3-Hydroxyanthralinic acid metabolism controls the hepatic SREBP/lipoprotein axis, inhibits inflammasome activation in macrophages, and decreases atherosclerosis in Ldlr−/− mice. Issue 12 (7th October 2019)

• Record Type: Journal Article
• Authors: Berg, Martin; Polyzos, Konstantinos A; Agardh, Hanna; Baumgartner, Roland; Forteza, Maria J; Kareinen, Ilona; Gisterå, Anton; Bottcher, Gerhard; Hurt-Camejo, Eva; Hansson, Göran K; Ketelhuth, Daniel F J
• Is Part Of: Cardiovascular research. Volume 116:Issue 12(2020)
• Page Start: 1948
• Page End: 1957
• Publication Date: 2019-10-07
• Subjects: Atherosclerosis -- Kynurenine -- IDO -- Inflammation -- Immunometabolism; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvz258
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Atherosclerosis 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 results: In 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. Conclusions: We 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.