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  • Published:

Transcriptional regulation of hepatic lipogenesis

A Corrigendum to this article was published on 16 December 2015

Key Points

  • Lipogenic genes are coordinately regulated at the transcriptional level during the fasting–feeding cycle and by circadian rhythms.

  • Having common features at their promoter regions, lipogenic genes are coordinately regulated. Transcription factors such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles.

  • Post-translational modifications of lipogenic transcription factors and co-regulators by hormones and nutrients are tightly regulated by several signalling pathways. Various kinases–phosphatases, including DNA-dependent protein kinase (DNA–PK), atypical protein kinase C (aPKC) and AKT–mTOR, and acetyltransferase–deacetylases such as p300, affect their function, stability and/or localization.

  • Chromatin remodelling by histone acetylation and methylation, as well as recruitment of the lipoBAF complex, have crucial roles in lipogenic gene transcription.

  • Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance. Furthermore, persistent lipogenesis during insulin resistance may occur, owing to nutrient fluxes to the liver.

Abstract

Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT–mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.

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Figure 1: Transcription factors, co-regulators and signalling pathways for hepatic lipogenic gene activation by insulin and glucose.
Figure 2: Modifications of upstream stimulatory factors (USFs) during the fasting–feeding cycle.
Figure 3: Transcription factors and co-regulators involved in the regulation of lipogenesis by circadian rhythms.

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References

  1. Czech, M. P., Tencerova, M., Pedersen, D. J. & Aouadi, M. Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 56, 949–964 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Rui, L. Energy metabolism in the liver. Compr. Physiol. 4, 177–197 (2014).

    PubMed  PubMed Central  Google Scholar 

  3. Kemper, J. K., Choi, S. E. & Kim, D. H. Sirtuin 1 deacetylase: a key regulator of hepatic lipid metabolism. Vitam. Horm. 91, 385–404 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Viollet, B. et al. Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J. Physiol. 574, 41–53 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang, D. & Sul, H. S. Upstream stimulatory factor binding to the E-box at -65 is required for insulin regulation of the fatty acid synthase promoter. J. Biol. Chem. 272, 26367–26374 (1997). This work demonstrates that USF binding to the -65 E-box in the Fas promoter is required for transcriptional activation of the Fas gene by insulin.

    CAS  PubMed  Google Scholar 

  6. Casado, M., Vallet, V. S., Kahn, A. & Vaulont, S. Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J. Biol. Chem. 274, 2009–2013 (1999).

    CAS  PubMed  Google Scholar 

  7. Vallet, V. S. et al. Differential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose. J. Biol. Chem. 273, 20175–20179 (1998).

    CAS  PubMed  Google Scholar 

  8. Vallet, V. S. et al. Glucose-dependent liver gene expression in upstream stimulatory factor 2 −/− mice. J. Biol. Chem. 272, 21944–21949 (1997).

    CAS  PubMed  Google Scholar 

  9. Pajukanta, P. et al. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat. Genet. 36, 371–376 (2004).

    CAS  PubMed  Google Scholar 

  10. Wang, D. & Sul, H. S. Upstream stimulatory factors bind to insulin response sequence of the fatty acid synthase promoter. USF1 is regulated. J. Biol. Chem. 270, 28716–28722 (1995).

    CAS  PubMed  Google Scholar 

  11. Wong, R. H. F. & Sul, H. S. Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective. Curr. Opin. Pharmacol. 10, 684–691 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu, Z., Thompson, K. S. & Towle, H. C. Carbohydrate regulation of the rat L-type pyruvate kinase gene requires two nuclear factors: LF-A1 and a member of the c-myc family. J. Biol. Chem. 268, 12787–12795 (1993).

    CAS  PubMed  Google Scholar 

  13. Diaz Guerra, M. J. et al. Functional characterization of the L-type pyruvate kinase gene glucose response complex. Mol. Cell. Biol. 13, 7725–7733 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Soncini, M., Yet, S.-F., Moon, Y., Chun, J.-Y. & Sul, H. S. Hormonal and nutritional control of the fatty acid synthase promoter in transgenic mice. J. Biol. Chem. 270, 30339–30343 (1995).

    CAS  PubMed  Google Scholar 

  15. Moon, Y. S., Latasa, M.-J., Kim, K.-H., Wang, D. & Sul, H. S. Two 5′-regions are required for nutritional and insulin regulation of the fatty-acid synthase promoter in transgenic mice. J. Biol. Chem. 275, 10121–10127 (2000).

    CAS  PubMed  Google Scholar 

  16. Shin, D. H., Paulauskis, J. D., Moustaïd, N. & Sul, H. S. Transcriptional regulation of p90 with sequence homology to Escherichia coli glycerol-3-phosphate acyltransferase. J. Biol. Chem. 266, 23834–23839 (1991).

    CAS  PubMed  Google Scholar 

  17. Moustaïd, N., Beyer, R. S. & Sul, H. S. Identification of an insulin response element in the fatty acid synthase promoter. J. Biol. Chem. 269, 5629–5634 (1994).

    PubMed  Google Scholar 

  18. Sul, H. S. & Wang, D. Nutritional and hormonal regulation of enzymes in fat synthesis: studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu. Rev. Nutr. 18, 331–351 (1998).

    CAS  PubMed  Google Scholar 

  19. Wang, D. & Sul, H. S. Insulin stimulation of the fatty acid synthase promoter is mediated by the phosphatidylinositol 3-kinase pathway. Involvement of protein kinase B/Akt. J. Biol. Chem. 273, 25420–25426 (1998).

    CAS  PubMed  Google Scholar 

  20. Paulauskis, J. D. & Sul, H. S. Hormonal regulation of mouse fatty acid synthase gene transcription in liver. J. Biol. Chem. 264, 574–577 (1989).

    CAS  PubMed  Google Scholar 

  21. Wong, R. H. F. & Sul, H. S. DNA-PK: relaying the insulin signal to USF in lipogenesis. Cell Cycle 8, 1973–1978 (2009).

    Google Scholar 

  22. Wong, R. H. et al. A role of DNA-PK for the metabolic gene regulation in response to insulin. Cell 136, 1056–1072 (2009). This work demonstrates that insulin activates a distinct pathway involving PP1 and DNA-PK that phosphorylates USF1, which can then be acetylated by PCAF for lipogenic gene transcription.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chanda, D. et al. Hepatocyte growth factor family negatively regulates hepatic gluconeogenesis via induction of orphan nuclear receptor small heterodimer partner in primary hepatocytes. J. Biol. Chem. 284, 28510–28521 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ju, B. G. et al. A topoisomerase IIβ-mediated dsDNA break required for regulated transcription. Science 312, 1798–1802 (2006).

    CAS  PubMed  Google Scholar 

  25. Puc, J. et al. Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160, 367–380 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Haince, J.-F., Rouleau, M. & Poirier, G. G. Gene expression needs a break to unwind before carrying on. Science 312, 1752–1753 (2006).

    CAS  PubMed  Google Scholar 

  27. Ryu, K. W., Kim, D.-S. & Kraus, W. L. New facets in the regulation of gene expression by ADP-ribosylation and poly(ADP-ribose) polymerases. Chem. Rev. 115, 2453–2481 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shimano, H. et al. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J. Clin. Invest. 100, 2115–2124 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Shimano, H. et al. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J. Clin. Invest. 99, 846–854 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Jiang, T. et al. Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway. J. Biol. Chem. 280, 32317–32325 (2005).

    CAS  PubMed  Google Scholar 

  31. Ponugoti, B. et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J. Biol. Chem. 285, 33959–33970 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Liang, G. et al. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J. Biol. Chem. 277, 9520–9528 (2002).

    CAS  PubMed  Google Scholar 

  33. Kim, J. B. et al. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J. Biol. Chem. 101, 1–9 (1998).

    CAS  Google Scholar 

  34. Kim, J. B. et al. Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix-loop-helix domain. Mol. Cell. Biol. 15, 2582–2588 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Tontonoz, P., Kim, J. B., Graves, R. A. & Spiegelman, B. M. ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation. Mol. Cell. Biol. 13, 4753–4759 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Latasa, M. J., Griffin, M. J., Moon, Y. S., Kang, C. & Sul, H. S. Occupancy and function of the -150 sterol regulatory element and -65 E-box in nutritional regulation of the fatty acid synthase gene in living animals. Mol. Cell. Biol. 23, 5896–5907 (2003). This work shows that binding of SREBPs to the -150 SRE and of USFs to the -65 E-box are required for activation of the Fas promoter in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Griffin, M. J., Wong, R. H., Pandya, N. & Sul, H. S. Direct interaction between USF and SREBP-1c mediates synergistic activation of the fatty-acid synthase promoter. J. Biol. Chem. 282, 5453–5467 (2007).

    CAS  PubMed  Google Scholar 

  38. Latasa, M.-J., Moon, Y. S., Kim, K.-H. & Sul, H. S. Nutritional regulation of the fatty acid synthase promoter in vivo: sterol regulatory element binding protein functions through an upstream region containing a sterol regulatory element. Proc. Natl Acad. Sci. USA 97, 10619–10624 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Deng, X. et al. Expression of the rat sterol regulatory element-binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1 (Sp1). J. Biol. Chem. 282, 17517–17529 (2007).

    CAS  PubMed  Google Scholar 

  40. Yang, L. et al. Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms. J. Biol. Chem. 280, 207–214 (2005).

    CAS  PubMed  Google Scholar 

  41. Zhang, C., Shin, D. J. & Osborne, T. F. A simple promoter containing two Sp1 sites controls the expression of sterol-regulatory-element-binding protein 1a (SREBP-1a). Biochem. J. 386, 161–168 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Athanikar, J. N., Sanchez, H. B. & Osborne, T. F. Promoter selective transcriptional synergy mediated by sterol regulatory element binding protein and Sp1: a critical role for the Btd domain of Sp1. Mol. Cell. Biol. 17, 5193–5200 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Magana, M. M., Koo, S. H., Towle, H. C. & Osborne, T. F. Different sterol regulatory element-binding protein-1 isoforms utilize distinct co-regulatory factors to activate the promoter for fatty acid synthase. J. Biol. Chem. 275, 4726–4733 (2000).

    CAS  PubMed  Google Scholar 

  44. Lopez, J. M., Bennett, M. K., Sanchez, H. B., Rosenfeld, J. M. & Osborne, T. F. Sterol regulation of acetyl coenzyme A carboxylase: a mechanism for coordinate control of cellular lipid. Proc. Natl Acad. Sci. USA 93, 1049–1053 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Jerkins, A. A., Liu, W. R., Lee, S. & Sul, H. S. Characterization of the murine mitochondrial glycerol-3-phosphate acyltransferase promoter. J. Biol. Chem. 270, 1416–1421 (1995).

    CAS  PubMed  Google Scholar 

  46. Amemiya-Kudo, M. et al. Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene. J. Biol. Chem. 275, 31078–31085 (2000).

    CAS  PubMed  Google Scholar 

  47. Repa, J. J. et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 14, 2819–2830 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Yellaturu, C. R. et al. Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J. Biol. Chem. 284, 7518–7532 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Li, S., Brown, M. S. & Goldstein, J. L. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc. Natl Acad. Sci. USA 107, 3441–3446 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Owen, J. L. et al. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc. Natl Acad. Sci. USA 109, 16184–16189 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Bakan, I. & Laplante, M. Connecting mTORC1 signaling to SREBP-1 activation. Curr. Opin. Lipidol. 23, 226–234 (2012).

    CAS  PubMed  Google Scholar 

  52. Yabe, D., Komuro, R., Liang, G., Goldstein, J. L. & Brown, M. S. Liver-specific mRNA for Insig-2 down-regulated by insulin: implications for fatty acid synthesis. Proc. Natl Acad. Sci. USA 100, 3155–3160 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Yecies, J. L. et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 14, 21–32 (2011). This work shows that insulin activates AKT and mTORC1, resulting in induction and processing of SREBP1C.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Roth, G. et al. MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro. J. Biol. Chem. 275, 33302–33307 (2000).

    CAS  PubMed  Google Scholar 

  55. Kotzka, J. et al. Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. PLoS ONE 7, e32609 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Lu, M. & Shyy, J. Y. Sterol regulatory element-binding protein 1 is negatively modulated by PKA phosphorylation. Am. J. Physiol. Cell Physiol. 290, C1477–C1486 (2006).

    CAS  PubMed  Google Scholar 

  57. Kim, K. H. et al. Regulatory role of glycogen synthase kinase 3 for transcriptional activity of ADD1/SREBP1c. J. Biol. Chem. 279, 51999–52006 (2004).

    CAS  PubMed  Google Scholar 

  58. Walker, A. K. et al. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 24, 1403–1417 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Lee, G. Y. et al. PIASy-mediated sumoylation of SREBP1c regulates hepatic lipid metabolism upon fasting signaling. Mol. Cell. Biol. 34, 926–938 (2014).

    PubMed  PubMed Central  Google Scholar 

  60. Chen, W., Chen, G., Head, D. L., Mangelsdorf, D. J. & Russell, D. W. Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab. 5, 73–79 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Janowski, B. A., Willy, P. J., Devi, T. R., Falck, J. R. & Mangelsdorf, D. J. An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature 383, 728–731 (1996).

    CAS  PubMed  Google Scholar 

  62. Wagner, B. L. et al. Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression. Mol. Cell. Biol. 23, 5780–5789 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Feldmann, R. et al. Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells. Nucleic Acids Res. 41, 3518–3531 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kalaany, N. Y. et al. LXRs regulate the balance between fat storage and oxidation. Cell Metab. 1, 231–244 (2005).

    CAS  PubMed  Google Scholar 

  65. Beaven, S. W. et al. Reciprocal regulation of hepatic and adipose lipogenesis by liver X receptors in obesity and insulin resistance. Cell Metab. 18, 106–117 (2013). This work demonstrates the role of LXRs in the regulation of lipogenesis in liver and adipose tissue.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Yoshikawa, T. et al. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol. Cell. Biol. 21, 2991–3000 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen, G., Liang, G., Ou, J., Goldstein, J. L. & Brown, M. S. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc. Natl Acad. Sci. USA 101, 11245–11250 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Cha, J. Y. & Repa, J. J. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J. Biol. Chem. 282, 743–751 (2007).

    CAS  PubMed  Google Scholar 

  69. Mitro, N. et al. The nuclear receptor LXR is a glucose sensor. Nature 445, 219–223 (2007).

    CAS  PubMed  Google Scholar 

  70. Denechaud, P. D. et al. ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J. Clin. Invest. 118, 956–964 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Joseph, S. B. et al. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J. Biol. Chem. 277, 11019–11025 (2002).

    CAS  PubMed  Google Scholar 

  72. Schultz, J. R. et al. Role of LXRs in control of lipogenesis. Genes Dev. 14, 2831–2838 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Anthonisen, E. H. et al. Nuclear receptor liver X receptor is O-GlcNAc-modified in response to glucose. J. Biol. Chem. 285, 1607–1615 (2010).

    CAS  PubMed  Google Scholar 

  74. Tobin, K. A. et al. Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. J. Biol. Chem. 277, 10691–10697 (2002).

    CAS  PubMed  Google Scholar 

  75. Bindesboll, C. et al. Liver X receptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity. J. Lipid Res. 56, 771–785 (2015).

    PubMed  PubMed Central  Google Scholar 

  76. Lee, S., Lee, J., Lee, S. K. & Lee, J. W. Activating signal cointegrator-2 is an essential adaptor to recruit histone H3 lysine 4 methyltransferases MLL3 and MLL4 to the liver X receptors. Mol. Endocrinol. 22, 1312–1319 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Mouchiroud, L., Eichner, L. J., Shaw, R. J. & Auwerx, J. Transcriptional coregulators: fine-tuning metabolism. Cell Metab. 20, 26–40 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Yamamoto, T. et al. Protein kinase A suppresses sterol regulatory element-binding protein-1C expression via phosphorylation of liver X receptor in the liver. J. Biol. Chem. 282, 11687–11695 (2007).

    CAS  PubMed  Google Scholar 

  79. Hwahng, S. H., Ki, S. H., Bae, E. J., Kim, H. E. & Kim, S. G. Role of adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway in repression of liver X receptor-alpha-dependent lipogenic gene induction and hepatic steatosis by a novel class of dithiolethiones. Hepatology 49, 1913–1925 (2009).

    CAS  PubMed  Google Scholar 

  80. Ma, L., Tsatsos, N. G. & Towle, H. C. Direct role of ChREBP·Mlx in regulating hepatic glucose-responsive genes. J. Biol. Chem. 280, 12019–12027 (2005).

    CAS  PubMed  Google Scholar 

  81. Stoeckman, A. K., Ma, L. & Towle, H. C. Mlx is the functional heteromeric partner of the carbohydrate response element-binding protein in glucose regulation of lipogenic enzyme genes. J. Biol. Chem. 279, 15662–15669 (2004).

    CAS  PubMed  Google Scholar 

  82. Filhoulaud, G., Guilmeau, S., Dentin, R., Girard, J. & Postic, C. Novel insights into ChREBP regulation and function. Trends Endocrinol. Metab. 24, 257–268 (2013).

    CAS  PubMed  Google Scholar 

  83. Ma, L., Robinson, L. N. & Towle, H. C. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J. Biol. Chem. 281, 28721–28730 (2006).

    CAS  PubMed  Google Scholar 

  84. Girard, J., Ferre, P. & Foufelle, F. Mechanisms by which carbohydrates regulate expression of genes for glycolytic and lipogenic enzymes. Annu. Rev. Nutr. 17, 325–352 (1997).

    CAS  PubMed  Google Scholar 

  85. Iizuka, K., Bruick, R. K., Liang, G., Horton, J. D. & Uyeda, K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc. Natl Acad. Sci. USA 101, 7281–7286 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Herman, M. A. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Eissing, L. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health. Nat. Commun. 4, 1528 (2013).

    PubMed  Google Scholar 

  88. Stiles, B. et al. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc. Natl Acad. Sci. USA 101, 2082–2087 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Dentin, R. et al. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 55, 2159–2170 (2006).

    CAS  PubMed  Google Scholar 

  90. Benhamed, F. et al. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J. Clin. Invest. 122, 2176–2194 (2012). This work demonstrates that although ChREBP promotes hepatic lipogenesis and lipid accumulation, it does not promote insulin resistance.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kabashima, T., Kawaguchi, T., Wadzinski, B. E. & Uyeda, K. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proc. Natl Acad. Sci. USA 100, 5107–5112 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kawaguchi, T., Takenoshita, M., Kabashima, T. & Uyeda, K. Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein. Proc. Natl Acad. Sci. USA 98, 13710–13715 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kawaguchi, T., Osatomi, K., Yamashita, H., Kabashima, T. & Uyeda, K. Mechanism for fatty acid “sparing” effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. J. Biol. Chem. 277, 3829–3835 (2002).

    CAS  PubMed  Google Scholar 

  94. Sakiyama, H. et al. Regulation of nuclear import/export of carbohydrate response element-binding protein (ChREBP): interaction of an α-helix of ChREBP with the 14-3-3 proteins and regulation by phosphorylation. J. Biol. Chem. 283, 24899–24908 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Arden, C. et al. Fructose 2,6-bisphosphate is essential for glucose-regulated gene transcription of glucose-6-phosphatase and other ChREBP target genes in hepatocytes. Biochem. J. 443, 111–123 (2012).

    CAS  PubMed  Google Scholar 

  96. Ge, Q. et al. Structural characterization of a unique interface between carbohydrate response element-binding protein (ChREBP) and 14-3-3β protein. J. Biol. Chem. 287, 41914–41921 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Dentin, R. et al. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver. J. Hepatol. 56, 199–209 (2012).

    CAS  PubMed  Google Scholar 

  98. Bricambert, J. et al. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J. Clin. Invest. 120, 4316–4331 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Li, M. V., Chang, B., Imamura, M., Poungvarin, N. & Chan, L. Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module. Diabetes 55, 1179–1189 (2006).

    CAS  PubMed  Google Scholar 

  100. Li, M. V., Chen, W., Poungvarin, N., Imamura, M. & Chan, L. Glucose-mediated transactivation of carbohydrate response element-binding protein requires cooperative actions from Mondo conserved regions and essential trans-acting factor 14-3-3. Mol. Endocrinol. 22, 1658–1672 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Guinez, C. et al. O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes 60, 1399–1413 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Sakiyama, H. et al. The role of O-linked GlcNAc modification on the glucose response of ChREBP. Biochem. Biophys. Res. Commun. 402, 784–789 (2010).

    CAS  PubMed  Google Scholar 

  103. Wang, Y. et al. Phosphorylation and recruitment of BAF60c in chromatin remodeling for lipogenesis in response to insulin. Mol. Cell 49, 283–297 (2013). This work demonstrates that insulin activates aPKC to phosphorylate BAF60C, resulting in the recruitment of BAF60C and the lipoBAF complex to the Fas promoter for chromatin remodelling.

    CAS  PubMed  Google Scholar 

  104. Abdulla, A. et al. Regulation of lipogenic gene expression by lysine-specific histone demethylase-1 (LSD1). J. Biol. Chem. 289, 29937–29947 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Taniguchi, C. M. et al. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKCλ/ζ. Cell Metab. 3, 343–353 (2006).

    CAS  PubMed  Google Scholar 

  106. Matsumoto, M. et al. PKCλ in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. J. Clin. Invest. 112, 935–944 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Li, S. et al. Genome-wide coactivation analysis of PGC-1α identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metab. 8, 105–117 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lamming, D. W. & Sabatini, D. M. A central role for mTOR in lipid homeostasis. Cell Metab. 18, 465–469 (2013).

    CAS  PubMed  Google Scholar 

  109. Peterson, T. R. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408–420 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Hagiwara, A. et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 15, 725–738 (2012). This work demonstrates that mTORC2 regulates hepatic glucose and lipid metabolism through phosphorylation of AKT.

    CAS  PubMed  Google Scholar 

  111. Yuan, M., Pino, E., Wu, L., Kacergis, M. & Soukas, A. A. Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J. Biol. Chem. 287, 29579–29588 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Asher, G. & Sassone-Corsi, P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 161, 84–92 (2015).

    CAS  PubMed  Google Scholar 

  113. Nakahata, Y. et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Liu, S. et al. A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 502, 550–554 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Bartok, O. et al. The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing. EMBO J. 34, 1538–1553 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Giguere, V. et al. Isoform-specific amino-terminal domains dictate DNA-binding properties of RORα, a novel family of orphan hormone nuclear receptors. Genes Dev. 8, 538–553 (1994).

    CAS  PubMed  Google Scholar 

  117. Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bugge, A. et al. Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function. Genes Dev. 26, 657–667 (2012). This work establishes REV-ERBα and REV-ERBβ as major regulators of the circadian clock and of metabolism.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Cho, H. et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485, 123–127 (2012). This work links REV-ERBα and REV-ERBβ to PER, CRY and other components of the circadian clock, for regulation of circadian rhythm and metabolism.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Delezie, J. et al. The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism. FASEB J. 26, 3321–3335 (2012).

    CAS  PubMed  Google Scholar 

  121. Feng, D. et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Yin, L. & Lazar, M. A. The orphan nuclear receptor Rev-erbα recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol. Endocrinol. 19, 1452–1459 (2005).

    CAS  PubMed  Google Scholar 

  123. Sun, Z. et al. Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor. Mol. Cell 52, 769–782 (2013).

    CAS  PubMed  Google Scholar 

  124. Kang, H. S. et al. Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis. Physiol. Genomics 43, 818–828 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhang, D. et al. Liver clock protein BMAL1 promotes de novo lipogenesis through insulin-mTORC2-AKT signaling. J. Biol. Chem. 289, 25925–25935 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Cretenet, G., Le Clech, M. & Gachon, F. Circadian clock-coordinated 12 hr period rhythmic activation of the IRE1α pathway controls lipid metabolism in mouse liver. Cell Metab. 11, 47–57 (2010).

    CAS  PubMed  Google Scholar 

  127. Basseri, S. & Austin, R. C. ER stress and lipogenesis: a slippery slope toward hepatic steatosis. Dev. Cell 15, 795–796 (2008).

    CAS  PubMed  Google Scholar 

  128. Smith, E. M., Finn, S. G., Tee, A. R., Browne, G. J. & Proud, C. G. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J. Biol. Chem. 280, 18717–18727 (2005).

    CAS  PubMed  Google Scholar 

  129. Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    CAS  PubMed  Google Scholar 

  130. Haeusler, R. A. et al. Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. Nat. Commun. 5, 5190 (2014).

    CAS  PubMed  Google Scholar 

  131. Zhang, W. et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J. Biol. Chem. 281, 10105–10117 (2006).

    CAS  PubMed  Google Scholar 

  132. Otero, Y. F., Stafford, J. M. & McGuinness, O. P. Pathway-selective insulin resistance and metabolic disease: the importance of nutrient flux. J. Biol. Chem. 289, 20462–20469 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Gerhart-Hines, Z. & Lazar, M. A. Circadian metabolism in the light of evolution. Endocr. Rev. 36, 289–304 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the authors' laboratory was supported by DK081098 (to H.S.S), and J.A.V. was supported by DK105671 from the US National institutes of Health.

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Glossary

Glycolysis

A series of enzyme-catalysed reactions that convert glucose into pyruvate.

Hyperlipidaemia

Abnormally elevated levels of any or all lipids and/or lipoproteins in the blood.

Poly (ADP-ribose) polymerase 1

(PARP1). A nuclear protein, the main role of which is to detect and signal single-strand breaks (SSBs) in DNA to the enzymatic machinery involved in SSB repair. PARP1 activation is an immediate cellular response to metabolic, chemical or radiation-induced DNA SSB damage.

p300/CBP-associated factor

(PCAF; also known as lysine acetyltransferase 2B (KAT2B)). A transcriptional coactivator that has in vitro and in vivo binding activity with CREB-binding protein (CBP) and p300, and competes with E1A for binding sites in p300 and CBP. PCAF has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that it plays a direct part in transcriptional regulation.

ATP-binding cassette (ABC) transporters

Transmembrane proteins that utilize the energy from ATP binding and hydrolysis to carry out certain biological processes, including translocation of various substrates across membranes.

Peroxisome proliferator-activated receptor c co-activator 1α

(PGC1α). A transcriptional co-activator that is a central inducer of mitochondrial biogenesis in cells. PGC1α both increases mitochondrial functions and minimizes the build-up of their by-products, ensuring a global positive impact on oxidative metabolism.

Hypolipidaemia

Abnormally low levels of any or all lipids and/or lipoproteins in the blood.

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Wang, Y., Viscarra, J., Kim, SJ. et al. Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol 16, 678–689 (2015). https://doi.org/10.1038/nrm4074

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