IKKβ links vascular inflammation to obesity and atherosclerosis

Journal of Experimental Medicine

Volumn 211, Issue 5, 2014, Pages 869-886

  Sui, Yipeng ^a   Park, Se Hyung ^a   Xu, Jinxian ^a   Monette, Sébastien ^c   Helsley, Robert N ^a   Han, Seong Su ^d   Zhou, Changcheng ^a,b  

^a UNIVERSITY OF KENTUCKY   (United States)

^b UNIVERSITY OF KENTUCKY   (United States)

^c MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^d UNIVERSITY OF IOWA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA CATENIN; CRE RECOMBINASE; GAMMA INTERFERON; I KAPPA B KINASE BETA; I KAPPA B KINASE INHIBITOR; INTERLEUKIN 1ALPHA; INTERLEUKIN 1BETA; INTERLEUKIN 6; LOW DENSITY LIPOPROTEIN RECEPTOR; MONOCYTE CHEMOTACTIC PROTEIN 1; NUCLEAR PROTEIN; PROTEASOME; SHORT HAIRPIN RNA; SM22CRE PROTEIN; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; UNCOUPLING PROTEIN 1;

ADIPOGENESIS; ADIPOSE TISSUE CELL; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; ATHEROSCLEROSIS; CELL DIFFERENTIATION; CELL ISOLATION; CELL LINEAGE; CONTROLLED STUDY; DUAL ENERGY X RAY ABSORPTIOMETRY; FATTY LIVER; FLOW CYTOMETRY; GEL MOBILITY SHIFT ASSAY; GENE EXPRESSION; GENE FUNCTION; GENE SILENCING; GLUCOSE INTOLERANCE; HYPERLIPIDEMIA; IMMUNOCYTOCHEMISTRY; IMMUNOFLUORESCENCE; LIMIT OF QUANTITATION; LIPID DIET; MALE; METABOLIC DISORDER; MOUSE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OBESITY; PRIORITY JOURNAL; PROTEIN DEFICIENCY; PROTEIN DEGRADATION; PROTEIN DNA BINDING; PROTEIN FUNCTION; RNA ISOLATION; SMOOTH MUSCLE FIBER; UBIQUITINATION; VASCULITIS; WEIGHT GAIN; WESTERN BLOTTING;

ABSORPTIOMETRY, PHOTON; ADIPOGENESIS; ANIMALS; ATHEROSCLEROSIS; BETA CATENIN; BLOTTING, WESTERN; BODY COMPOSITION; BODY WEIGHT; CELL LINEAGE; CHOLESTEROL; CHROMATOGRAPHY, LIQUID; ELECTROPHORETIC MOBILITY SHIFT ASSAY; GENE EXPRESSION REGULATION; I-KAPPA B KINASE; MAGNETIC RESONANCE SPECTROSCOPY; MICE; MICROFILAMENT PROTEINS; MUSCLE PROTEINS; MYOCYTES, SMOOTH MUSCLE; OBESITY; TRIGLYCERIDES; UBIQUITINATION; VASCULITIS;

EID: 84899741827     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20131281     Document Type: Article

References (74)

1. Arkan, M.C., A.L. Hevener, F.R. Greten, S. Maeda, Z.W. Li, J.M. Long, A. Wynshaw-Boris, G. Poli, J. Olefsky, and M. Karin. 2005. IKK-beta links inflammation to obesity-induced insulin resistance. Nat. Med. 11:191-198. http://dx.doi.org/10.1038/nm1185
2. Baker, R.G., M.S. Hayden, and S. Ghosh. 2011. NF-κB, inflammation, and metabolic disease. Cell Metab. 13:11-22. http://dx.doi.org/10.1016/j.cmet.2010.12.008
3. Berry, R., and M.S. Rodeheffer. 2013. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 15:302-308. http://dx.doi.org/10.1038/ncb2696
4. Boaz, M., L. Lisy, G. Zandman-Goddard, and J. Wainstein. 2009. The effect of anti-inflammatory (aspirin and/or statin) therapy on body weight in Type 2 diabetic individuals: EAT, a retrospective study. Diabet. Med. 26:708-713. http://dx.doi.org/10.1111/j.1464-5491.2009.02747.x
5. Brand, K., S. Page, G. Rogler, A. Bartsch, R. Brandl, R. Knuechel, M. Page, C. Kaltschmidt, P.A. Baeuerle, and D. Neumeier. 1996. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J. Clin. Invest. 97:1715-1722. http://dx.doi.org/10.1172/JCI118598
6. Burke, J.R., M.A. Pattoli, K.R. Gregor, P.J. Brassil, J.F. MacMaster, K.W. McIntyre, X. Yang, V.S. Iotzova, W. Clarke, J. Strnad, et al. 2003. BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J. Biol. Chem. 278:1450-1456. http://dx.doi.org/10.1074/jbc. M209677200
7. Cai, D., M. Yuan, D.F. Frantz, P.A. Melendez, L. Hansen, J. Lee, and S.E. Shoelson. 2005. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat. Med. 11:183-190. http://dx.doi.org/10.1038/nm1166
8. Cai, X., Y. Lin, P.V. Hauschka, and B.E. Grottkau. 2011. Adipose stem cells originate from perivascular cells. Biol. Cell. 103:435-447. http://dx.doi.org/10.1042/BC20110033
9. Calay, E.S., and G.S. Hotamisligil. 2013. Turning offthe inflammatory, but not the metabolic, flames. Nat. Med. 19:265-267. http://dx.doi.org/10.1038/nm.3114
10. Cawthorn, W.P., E.L. Scheller, and O.A. MacDougald. 2012. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J. Lipid Res. 53:227-246. http://dx.doi.org/10.1194/jlr. R021089
11. Chang, L., L. Villacorta, R. Li, M. Hamblin, W. Xu, C. Dou, J. Zhang, J. Wu, R. Zeng, and Y.E. Chen. 2012. Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation. 126:1067-1078. http://dx.doi.org/10.1161/CIRCULATIONAHA.112.104489
12. Chang, J., F. Liu, M. Lee, B. Wu, K. Ting, J.N. Zara, C. Soo, K. Al Hezaimi, W. Zou, X. Chen, et al. 2013. NF-κB inhibits osteogenic differentiation of mesenchymal stem cells by promoting β-catenin degradation. Proc. Natl. Acad. Sci. USA. 110:9469-9474. http://dx.doi.org/10.1073/pnas.1300532110
13. Chiang, S.H., M. Bazuine, C.N. Lumeng, L.M. Geletka, J. Mowers, N.M. White, J.T. Ma, J. Zhou, N. Qi, D. Westcott, et al. 2009. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell. 138:961-975. http://dx.doi.org/10.1016/j.cell.2009.06.046
14. Cho, Y.W., S. Hong, Q. Jin, L. Wang, J.E. Lee, O. Gavrilova, and K. Ge. 2009. Histone methylation regulator PTIP is required for PPARgamma and C/EBPalpha expression and adipogenesis. Cell Metab. 10:27-39. http://dx.doi.org/10.1016/j.cmet.2009.05.010
15. Cristancho, A.G., and M.A. Lazar. 2011. Forming functional fat: a growing understanding of adipocyte differentiation. Nat. Rev. Mol. Cell Biol. 12:722-734. http://dx.doi.org/10.1038/nrm3198
16. De Santa, F., M.G. Totaro, E. Prosperini, S. Notarbartolo, G. Testa, and G. Natoli. 2007. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 130: 1083-1094. http://dx.doi.org/10.1016/j.cell.2007.08.019
17. Ferreira, V., K.W. van Dijk, A.K. Groen, R.M. Vos, J. van der Kaa, M.J. Gijbels, L.M. Havekes, and H. Pannekoek. 2007. Macrophage-specific inhibition of NF-kappaB activation reduces foam-cell formation. Atherosclerosis. 192: 283-290. http://dx.doi.org/10.1016/j.atherosclerosis.2006.07.018
18. Gareus, R., E. Kotsaki, S. Xanthoulea, I. van der Made, M.J. Gijbels, R. Kardakaris, A. Polykratis, G. Kollias, M.P. de Winther, and M. Pasparakis. 2008. Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis. Cell Metab. 8:372-383. http://dx.doi.org/10.1016/j.cmet.2008.08.016
19. Gerondakis, S., A. Banerjee, G. Grigoriadis, A. Vasanthakumar, R. Gugasyan, T. Sidwell, and R.J. Grumont. 2012. NF-κB subunit specificity in hemopoiesis. Immunol. Rev. 246:272-285. http://dx.doi.org/10.1111/j.1600-065X.2011.01090.x
20. Goossens, P., M.N. Vergouwe, M.J. Gijbels, D.M. Curfs, J.H. van Woezik, M.A. Hoeksema, S. Xanthoulea, P.J. Leenen, R.A. Rupec, M.H. Hofker, and M.P. de Winther. 2011. Myeloid IκBα deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques. PLoS ONE. 6:e22327. http://dx.doi.org/10.1371/journal.pone.0022327
21. Gregor, M.F., and G.S. Hotamisligil. 2011. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29:415-445. http://dx.doi.org/10.1146/annurev-immunol-031210-101322 Gupta, R.K., Z. Arany, P. Seale, R.J. Mepani, L. Ye, H.M. Conroe, Y.A. Roby, H. Kulaga, R.R. Reed, and B.M. Spiegelman. 2010. Transcriptional control of preadipocyte determination by Zfp423. Nature. 464:619-623. http://dx.doi.org/10.1038/nature08816
22. Gupta, R.K., Z. Arany, P. Seale, R.J. Mepani, L. Ye, H.M. Conroe, Y.A. Roby, H. Kulaga, R.R. Reed, and B.M. Spiegelman. 2010. Transcriptional control of preadipocyte determination by Zfp423. Nature. 464:619-623. http://dx.doi.org/10.1038/nature08816
23. Gupta, R.K., R.J. Mepani, S. Kleiner, J.C. Lo, M.J. Khandekar, P. Cohen, A. Frontini, D.C. Bhowmick, L. Ye, S. Cinti, and B.M. Spiegelman. 2012. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab. 15:230-239. http://dx.doi.org/10.1016/j.cmet.2012.01.010
24. Han, G., A.G. Li, Y.Y. Liang, P. Owens, W. He, S. Lu, Y. Yoshimatsu, D. Wang, P. Ten Dijke, X. Lin, and X.J. Wang. 2006. Smad7-induced beta-catenin degradation alters epidermal appendage development. Dev. Cell. 11:301-312. http://dx.doi.org/10.1016/j.devcel.2006.06.014
25. Hayden, M.S., and S. Ghosh. 2008. Shared principles in NF-kappaB signaling. Cell. 132:344-362. http://dx.doi.org/10.1016/j.cell.2008.01.020
26. Hideshima, T., P. Richardson, D. Chauhan, V.J. Palombella, P.J. Elliott, J. Adams, and K.C. Anderson. 2001. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 61:3071-3076.
27. Holtwick, R., M. Gotthardt, B. Skryabin, M. Steinmetz, R. Potthast, B. Zetsche, R.E. Hammer, J. Herz, and M. Kuhn. 2002. Smooth muscleselective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc. Natl. Acad. Sci. USA. 99:7142-7147. http://dx.doi.org/10.1073/pnas.102650499
28. Hou, Y., F. Li, M. Karin, and M.C. Ostrowski. 2008. Analysis of the IKKbeta/NF-kappaB signaling pathway during embryonic angiogenesis. Dev. Dyn. 237:2926-2935. http://dx.doi.org/10.1002/dvdy.21723
29. Jiao, P., J. Ma, B. Feng, H. Zhang, J.A. Diehl, Y.E. Chin, W. Yan, and H. Xu. 2011. FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKβ pathways. Obesity (Silver Spring). 19:483-491. http://dx.doi.org/10.1038/oby.2010.200
30. Kanters, E., M. Pasparakis, M.J. Gijbels, M.N. Vergouwe, I. Partouns-Hendriks, R.J. Fijneman, B.E. Clausen, I. Förster, M.M. Kockx, K. Rajewsky, et al. 2003. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest. 112:1176-1185. http://dx.doi.org/10.1172/JCI200318580
31. Karin, M. 2006. Nuclear factor-kappaB in cancer development and progression. Nature. 441:431-436. http://dx.doi.org/10.1038/nature04870
32. Kim, J.K., Y.J. Kim, J.J. Fillmore, Y. Chen, I. Moore, J. Lee, M. Yuan, Z.W. Li, M. Karin, P. Perret, et al. 2001. Prevention of fat-induced insulin resistance by salicylate. J. Clin. Invest. 108:437-446. http://dx.doi.org/10.1172/JCI11559
33. Lancaster, G.I., B. Skiba, C. Yang, H.T. Nicholls, K.G. Langley, M.H. Chan, C.R. Bruce, G.W. Rewcastle, P.R. Shepherd, M. Karin, and M.A. Febbraio. 2012. IκB kinase β (IKKβ) does not mediate feedback inhibition of the insulin signalling cascade. Biochem. J. 442:723-732. http://dx.doi.org/10.1042/BJ20112037
34. Lee, J., N. Sayed, A. Hunter, K.F. Au, W.H. Wong, E.S. Mocarski, R.R. Pera, E. Yakubov, and J.P. Cooke. 2012a. Activation of innate immunity is required for efficient nuclear reprogramming. Cell. 151:547-558. http://dx.doi.org/10.1016/j.cell.2012.09.034
35. Lee, Y.H., A.P. Petkova, E.P. Mottillo, and J.G. Granneman. 2012b. In vivo identification of bipotential adipocyte progenitors recruited by ?3-
36. Li, Z.W., S.A. Omori, T. Labuda, M. Karin, and R.C. Rickert. 2003. IKK beta is required for peripheral B cell survival and proliferation. J. Immunol. 170:4630-4637.
37. Libby, P. 2002. Inflammation in atherosclerosis. Nature. 420:868-874. http://dx.doi.org/10.1038/nature01323
38. Mao, X., Y. Fujiwara, A. Chapdelaine, H. Yang, and S.H. Orkin. 2001. Activation of EGFP expression by Cre-mediated excision in a new ROSA26 reporter mouse strain. Blood. 97:324-326. http://dx.doi.org/10.1182/blood. V97.1.324
39. Melzner, I., V. Scott, K. Dorsch, P. Fischer, M. Wabitsch, S. Brüderlein, C. Hasel, and P. Möller. 2002. Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter. J. Biol. Chem. 277:45420-45427. http://dx.doi.org/10.1074/jbc. M208511200
40. Mikkelsen, T.S., Z. Xu, X. Zhang, L. Wang, J.M. Gimble, E.S. Lander, and E.D. Rosen. 2010. Comparative epigenomic analysis of murine and human adipogenesis. Cell. 143:156-169. http://dx.doi.org/10.1016/j.cell.2010.09.006
41. Millar, S.E. 2006. Smad7: licensed to kill beta-catenin. Dev. Cell. 11:274-276. http://dx.doi.org/10.1016/j.devcel.2006.08.008
42. Monaco, C., E. Andreakos, S. Kiriakidis, C. Mauri, C. Bicknell, B. Foxwell, N. Cheshire, E. Paleolog, and M. Feldmann. 2004. Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Proc. Natl. Acad. Sci. USA. 101:5634-5639. http://dx.doi.org/10.1073/pnas.0401060101
43. Moore, K.J., and I. Tabas. 2011. Macrophages in the pathogenesis of atherosclerosis. Cell. 145:341-355. http://dx.doi.org/10.1016/j.cell.2011.04.005
44. O'Neill, L.A. 2012. "Transflammation": when innate immunity meets induced pluripotency. Cell. 151:471-473. http://dx.doi.org/10.1016/j.cell.2012.10.006 Olefsky, J.M., and C.K. Glass. 2010. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72:219-246. http://dx.doi.org/10.1146/annurev-physiol-021909-135846
45. Olefsky, J.M., and C.K. Glass. 2010. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72:219-246. http://dx.doi.org/10.1146/annurev-physiol-021909-135846
46. Olson, L.E., and P. Soriano. 2011. PDGFRβ signaling regulates mural cell plasticity and inhibits fat development. Dev. Cell. 20:815-826. http://dx.doi.org/10.1016/j.devcel.2011.04.019
47. Park, S.H., Y. Sui, F. Gizard, J. Xu, J. Rios-Pilier, R.N. Helsley, S.S. Han, and C. Zhou. 2012. Myeloid-specific IκB kinase β deficiency decreases atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 32:2869-2876. http://dx.doi.org/10.1161/ATVBAHA.112.254573
48. Purkayastha, S., G. Zhang, and D. Cai. 2011. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat. Med. 17:883-887. http://dx.doi.org/10.1038/nm.2372
49. Reid, J., A.I. MacDougall, and M.M. Andrews. 1957. Aspirin and diabetes mellitus. BMJ. 2:1071-1074. http://dx.doi.org/10.1136/bmj.2.5053.1071
50. Rodeheffer, M.S., K. Birsoy, and J.M. Friedman. 2008. Identification of white adipocyte progenitor cells in vivo. Cell. 135:240-249. http://dx.doi.org/10.1016/j.cell.2008.09.036
51. Röhl, M., M. Pasparakis, S. Baudler, J. Baumgartl, D. Gautam, M. Huth, R. De Lorenzi, W. Krone, K. Rajewsky, and J.C. Brüning. 2004. Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance. J. Clin. Invest. 113:474-481. http://dx.doi.org/10.1172/JCI200418712
52. Ross, S.E., N. Hemati, K.A. Longo, C.N. Bennett, P.C. Lucas, R.L. Erickson, and O.A. MacDougald. 2000. Inhibition of adipogenesis by Wnt signaling. Science. 289:950-953. http://dx.doi.org/10.1126/science.289.5481.950
53. Sarkar, F.H., Y. Li, Z. Wang, and D. Kong. 2008. NF-kappaB signaling pathway and its therapeutic implications in human diseases. Int. Rev. Immunol. 27:293-319. http://dx.doi.org/10.1080/08830180802276179
54. Solinas, G., and M. Karin. 2010. JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J. 24:2596-2611. http://dx.doi.org/10.1096/fj.09-151340
55. Spalding, K.L., E. Arner, P.O. Westermark, S. Bernard, B.A. Buchholz, O. Bergmann, L. Blomqvist, J. Hoffstedt, E. Näslund, T. Britton, et al. 2008. Dynamics of fat cell turnover in humans. Nature. 453:783-787. http://dx.doi.org/10.1038/nature06902
56. Sui, Y., J. Xu, J. Rios-Pilier, and C. Zhou. 2011. Deficiency of PXR decreases atherosclerosis in apoE-deficient mice. J. Lipid Res. 52:1652-1659. http://dx.doi.org/10.1194/jlr. M017376
57. Tang, Q.Q., and M.D. Lane. 2012. Adipogenesis: from stem cell to adipocyte. Annu. Rev. Biochem. 81:715-736. http://dx.doi.org/10.1146/annurevbiochem-052110-115718
58. Tang, W., D. Zeve, J.M. Suh, D. Bosnakovski, M. Kyba, R.E. Hammer, M.D. Tallquist, and J.M. Graff. 2008. White fat progenitor cells reside in the adipose vasculature. Science. 322:583-586. http://dx.doi.org/10.1126/science.1156232
59. Tang, W., D. Zeve, J. Seo, A.Y. Jo, and J.M. Graff. 2011. Thiazolidinediones regulate adipose lineage dynamics. Cell Metab. 14:116-122. http://dx.doi.org/10.1016/j.cmet.2011.05.012
60. Teupser, D., A.D. Persky, and J.L. Breslow. 2003. Induction of atherosclerosis by low-fat, semisynthetic diets in LDL receptor-deficient C57BL/6J and FVB/NJ mice: comparison of lesions of the aortic root, brachiocephalic artery, and whole aorta (en face measurement). Arterioscler. Thromb. Vasc. Biol. 23:1907-1913. http://dx.doi.org/10.1161/01.ATV.0000090126.34881.B1
61. Vallabhapurapu, S., and M. Karin. 2009. Regulation and function of NFkappaB transcription factors in the immune system. Annu. Rev. Immunol. 27:693-733. http://dx.doi.org/10.1146/annurev.immunol.021908.132641Wang, L., Q. Jin, J.E. Lee, I.H. Su, and K. Ge. 2010. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc. Natl. Acad. Sci. USA. 107:7317-7322. http://dx.doi.org/10.1073/pnas.1000031107
62. Wang, L., Q. Jin, J.E. Lee, I.H. Su, and K. Ge. 2010. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc. Natl. Acad. Sci. USA. 107:7317-7322. http://dx.doi.org/10.1073/pnas.1000031107
63. Wang, L., S. Xu, J.E. Lee, A. Baldridge, S. Grullon, W. Peng, and K. Ge.2013. Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. EMBO J. 32:45-59. http://dx.doi.org/10.1038/emboj.2012.306
64. Williamson, R.T. 1901. On the Treatment of Glycosuria and Diabetes Mellitus with Sodium Salicylate. BMJ. 1:760-762. http://dx.doi.org/10.1136/bmj.1.2100.760
65. Wolfrum, S., D. Teupser, M. Tan, K.Y. Chen, and J.L. Breslow. 2007. The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappaB target genes. Proc. Natl. Acad. Sci. USA. 104:18601-18606. http://dx.doi.org/10.1073/pnas.0709011104
66. Wright, W.S., K.A. Longo, V.W. Dolinsky, I. Gerin, S. Kang, C.N. Bennett, S.H. Chiang, T.C. Prestwich, C. Gress, C.F. Burant, et al. 2007. Wnt10b inhibits obesity in ob/ob and agouti mice. Diabetes. 56:295-303. http://dx.doi.org/10.2337/db06-1339
67. Yu, Y.L., R.H. Chou, W.C. Shyu, S.C. Hsieh, C.S. Wu, S.Y. Chiang, W.J. Chang, J.N. Chen, Y.J. Tseng, Y.H. Lin, et al. 2013. Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke. EMBO Mol. Med. 5:531-547. http://dx.doi.org/10.1002/emmm.201201783
68. Yuan, M., N. Konstantopoulos, J. Lee, L. Hansen, Z.W. Li, M. Karin, and S.E. Shoelson. 2001. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 293:1673-1677. http://dx.doi.org/10.1126/science.1061620
69. Zeve, D., W. Tang, and J. Graff. 2009. Fighting fat with fat: the expanding field of adipose stem cells. Cell Stem Cell. 5:472-481. http://dx.doi.org/10.1016/j.stem.2009.10.014
70. Zhang, X., G. Zhang, H. Zhang, M. Karin, H. Bai, and D. Cai. 2008. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 135:61-73. http://dx.doi.org/10.1016/j.cell.2008.07.043
71. Zhang, Y., J. Liu, S. Yao, F. Li, L. Xin, M. Lai, V. Bracchi-Ricard, H. Xu, W. Yen, W. Meng, et al. 2012. Nuclear factor kappa B signaling initiates early differentiation of neural stem cells. Stem Cells. 30:510-524. http://dx.doi.org/10.1002/stem.1006
72. Zhou, C., M.M. Tabb, A. Sadatrafiei, F. Grün, A. Sun, and B. Blumberg. 2004. Hyperforin, the active component of St. John's wort, induces IL-8 expression in human intestinal epithelial cells via a MAPK-dependent, NF-kappaB-independent pathway. J. Clin. Immunol. 24:623-636. http://dx.doi.org/10.1007/s10875-004-6248-z
73. Zhou, C., M.M. Tabb, E.L. Nelson, F. Grün, S. Verma, A. Sadatrafiei, M. Lin, S. Mallick, B.M. Forman, K.E. Thummel, and B. Blumberg. 2006. Mutual repression between steroid and xenobiotic receptor and NFkappaB signaling pathways links xenobiotic metabolism and inflammation. J. Clin. Invest. 116:2280-2289. http://dx.doi.org/10.1172/JCI26283
74. -/- mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease. J. Lipid Res. 52:1483-1493. http://dx.doi.org/10.1194/jlr. M014092