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 atherosclerosis.
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-hydroxyanthranilic acid 3,4-dioxygenase (HAAO), which increases the endogenous levels of 3-HAA, decreases atherosclerosis and plasma lipids. Notably, HAAO inhibition led to decreased hepatic SREBP-2 mRNA levels and lipid accumulation, and improved liver pathology scores.
CONCLUSIONS: We discovered 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 hypercholesterolemia and atherosclerosis.
TRANSLATIONAL PERSPECTIVE: Atherosclerosis is a chronic inflammatory disease driven by maladaptive immune responses in the artery wall. Novel insights into cellular processes driving immune cell activation revealed that intracellular metabolic pathways regulate immune cell functions and inflammation. Thus, our present work identifies 3-Hydroxyanthranilate 3,4-Dioxygenase (HAAO) and promising immunometabolic target to combat atherosclerotic CVD. Importantly, our findings indicate targeting tryptophan metabolism offers the possibility affect both lipid metabolism and vascular inflammation in the course of disease. Our findings encourage further investigations that can lead to novel drugs to tested in humans in the near future.