Whole-Body Knockout of the AhR (Aryl Hydrocarbon Receptor) Ameliorates Atherosclerosis Due to Altered Lipid Metabolism

BACKGROUND: Atherosclerotic cardiovascular disease, characterized by an imbalanced lipid metabolism and a dysregulated immune response, is a major cause of death worldwide. The AhR (aryl hydrocarbon receptor) is a ligand-activated transcription factor that is highly expressed in the liver and primarily known for its role in detoxification. However, recent studies suggest that the AhR also plays a key role in immune regulation, indicating that this receptor can influence the development of atherosclerosis. METHODS: Apoe −/− and Apoe −/− Ahr −/− mice were fed a western-type diet for 12 weeks to induce atherosclerosis. Aortic roots were analyzed for size and composition of atherosclerotic plaques. Plasma samples were characterized for inflammation and lipid levels. Liver samples were analyzed for cytokines and lipid accumulation and subjected to RNA sequencing and kinomics. A PheWAS (Phenome-Wide Association Study) was performed to identify associations of genetic AHR variants with atherosclerotic cardiovascular disease and lipid phenotypes in humans. RESULTS: The number of circulating leukocytes was increased in Apoe −/− Ahr −/− mice compared with Apoe −/− controls. Surprisingly, however, mice lacking Ahr showed significantly smaller plaques than Apoe −/− mice, which coincided with strongly reduced plasma cholesterol and triglyceride levels. The liver lipid levels showed a similar effect, indicating a key role of the AhR in lipid metabolism. RNA sequencing of the liver revealed that lipid metabolism pathways were particularly impacted in Apoe −/− Ahr −/− mice. Furthermore, through kinomics, we identified signaling pathways affected by the absence of Ahr . PheWAS analysis revealed significant associations between the AHR variant rs4410790 and lipid traits, including plasma triglycerides, LDL (low-density lipoprotein), and total cholesterol. CONCLUSIONS: Our study demonstrates a remarkable role for AhR in the pathogenesis of atherosclerosis, interfering with both lipid metabolism and inflammatory pathways. Although the underlying mechanisms remain unclear, these results demonstrate a novel and crucial role for AhR in atherosclerotic cardiovascular disease.