Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis

K. K. Gkouskou, M. Ioannou, G. A. Pavlopoulos, K. Georgila, A. Siganou, G. Nikolaidis, D. C. Kanellis, S. Moore, Konstantinos Papadakis, D. Kardassis, I. Iliopoulos, F. A. McDyer, E. Drakos, A. G. Eliopoulos

Research output: Contribution to journalArticle

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Abstract

In both humans with long-standing ulcerative colitis and mouse models of colitis-associated carcinogenesis (CAC), tumors develop predominantly in the distal part of the large intestine but the biological basis of this intriguing pathology remains unknown. Herein we report intrinsic differences in gene expression between proximal and distal colon in the mouse, which are augmented during dextran sodium sulfate (DSS)/azoxymethane (AOM)-induced CAC. Functional enrichment of differentially expressed genes identified discrete biological pathways operating in proximal vs distal intestine and revealed a cluster of genes involved in lipid metabolism to be associated with the disease-resistant proximal colon. Guided by this finding, we have further interrogated the expression and function of one of these genes, apolipoprotein A-I (ApoA-I), a major component of high-density lipoprotein. We show that ApoA-I is expressed at higher levels in the proximal compared with the distal part of the colon and its ablation in mice results in exaggerated DSS-induced colitis and disruption of epithelial architecture in larger areas of the large intestine. Conversely, treatment with an ApoA-I mimetic peptide ameliorated the phenotypic, histopathological and inflammatory manifestations of the disease. Genetic interference with ApoA-I levels in vivo impacted on the number, size and distribution of AOM/DSS-induced colon tumors. Mechanistically, ApoA-I was found to modulate signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB activation in response to the bacterial product lipopolysaccharide with concomitant impairment in the production of the pathogenic cytokine interleukin-6. Collectively, these data demonstrate a novel protective role for ApoA-I in colitis and CAC and unravel an unprecedented link between lipid metabolic processes and intestinal pathologies.

Original languageEnglish (US)
Pages (from-to)2496-2505
Number of pages10
JournalOncogene
Volume35
Issue number19
DOIs
StatePublished - May 12 2016

Fingerprint

Apolipoprotein A-I
Colitis
Carcinogenesis
Dextran Sulfate
Colon
Azoxymethane
Large Intestine
Pathology
STAT3 Transcription Factor
HDL Lipoproteins
Multigene Family
Ulcerative Colitis
Lipid Metabolism
Genes
Intestines
Lipopolysaccharides
Interleukin-6
Neoplasms
Cytokines
Lipids

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Gkouskou, K. K., Ioannou, M., Pavlopoulos, G. A., Georgila, K., Siganou, A., Nikolaidis, G., ... Eliopoulos, A. G. (2016). Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis. Oncogene, 35(19), 2496-2505. https://doi.org/10.1038/onc.2015.307

Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis. / Gkouskou, K. K.; Ioannou, M.; Pavlopoulos, G. A.; Georgila, K.; Siganou, A.; Nikolaidis, G.; Kanellis, D. C.; Moore, S.; Papadakis, Konstantinos; Kardassis, D.; Iliopoulos, I.; McDyer, F. A.; Drakos, E.; Eliopoulos, A. G.

In: Oncogene, Vol. 35, No. 19, 12.05.2016, p. 2496-2505.

Research output: Contribution to journalArticle

Gkouskou, KK, Ioannou, M, Pavlopoulos, GA, Georgila, K, Siganou, A, Nikolaidis, G, Kanellis, DC, Moore, S, Papadakis, K, Kardassis, D, Iliopoulos, I, McDyer, FA, Drakos, E & Eliopoulos, AG 2016, 'Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis', Oncogene, vol. 35, no. 19, pp. 2496-2505. https://doi.org/10.1038/onc.2015.307
Gkouskou KK, Ioannou M, Pavlopoulos GA, Georgila K, Siganou A, Nikolaidis G et al. Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis. Oncogene. 2016 May 12;35(19):2496-2505. https://doi.org/10.1038/onc.2015.307
Gkouskou, K. K. ; Ioannou, M. ; Pavlopoulos, G. A. ; Georgila, K. ; Siganou, A. ; Nikolaidis, G. ; Kanellis, D. C. ; Moore, S. ; Papadakis, Konstantinos ; Kardassis, D. ; Iliopoulos, I. ; McDyer, F. A. ; Drakos, E. ; Eliopoulos, A. G. / Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis. In: Oncogene. 2016 ; Vol. 35, No. 19. pp. 2496-2505.
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