Deficiency of IKKε inhibits inflammation and induces cardiac protection in high-fat diet-induced obesity in mice

Cao,Changchun; Li,Liangpeng; Chen,Wen; Zhu,Yifan; Qi,Yongchao; Wang,Xiaodi; Wan,Xin; Chen,Xin

doi:10.3892/ijmm.2014.1746

Deficiency of IKKε inhibits inflammation and induces cardiac protection in high-fat diet-induced obesity in mice

Authors:
- Changchun Cao
- Liangpeng Li
- Wen Chen
- Yifan Zhu
- Yongchao Qi
- Xiaodi Wang
- Xin Wan
- Xin Chen
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Affiliations: Department of Nephrology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China, Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
Published online on: April 17, 2014 https://doi.org/10.3892/ijmm.2014.1746
Pages: 244-252

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Abstract

Immune response and metabolic regulation have been recognized as a central homeostatic mechanism, the dysfunction of which can trigger a cluster of chronic metabolic disorders, particularly obesity, type Ⅱ diabetes and cardiovascular disease. Serine/threonine kinase IκB kinase (IKK) ε is a multifunctional regulator that participates in immune regulation, cell proliferation and transformation, and oncogenesis. In the present study, we investigated the role of IKKε in cardiovascular disorders using murine models of apolipoprotein E‑deficient [ApoE(-/-)] mice and ApoE/IKKε double‑knockout [ApoE(-/-)/IKKε(-/-)]mice, which were fed a normal diet (ND) and high-fat diet (HFD) for 12 weeks, respectively. Results of this study showed that mouse obesity correlated in vivo with an increased expression of IKKε. Additionally, chronic low‑grade inflammation in cardiac tissue was evident in ApoE(-/-) mice, but was markedly reduced in ApoE(-/-)/IKKε(-/-) mice. However, serum lipid levels in the ApoE(-/-) mice group were not significantly higher than those of the ApoE(-/-)/IKKε(-/-) group. Furthermore, immunofluorescence and western blot analysis demonstrated evident increases in the expression of nuclear factor-κB (NF-κB) pathway components and downstream factors in the ApoE(-/-) mice group, while these increases were blocked in the ApoE(-/-)/IKKε(-/-) group. Taken together, these data indicate that deficiency of IKKε prevented obesity and inflammatory response in the murine hearts in ApoE(-/-) and ApoE(-/-)/IKKε(-/-) mice fed an ND and HFD, respectively, suggesting that IKKε may play a role in HFD-induced inflammation in hearts of obese mice and may serve as a novel target for the treatment of a variety of metabolism-associated cardiovascular diseases.

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1	Hotamisligil GS: Inflammation and metabolic disorders. Nature. 444:860–867. 2006. View Article : Google Scholar
2	Mauro C and Marelli-Berg FM: T cell immunity and cardiovascular metabolic disorders: does metabolism fuel inflammation? Front Immunol. 3:1732012. View Article : Google Scholar : PubMed/NCBI
3	Chen H: Cellular inflammatory responses: novel insights for obesity and insulin resistance. Pharmacol Res. 53:469–477. 2006. View Article : Google Scholar : PubMed/NCBI
4	Hansson GK and Hermansson A: The immune system in atherosclerosis. Nat Immunol. 12:204–212. 2011. View Article : Google Scholar : PubMed/NCBI
5	Harrison DG, Vinh A, Lob H and Madhur MS: Role of the adaptive immune system in hypertension. Curr Opin Pharmacol. 10:203–207. 2010. View Article : Google Scholar : PubMed/NCBI
6	Baker RG, Hayden MS and Ghosh S: NF-κB, inflammation, and metabolic disease. Cell Metab. 13:11–22. 2011.
7	Ghosh S and Hayden MS: New regulators of NF-kappaB in inflammation. Nat Rev Immunol. 8:837–848. 2008. View Article : Google Scholar : PubMed/NCBI
8	Pasparakis M: Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol. 9:778–788. 2009. View Article : Google Scholar : PubMed/NCBI
9	Hayden MS and Ghosh S: Shared principles in NF-kappaB signaling. Cell. 132:344–362. 2008. View Article : Google Scholar : PubMed/NCBI
10	Oeckinghaus A, Hayden MS and Ghosh S: Crosstalk in NF-κB signaling pathways. Nat Immunol. 12:695–708. 2011.
11	Liu F, Xia Y, Parker AS and Verma IM: IKK biology. Immunol Rev. 246:239–253. 2012. View Article : Google Scholar : PubMed/NCBI
12	Wang N, Ahmed S and Haqqi TM: Genomic structure and functional characterization of the promoter region of human IkappaB kinase-related kinase IKKi/IKKvarepsilon gene. Gene. 353:118–133. 2005. View Article : Google Scholar : PubMed/NCBI
13	Häcker H and Karin M: Regulation and function of IKK and IKK-related kinases. Sci STKE 2006. re132006.PubMed/NCBI
14	Chau TL, Gioia R, Gatot JS, et al: Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated? Trends Biochem Sci. 33:171–180. 2008. View Article : Google Scholar : PubMed/NCBI
15	Chiang SH, Bazuine M, Lumeng CN, et al: The protein kinase IKKepsilon regulates energy balance in obese mice. Cell. 138:961–975. 2009. View Article : Google Scholar : PubMed/NCBI
16	Dai J, Shen DF, Bian ZY, et al: IKKi deficiency promotes pressure overload-induced cardiac hypertrophy and fibrosis. PloS One. 8:e534122013. View Article : Google Scholar : PubMed/NCBI
17	Guo J, Kim D, Gao J, et al: IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer. Oncogene. 32:151–159. 2013. View Article : Google Scholar : PubMed/NCBI
18	Guo JP, Coppola D and Cheng JQ: IKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation. J Biol Chem. 286:37389–37398. 2011. View Article : Google Scholar : PubMed/NCBI
19	Tenoever BR, Ng SL, Chua MA, McWhirter SM, García-Sastre A and Maniatis T: Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science. 315:1274–1278. 2007. View Article : Google Scholar : PubMed/NCBI
20	Ng SL, Friedman BA, Schmid S, et al: IκB kinase epsilon (IKK(epsilon)) regulates the balance between type I and type II interferon responses. Proc Natl Acad Sci USA. 108:21170–21175. 2011.
21	Cao C, Zhu Y, Chen W, et al: IKKɛ knockout prevents high fat diet induced arterial atherosclerosis and NF-κB signaling in mice. PloS One. 8:e649302013.
22	Shoelson SE, Herrero L and Naaz A: Obesity, inflammation, and insulin resistance. Gastroenterology. 132:2169–2180. 2007. View Article : Google Scholar : PubMed/NCBI
23	Wellen KE and Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest. 115:1111–1119. 2005. View Article : Google Scholar : PubMed/NCBI
24	Scheja L, Heese B and Seedorf K: Beneficial effects of IKKɛ-deficiency on body weight and insulin sensitivity are lost in high fat diet-induced obesity in mice. Biochem Biophys Res Commun. 407:288–294. 2011.
25	Reilly SM, Chiang SH, Decker SJ, et al: An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice. Nat Med. 19:313–321. 2013.
26	Olefsky JM: IKKepsilon: a bridge between obesity and inflammation. Cell. 138:834–836. 2009. View Article : Google Scholar : PubMed/NCBI
27	Karin M and Ben-Neriah Y: Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 18:621–663. 2000.PubMed/NCBI