3-Hydroxyanthralinic acid metabolism controls the hepatic SREBP/lipoprotein axis, inhibits inflammasome activation in macrophages, and decreases atherosclerosis in Ldlr-/- mice

Cardiovasc Res. 2020 Oct 1;116(12):1948-1957. doi: 10.1093/cvr/cvz258.


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.

Keywords: Atherosclerosis; IDO; Immunometabolism; Inflammation; Kynurenine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxyanthranilate 3,4-Dioxygenase / antagonists & inhibitors
  • 3-Hydroxyanthranilate 3,4-Dioxygenase / metabolism
  • 3-Hydroxyanthranilic Acid / analogs & derivatives
  • 3-Hydroxyanthranilic Acid / metabolism*
  • 3-Hydroxyanthranilic Acid / pharmacology
  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Hep G2 Cells
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Lipoproteins / blood*
  • Liver / drug effects
  • Liver / metabolism*
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plaque, Atherosclerotic
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism*


  • 4,6-dibromo-3-hydroxyanthranilic acid
  • Enzyme Inhibitors
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Lipoproteins
  • Receptors, LDL
  • SREBF2 protein, human
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 2
  • 3-Hydroxyanthranilic Acid
  • 3-Hydroxyanthranilate 3,4-Dioxygenase