IKKβ links vascular inflammation to obesity and atherosclerosis Journal Article
| Authors: | Sui, Y.; Park, S. H.; Xu, J.; Monette, S.; Helsley, R. N.; Han, S. S.; Zhou, C. |
| Article Title: | IKKβ links vascular inflammation to obesity and atherosclerosis |
| Abstract: | IκB kinase β (IKKβ), a central coordinator of inflammatory responses through activation of NF-κB, has been implicated in vascular pathologies, but its role in atherogenesis remains elusive. Here, we demonstrate that IKKβ functions in smooth muscle cells (SMCs) to regulate vascular inflammatory responses and atherosclerosis development. IKKβ deficiency in SMCs driven by a SM22Cre-IKKβ-flox system rendered low density lipoprotein receptornull mice resistant to vascular inflammation and atherosclerosis induced by high-fat feeding. Unexpectedly, IKKβ-deficient mice were also resistant to diet-induced obesity and metabolic disorders. Cell lineage analysis revealed that SM22Cre is active in primary adipose stromal vascular cells and deficiency of IKKβ diminished the ability of these cells to differentiate, leading to accumulation of adipocyte precursor cells in adipose tissue. Mechanistically, reduction of IKKβ expression or pharmacological inhibition of IKKβ inhibited proteasome-mediated β-catenin ubiquitination and degradation in murine preadipocytes, resulting in elevated β-catenin levels and impaired adipocyte differentiation. Further, chronic treatment of mice with a potent IKKβ inhibitor decreased adipogenesis and ameliorated diet-induced obesity. Our findings demonstrate a pivotal role of IKKβ in linking vascular inflammation to atherosclerosis and adipose tissue development, and provide evidence for using appropriate IKKβ inhibitors in the treatment of obesity and metabolic disorders. © 2014 Sui et al. |
| Keywords: | controlled study; unclassified drug; nonhuman; flow cytometry; protein function; animal cell; mouse; smooth muscle fiber; proteasome; gene expression; nuclear protein; protein degradation; protein dna binding; interleukin 1beta; animal experiment; obesity; gene function; cell differentiation; immunofluorescence; cell lineage; ubiquitination; gamma interferon; immunocytochemistry; atherosclerosis; western blotting; cell isolation; interleukin 6; nuclear magnetic resonance spectroscopy; i kappa b kinase beta; protein deficiency; gene silencing; interleukin 1alpha; gel mobility shift assay; beta catenin; cre recombinase; metabolic disorder; hyperlipidemia; short hairpin rna; monocyte chemotactic protein 1; tumor necrosis factor; fatty liver; dual energy x ray absorptiometry; weight gain; lipid diet; rna isolation; vasculitis; adipogenesis; i kappa b kinase inhibitor; glucose intolerance; limit of quantitation; male; priority journal; article; low density lipoprotein receptor; sm22cre protein; uncoupling protein 1; adipose tissue cell |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 211 |
| Issue: | 5 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2014-05-05 |
| Start Page: | 869 |
| End Page: | 886 |
| Language: | English |
| DOI: | 10.1084/jem.20131281 |
| PROVIDER: | scopus |
| PMCID: | PMC4010900 |
| PUBMED: | 24799533 |
| DOI/URL: | |
| Notes: | J. Exp. Med. -- Export Date: 2 June 2014 -- CODEN: JEMEA -- Source: Scopus |
