Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

TAK1 regulates hepatic lipid homeostasis through SREBP

Oncogene volume 35, pages 3829–3838 (2016)Cite this article

Subjects

Abstract

Sterol-regulatory element-binding proteins (SREBPs) are key transcription factors regulating cholesterol and fatty acid biosynthesis. SREBP activity is tightly regulated to maintain lipid homeostasis, and is modulated upon extracellular stimuli such as growth factors. While the homeostatic SREBP regulation is well studied, stimuli-dependent regulatory mechanisms are still elusive. Here we demonstrate that SREBPs are regulated by a previously uncharacterized mechanism through transforming growth factor-β activated kinase 1 (TAK1), a signaling molecule of inflammation. We found that TAK1 binds to and inhibits mature forms of SREBPs. In an in vivo setting, hepatocyte-specific Tak1 deletion upregulates liver lipid deposition and lipogenic enzymes in the mouse model. Furthermore, hepatic Tak1 deficiency causes steatosis pathologies including elevated blood triglyceride and cholesterol levels, which are established risk factors for the development of hepatocellular carcinoma (HCC) and are indeed correlated with Tak1-deficiency-induced HCC development. Pharmacological inhibition of SREBPs alleviated the steatosis and reduced the expression level of the HCC marker gene in the Tak1-deficient liver. Thus, TAK1 regulation of SREBP critically contributes to the maintenance of liver homeostasis to prevent steatosis, which is a potentially important mechanism to prevent HCC development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Horton JD, Goldstein JL, Brown MS . SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109: 1125–1131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brown MS, Goldstein JL . The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997; 89: 331–340.

    Article  CAS  PubMed  Google Scholar 

  3. Shimano H, Shimomura I, Hammer RE, Herz J, Goldstein JL, Brown MS 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 1997; 100: 2115–2124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002; 110: 489–500.

    Article  CAS  PubMed  Google Scholar 

  5. Goldstein JL, DeBose-Boyd RA, Brown MS . Protein sensors for membrane sterols. Cell 2006; 124: 35–46.

    Article  CAS  PubMed  Google Scholar 

  6. Sundqvist A, Ericsson J . Transcription-dependent degradation controls the stability of the SREBP family of transcription factors. Proc Natl Acad Sci USA 2003; 100: 13833–13838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyanchuk V, Jin J, Harper JW et al. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metab 2005; 1: 379–391.

    Article  CAS  PubMed  Google Scholar 

  8. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011; 146: 408–420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Laplante M, Sabatini DM . mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proc Natl Acad Sci USA 2010; 107: 3281–3282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 2010; 39: 171–183.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8: 224–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 2011; 14: 21–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 2000; 6: 1355–1364.

    Article  CAS  PubMed  Google Scholar 

  14. Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 2009; 119: 1201–1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schuck S, Prinz WA, Thorn KS, Voss C, Walter P . Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response. J Cell Biol 2009; 187: 525–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ron D, Hampton RY . Membrane biogenesis and the unfolded protein response. J Cell Biol 2004; 167: 23–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 2011; 13: 376–388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mihaly SR, Ninomiya-Tsuji J, Morioka S . TAK1 control of cell death. Cell Death Differ 2014; 21: 1667–1676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Morioka S, Inagaki M, Komatsu Y, Mishina Y, Matsumoto K, Ninomiya-Tsuji J . TAK1 kinase signaling regulates embryonic angiogenesis by modulating endothelial cell survival and migration. Blood 2012; 120: 3846–3857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Omori E, Matsumoto K, Sanjo H, Sato S, Akira S, Smart RC et al. TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J Biol Chem 2006; 281: 19610–19617.

    Article  CAS  PubMed  Google Scholar 

  21. Kajino-Sakamoto R, Inagaki M, Lippert E, Akira S, Robine S, Matsumoto K et al. Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J Immunol 2008; 181: 1143–1152.

    Article  CAS  PubMed  Google Scholar 

  22. Ikeda Y, Morioka S, Matsumoto K, Ninomiya-Tsuji J . TAK1 binding protein 2 is essential for liver protection from stressors. PLoS ONE 2014; 9: e88037.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Inokuchi S, Aoyama T, Miura K, Osterreicher CH, Kodama Y, Miyai K et al. Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis. Proc Natl Acad Sci USA 2010; 107: 844–849.

    Article  CAS  PubMed  Google Scholar 

  24. Bettermann K, Vucur M, Haybaeck J, Koppe C, Janssen J, Heymann F et al. TAK1 suppresses a NEMO-dependent but NF-κB-independent pathway to liver cancer. Cancer Cell 2010; 17: 481–496.

    Article  CAS  PubMed  Google Scholar 

  25. Morioka S, Broglie P, Omori E, Ikeda Y, Takaesu G, Matsumoto K et al. TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation. J Cell Biol 2014; 204: 607–623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang L, Inokuchi S, Roh YS, Song J, Loomba R, Park EJ et al. Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1. Gastroenterology 2013; 144: 1042–1054 e1044.

    Article  CAS  PubMed  Google Scholar 

  27. Das M, Garlick DS, Greiner DL, Davis RJ . The role of JNK in the development of hepatocellular carcinoma. Genes Dev 2011; 25: 634–645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wagner EF, Nebreda AR . Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 2009; 9: 537–549.

    Article  CAS  PubMed  Google Scholar 

  29. Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 2007; 11: 119–132.

    Article  CAS  PubMed  Google Scholar 

  30. Maeda S, Kamata H, Luo JL, Leffert H, Karin M . IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005; 121: 977–990.

    Article  CAS  PubMed  Google Scholar 

  31. Karin M . Nuclear factor-κB in cancer development and progression. Nature 2006; 441: 431–436.

    Article  CAS  PubMed  Google Scholar 

  32. Sohda T, Iwata K, Soejima H, Kamimura S, Shijo H, Yun K . In situ detection of insulin-like growth factor II (IGF2) and H19 gene expression in hepatocellular carcinoma. J Hum Genet 1998; 43: 49–53.

    Article  CAS  PubMed  Google Scholar 

  33. Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A et al. The H19 non-coding RNA is essential for human tumor growth. PLoS ONE 2007; 2: e845.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Braeuning A, Jaworski M, Schwarz M, Kohle C . Rex3 (reduced in expression 3) as a new tumor marker in mouse hepatocarcinogenesis. Toxicology 2006; 227: 127–135.

    Article  CAS  PubMed  Google Scholar 

  35. Inokuchi-Shimizu S, Park EJ, Roh YS, Yang L, Zhang B, Song J et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest 2014; 124: 3566–3578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cohen JC, Horton JD, Hobbs HH . Human fatty liver disease: old questions and new insights. Science 2011; 332: 1519–1523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Browning JD, Horton JD . Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114: 147–152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sabio G, Cavanagh-Kyros J, Ko HJ, Jung DY, Gray S, Jun JY et al. Prevention of steatosis by hepatic JNK1. Cell Metab 2009; 10: 491–498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Momcilovic M, Hong SP, Carlson M . Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem 2006; 281: 25336–25343.

    Article  CAS  PubMed  Google Scholar 

  40. Kajino T, Omori E, Ishii S, Matsumoto K, Ninomiya-Tsuji J . TAK1 MAPK kinase kinase mediates transforming growth factor-β signaling by targeting SnoN oncoprotein for degradation. J Biol Chem 2007; 282: 9475–9481.

    Article  CAS  PubMed  Google Scholar 

  41. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K et al. TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell 2000; 5: 649–658.

    Article  CAS  PubMed  Google Scholar 

  42. Kishimoto K, Matsumoto K, Ninomiya-Tsuji J . TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop. J Biol Chem 2000; 275: 7359–7364.

    Article  CAS  PubMed  Google Scholar 

  43. Scholz R, Sidler CL, Thali RF, Winssinger N, Cheung PC, Neumann D . Autoactivation of transforming growth factor β-activated kinase 1 is a sequential bimolecular process. J Biol Chem 2010; 285: 25753–25766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kamisuki S, Mao Q, Abu-Elheiga L, Gu Z, Kugimiya A, Kwon Y et al. A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem Biol 2009; 16: 882–892.

    Article  CAS  PubMed  Google Scholar 

  45. Glass CK, Olefsky JM . Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab 2012; 15: 635–645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang HH, Halbleib M, Ahmad F, Manganiello VC, Greenberg AS . Tumor necrosis factor-α stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 2002; 51: 2929–2935.

    Article  CAS  PubMed  Google Scholar 

  47. Fon Tacer K, Kuzman D, Seliskar M, Pompon D, Rozman D . TNF-α interferes with lipid homeostasis and activates acute and proatherogenic processes. Physiol Genomics 2007; 31: 216–227.

    Article  PubMed  Google Scholar 

  48. Oliner JD, Andresen JM, Hansen SK, Zhou SL, Tjian R . SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein. Genes Dev 1996; 10: 2903–2911.

    Article  CAS  PubMed  Google Scholar 

  49. Osborne TF . Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J Biol Chem 2000; 275: 32379–32382.

    Article  CAS  PubMed  Google Scholar 

  50. Junttila MR, Li SP, Westermarck J . Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 2008; 22: 954–965.

    Article  CAS  PubMed  Google Scholar 

  51. Kim SI, Kwak JH, Wang L, Choi ME . Protein phosphatase 2A is a negative regulator of transforming growth factor-β1-induced TAK1 activation in mesangial cells. J Biol Chem 2008; 283: 10753–10763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kajino T, Ren H, Iemura S, Natsume T, Stefansson B, Brautigan DL et al. Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway. J Biol Chem 2006; 281: 39891–39896.

    Article  CAS  PubMed  Google Scholar 

  53. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 1998; 12: 3182–3194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nakayama H, Otabe S, Ueno T, Hirota N, Yuan X, Fukutani T et al. Transgenic mice expressing nuclear sterol regulatory element-binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis. Metabolism 2007; 56: 470–475.

    Article  CAS  PubMed  Google Scholar 

  55. Takahashi Y, Soejima Y, Fukusato T . Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2012; 18: 2300–2308.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci USA 2005; 102: 3389–3394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Heindryckx F, Colle I, Van Vlierberghe H . Experimental mouse models for hepatocellular carcinoma research. Int J Exp Pathol 2009; 90: 367–386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Farazi PA, DePinho RA . Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006; 6: 674–687.

    Article  CAS  PubMed  Google Scholar 

  59. Zhang L, Yang F, Yuan JH, Yuan SX, Zhou WP, Huo XS et al. Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis 2013; 34: 577–586.

    Article  PubMed  Google Scholar 

  60. Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T et al. Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat Immunol 2005; 6: 1087–1095.

    Article  CAS  PubMed  Google Scholar 

  61. Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic β cell-specific gene knock-outs using Cre recombinase. J Biol Chem 1999; 274: 305–315.

    Article  CAS  PubMed  Google Scholar 

  62. Pfeffer K, Matsuyama T, Kundig TM, Wakeham A, Kishihara K, Shahinian A et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 1993; 73: 457–467.

    Article  CAS  PubMed  Google Scholar 

  63. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K . The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 1999; 398: 252–256.

    Article  CAS  PubMed  Google Scholar 

  64. Toth JI, Datta S, Athanikar JN, Freedman LP, Osborne TF . Selective coactivator interactions in gene activation by SREBP-1a and -1c. Mol Cell Biol 2004; 24: 8288–8300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hua X, Nohturfft A, Goldstein JL, Brown MS . Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 1996; 87: 415–426.

    Article  CAS  PubMed  Google Scholar 

  66. Uemura N, Kajino T, Sanjo H, Sato S, Akira S, Matsumoto K et al. TAK1 is a component of the Epstein-Barr virus LMP1 complex and is essential for activation of JNK but not of NF-κB. J Biol Chem 2006; 281: 7863–7872.

    Article  CAS  PubMed  Google Scholar 

  67. Morioka S, Omori E, Kajino T, Kajino-Sakamoto R, Matsumoto K, Ninomiya-Tsuji J . TAK1 kinase determines TRAIL sensitivity by modulating reactive oxygen species and cIAP. Oncogene 2009; 28: 2257–2265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ninomiya-Tsuji J, Kajino T, Ono K, Ohtomo T, Matsumoto M, Shiina M et al. A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting the catalytic activity of TAK1 MAPK kinase kinase. J Biol Chem 2003; 278: 18485–18490.

    Article  CAS  PubMed  Google Scholar 

  69. Smith JR, Osborne TF, Goldstein JL, Brown MS . Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene. J Biol Chem 1990; 265: 2306–2310.

    CAS  PubMed  Google Scholar 

  70. Ringseis R, Rauer C, Rothe S, Gessner DK, Schutz LM, Luci S et al. Sterol regulatory element-binding proteins are regulators of the NIS gene in thyroid cells. Mol Endocrinol 2013; 27: 781–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank NC State biological animal facility for technical support, Dr Akira for Tak1-loxed mice and Simmons, A. for critical reading. This work was supported by National Institutes of Health Grant GM068812 (to JNT).

Author contributions

SM, KS, EO, YI and JNT performed the experiments and analyzed the data. SM, KM and JNT designed the experiments and wrote the manuscript.

Author information

Author notes

  1. S Morioka

    Present address: 3Current address: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.,

Authors and Affiliations

  1. Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA

    S Morioka, K Sai, E Omori, Y Ikeda & J Ninomiya-Tsuji

  2. Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan

    K Sai & K Matsumoto

Authors
  1. S Morioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Sai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Omori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Ninomiya-Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to S Morioka or J Ninomiya-Tsuji.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morioka, S., Sai, K., Omori, E. et al. TAK1 regulates hepatic lipid homeostasis through SREBP. Oncogene 35, 3829–3838 (2016). https://doi.org/10.1038/onc.2015.453

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.453

This article is cited by

Search

Advanced search

Quick links