Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis.
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.
Molecular and Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.
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Gkouskou
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece.
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Ioannou
Bioinformatics and Computational Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.
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Pavlopoulos
Molecular and Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.
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Georgila
Molecular and Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.
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Siganou
Molecular and Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.
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Nikolaidis
Molecular and Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.
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Kanellis
Almac Diagnostics, Craigavon, UK.
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Moore
Department of Gastroenterology, University of Crete Medical School, Heraklion, Greece.|Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Papadakis
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece.|Laboratory of Biochemistry, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.
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Kardassis
Bioinformatics and Computational Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.
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Iliopoulos
Almac Diagnostics, Craigavon, UK.
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McDyer
Department of Pathology, University of Crete Medical School, Heraklion, Greece.
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Drakos
Molecular and Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece.|Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece.
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Eliopoulos
D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D051379:Mice; D008810:Mice, Inbred C57BL
D016632:Apolipoprotein A-I; D016264:Dextran Sulfate