Background and Aims: Atherosclerotic cardiovascular disease (ASCVD), characterized by imbalanced lipid metabolism and a dysregulated immune response, is a major cause of death worldwide. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor highly expressed in the liver and intestine and primarily known for its role in detoxification. However, recent studies suggest that the AhR also plays a key role in immune regulation, suggesting that this receptor might have an impact on atherosclerosis development.
Methods: Apoe-/- & Apoe-/-Ahr-/- mice were fed a western-type diet for 12 weeks to induce atherosclerosis. Aortic roots were analyzed for atherosclerotic plaque size and plaque composition. Plasma samples were characterized regarding inflammation and lipids. Liver samples were analyzed for cytokines and lipid accumulation and subjected to RNA sequencing, proteomics and kinomics. Human data were analyzed in a phenome-wide association study (PheWAS) to identify AhR genetic mutations with lipid phenotypes.
Results: The number of circulating blood leukocytes was increased in Apoe-/-Ahr-/- mice compared to Apoe-/- controls, suggesting an anti-inflammatory role of the AhR. Surprisingly however, mice lacking Ahr demonstrated highly reduced plaque sizes compared to Apoe-/- mice. This coincided with strongly reduced plasma cholesterol and triglyceride levels in Apoe-/-Ahr-/- mice. Liver cholesterol and triglyceride levels showed a similar effect, indicating a key role of the AhR in lipid metabolism and hyperlipidemia. RNA sequencing of the liver revealed that particularly lipid-metabolism pathways were impacted in mice lacking Ahr. Furthermore, via kinomics, we discovered inflammatory and lipid-related pathways, that are affected by the lack of the Ahr. Analysis of data from the PheWAS study demonstrate that the AhR variant rs4410790 was significantly associated with lipid traits, including plasma triglyceride, LDL, and total cholesterol.
Conclusion: Our study demonstrates a remarkable reduction in lesion extension by the lack of AhR, by interfering with lipid metabolism as well as with inflammatory pathways. Although the underlying mechanisms are not fully elucidated, these results suggest a novel and crucial role of AhR in ASCVD.
