–1207 (2006).

  127. 127.

    Ballestri, S. et al. NAFLD as a sexual dimorphic disease: role of gender and reproductive status in the development and progression of nonalcoholic fatty liver disease and inherent cardiovascular risk. Adv. Ther. 34, 1291–1326 (2017).

  128. 128.

    Tilg, H., Moschen, A. R. & Roden, M. NAFLD and diabetes mellitus. Nat. Rev. Gastroenterol. Hepatol. 14, 32–42 (2017).

  129. 129.

    Das, K. et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 51, 1593–1602 (2010).

  130. 130.

    Singh, S. P. et al. Nonalcoholic fatty liver disease (NAFLD) without insulin resistance: is it different? Clin. Res. Hepatol. Gastroenterol. 39, 482–488 (2015).

  131. 131.

    Petersen, K. F. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 (2003).

  132. 132.

    Kim, J. A., Wei, Y. & Sowers, J. R. Role of mitochondrial dysfunction in insulin resistance. Circ. Res. 102, 401–414 (2008).

  133. 133.

    Turner, N. & Heilbronn, L. K. Is mitochondrial dysfunction a cause of insulin resistance? Trends Endocrinol. Metab. 19, 324–330 (2008).

  134. 134.

    Nagai, Y. et al. The role of peroxisome proliferator-activated receptor gamma coactivator-1 beta in the pathogenesis of fructose-induced insulin resistance. Cell Metab. 9, 252–264 (2009).

  135. 135.

    Vianna, C. R. et al. Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance. Cell Metab. 4, 453–464 (2006).

  136. 136.

    Oberkofler, H. et al. Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans. Diabetologia 53, 1971–1975 (2010).

  137. 137.

    Degasperi, E. & Colombo, M. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease. Lancet Gastroenterol. Hepatol. 1, 156–164 (2016).

  138. 138.

    Forner, A., Llovet, J. M. & Bruix, J. Hepatocellular carcinoma. Lancet 379, 1245–1255 (2012).

  139. 139.

    Kawada, N. et al. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J. Gastroenterol. 44, 1190–1194 (2009).

  140. 140.

    Huang, Q. et al. Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics. Cancer Res. 73, 4992–5002 (2013).

  141. 141.

    Rysman, E. et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 70, 8117–8126 (2010).

  142. 142.

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

  143. 143.

    Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

  144. 144.

    Zong, W. X., Rabinowitz, J. D. & White, E. Mitochondria and cancer. Mol. Cell 61, 667–676 (2016).

  145. 145.

    Vivekanandan, P., Daniel, H., Yeh, M. M. & Torbenson, M. Mitochondrial mutations in hepatocellular carcinomas and fibrolamellar carcinomas. Mod. Pathol. 23, 790–798 (2010).

  146. 146.

    Zheng, J. Energy metabolism of cancer: glycolysis versus oxidative phosphorylation. Oncol. Lett. 4, 1151–1157 (2012).

  147. 147.

    Fantin, V. R., St-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006).

  148. 148.

    Smolkova, K. et al. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int. J. Biochem. Cell Biol. 43, 950–968 (2011).

  149. 149.

    Pavlides, S. et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8, 3984–4001 (2009).

  150. 150.

    Wallace, D. C. Mitochondria and cancer. Nat. Rev. Cancer 12, 685–698 (2012).

  151. 151.

    Luo, C., Widlund, H. R. & Puigserver, P. PGC-1 coactivators: shepherding the mitochondrial biogenesis of tumors. Trends Cancer 2, 619–631 (2016).

  152. 152.

    Viollet, B. et al. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol. 196, 81–98 (2009).

  153. 153.

    Wilson, G. K., Tennant, D. A. & McKeating, J. A. Hypoxia inducible factors in liver disease and hepatocellular carcinoma: current understanding and future directions. J. Hepatol. 61, 1397–1406 (2014).

  154. 154.

    Wang, B., Hsu, S. H., Frankel, W., Ghoshal, K. & Jacob, S. T. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology 56, 186–197 (2012).

  155. 155.

    Martinez-Jimenez, C. P., Gomez-Lechon, M. J., Castell, J. V. & Jover, R. Underexpressed coactivators PGC1alpha and SRC1 impair hepatocyte nuclear factor 4 alpha function and promote dedifferentiation in human hepatoma cells. J. Biol. Chem. 281, 29840–29849 (2006).

  156. 156.

    Spath, G. F. & Weiss, M. C. Hepatocyte nuclear factor 4 expression overcomes repression of the hepatic phenotype in dedifferentiated hepatoma cells. Mol. Cell. Biol. 17, 1913–1922 (1997).

  157. 157.

    Li, J., Ning, G. & Duncan, S. A. Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev. 14, 464–474 (2000).

  158. 158.

    Xu, X. R. et al. Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. Proc. Natl Acad. Sci. USA 98, 15089–15094 (2001).

  159. 159.

    Zhang, P. et al. Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc. Natl Acad. Sci. USA 111, 10684–10689 (2014).

  160. 160.

    Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011).

  161. 161.

    Dominy, J. E. Jr et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol. Cell 48, 900–913 (2012).

  162. 162.

    Sen, N., Satija, Y. K. & Das, S. PGC-1alpha, a key modulator of p53, promotes cell survival upon metabolic stress. Mol. Cell 44, 621–634 (2011).

  163. 163.

    Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

  164. 164.

    Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).

  165. 165.

    Okoshi, R. et al. Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J. Biol. Chem. 283, 3979–3987 (2008).

  166. 166.

    Knutti, D., Kressler, D. & Kralli, A. Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor. Proc. Natl Acad. Sci. USA 98, 9713–9718 (2001).

  167. 167.

    Chaube, B. et al. AMPK maintains energy homeostasis and survival in cancer cells via regulating p38/PGC-1alpha-mediated mitochondrial biogenesis. Cell Death. Discov. 1, 15063 (2015).

  168. 168.

    Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013).

  169. 169.

    Bhalla, K. et al. PGC1alpha promotes tumor growth by inducing gene expression programs supporting lipogenesis. Cancer Res. 71, 6888–6898 (2011).

  170. 170.

    Piccinin, E. et al. Hepatic peroxisome proliferator-activated receptor gamma coactivator 1beta drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression in mice. Hepatology 67, 884–898 (2018).

  171. 171.

    Huang, D. et al. HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep. 8, 1930–1942 (2014).

  172. 172.

    Anastasiou, D. & Cantley, L. C. Breathless cancer cells get fat on glutamine. Cell Res. 22, 443–446 (2012).

  173. 173.

    Seo, K. & Shin, S. M. Induction of lipin1 by ROS-dependent SREBP-2 activation. Toxicol. Res. 33, 219–224 (2017).

  174. 174.

    LeBleu, V. S. et al. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16, 992–915 (2014).

  175. 175.

    Li, Y. et al. SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1alpha-mediated mitochondrial biogenesis. Oncotarget 7, 29255–29274 (2016).

  176. 176.

    Cheong, H., Lu, C., Lindsten, T. & Thompson, C. B. Therapeutic targets in cancer cell metabolism and autophagy. Nat. Biotechnol. 30, 671–678 (2012).

  177. 177.

    Lonard, D. M. & O’Malley, B. W. Nuclear receptor coregulators: modulators of pathology and therapeutic targets. Nat. Rev. Endocrinol. 8, 598–604 (2012).

  178. 178.

    Hofer, A. et al. Defining the action spectrum of potential PGC-1alpha activators on a mitochondrial and cellular level in vivo. Hum. Mol. Genet. 23, 2400–2415 (2014).

  179. 179.

    Aatsinki, S. M. et al. Metformin induces PGC-1alpha expression and selectively affects hepatic PGC-1alpha functions. Br. J. Pharmacol. 171, 2351–2363 (2014).

  180. 180.

    Koo, S. H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005).

  181. 181.

    Screaton, R. A. et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119, 61–74 (2004).

  182. 182.

    He, L. et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137, 635–646 (2009).

  183. 183.

    Kim, Y. D. et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 57, 306–314 (2008).

  184. 184.

    Yamagata, K., Yoshimochi, K., Daitoku, H., Hirota, K. & Fukamizu, A. Bile acid represses the peroxisome proliferator-activated receptor-gamma coactivator-1 promoter activity in a small heterodimer partner-dependent manner. Int. J. Mol. Med. 19, 751–756 (2007).

  185. 185.

    Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

  186. 186.

    Woo, S. L. et al. Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. PLOS ONE 9, e91111 (2014).

  187. 187.

    Mazza, A. et al. The role of metformin in the management of NAFLD. Exp. Diabetes Res. 2012, 716404 (2012).

  188. 188.

    Coste, A. et al. The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1{alpha}. Proc. Natl Acad. Sci. USA 105, 17187–17192 (2008).

  189. 189.

    Kelly, T. J., Lerin, C., Haas, W., Gygi, S. P. & Puigserver, P. GCN5-mediated transcriptional control of the metabolic coactivator PGC-1beta through lysine acetylation. J. Biol. Chem. 284, 19945–19952 (2009).

  190. 190.

    Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).

  191. 191.

    Price, N. L. et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675–690 (2012).

  192. 192.

    Smith, J. J. et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst. Biol. 3, 31 (2009).

  193. 193.

    Berman, A. Y., Motechin, R. A., Wiesenfeld, M. Y. & Holz, M. K. The therapeutic potential of resveratrol: a review of clinical trials. NPJ Precis. Oncol. 1, 35 (2017).

  194. 194.

    Sharabi, K. et al. Selective chemical inhibition of PGC-1alpha gluconeogenic activity ameliorates type 2 diabetes. Cell 169, 148–160 (2017).

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A.M. is funded by the Italian Association for Cancer Research (AIRC, IG 18987), NR-NET FP7 Marie Curie ITN, FATMAL (HDHL-INTIMIC Joint Call) and the Italian Ministry of Health (Young Researchers Grant GR-2010-2314703).

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Nature Reviews Gastroenterology & Hepatology thanks J. Hakkola and the other anonymous reviewers for their contribution to the peer review of this work.

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  1. Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy

    • Elena Piccinin
    •  & Antonio Moschetta
  2. INBB, National Institute for Biostructures and Biosystems, Rome, Italy

    • Elena Piccinin
  3. Department of Basic Medical Sciences, Neurosciences and Sense Organs, Aldo Moro University of Bari, Bari, Italy

    • Gaetano Villani
  4. National Cancer Center, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy

    • Antonio Moschetta


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All authors contributed equally to all aspects of the manuscript.

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The authors declare no competing interests.

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Correspondence to Antonio Moschetta.

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