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3-Hydroxyanthralini...
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Berg, MKarolinska Institutet
(author)
3-Hydroxyanthralinic acid metabolism controls the hepatic SREBP/lipoprotein axis, inhibits inflammasome activation in macrophages, and decreases atherosclerosis in Ldlr-/- mice
- Article/chapterEnglish2020
Publisher, publication year, extent ...
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2019-10-07
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Oxford University Press (OUP),2020
Numbers
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LIBRIS-ID:oai:prod.swepub.kib.ki.se:145465654
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http://kipublications.ki.se/Default.aspx?queryparsed=id:145465654URI
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https://doi.org/10.1093/cvr/cvz258DOI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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AimsAtherosclerosis is a chronic inflammatory disease involving immunological and metabolic processes. Metabolism of tryptophan (Trp) via the kynurenine pathway has shown immunomodulatory properties and the ability to modulate atherosclerosis. We identified 3-hydroxyanthranilic acid (3-HAA) as a key metabolite of Trp modulating vascular inflammation and lipid metabolism. The molecular mechanisms driven by 3-HAA in atherosclerosis have not been completely elucidated. In this study, we investigated whether two major signalling pathways, activation of SREBPs and inflammasome, are associated with the 3-HAA-dependent regulation of lipoprotein synthesis and inflammation in the atherogenesis process. Moreover, we examined whether inhibition of endogenous 3-HAA degradation affects hyperlipidaemia and plaque formation.Methods and resultsIn vitro, we showed that 3-HAA reduces SREBP-2 expression and nuclear translocation and apolipoprotein B secretion in HepG2 cell cultures, and inhibits inflammasome activation and IL-1β production by macrophages. Using Ldlr−/− mice, we showed that inhibition of 3-HAA 3,4-dioxygenase (HAAO), which increases the endogenous levels of 3-HAA, decreases plasma lipids and atherosclerosis. Notably, HAAO inhibition led to decreased hepatic SREBP-2 mRNA levels and lipid accumulation, and improved liver pathology scores.ConclusionsWe show that the activity of SREBP-2 and the inflammasome can be regulated by 3-HAA metabolism. Moreover, our study highlights that targeting HAAO is a promising strategy to prevent and treat hypercholesterolaemia and atherosclerosis.
Added entries (persons, corporate bodies, meetings, titles ...)
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Polyzos, KA
(author)
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Agardh, H
(author)
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Baumgartner, RKarolinska Institutet
(author)
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Forteza, MJKarolinska Institutet
(author)
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Kareinen, I
(author)
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Gistera, AKarolinska Institutet
(author)
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Bottcher, G
(author)
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Hurt-Camejo, E
(author)
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Hansson, GKKarolinska Institutet
(author)
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Ketelhuth, DFJKarolinska Institutet
(author)
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Karolinska Institutet
(creator_code:org_t)
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In:Cardiovascular research: Oxford University Press (OUP)116:12, s. 1948-19571755-32450008-6363
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Berg, M
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Polyzos, KA
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Agardh, H
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Baumgartner, R
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Forteza, MJ
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Kareinen, I
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show more...
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Gistera, A
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Bottcher, G
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Hurt-Camejo, E
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Hansson, GK
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Ketelhuth, DFJ
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Cardiovascular r ...
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Karolinska Institutet