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

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Gkouskou KK,Ioannou M,Pavlopoulos GA,Georgila K,Siganou A,Nikolaidis G,Kanellis DC,Moore S,Papadakis KA,Kardassis D,Iliopoulos I,McDyer FA,Drakos E,Eliopoulos AG

doi

10.1038/onc.2015.307

subject

Has Abstract

pub_date

2016-05-12 00:00:00

pages

2496-505

issue

19

eissn

0950-9232

issn

1476-5594

pii

onc2015307

journal_volume

35

pub_type

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