Deficiency of the aryl hydrocarbon receptor in intestinal epithelial cells, but not hepatocytes, ameliorates atherosclerosis development by sex-dependently targeting the lipid metabolism

BACKGROUND: The aryl hydrocarbon receptor (AhR) is a well-described regulator of xenobiotic stimuli, but recent studies highlight a potential bidirectional role in mediating lipid metabolism. The precise mechanisms underlying these effects are not yet fully understood. Therefore, this study aimed to investigate the impact of a genetic aberration in the AhR in hepatocytes and intestinal epithelial cells on lipid metabolism and the development of atherosclerosis. METHODS: ) were injected with AAV8-PCSK9. Both mouse models were fed a high-fat diet (HFD) for 12 weeks, after which alterations in plasma lipid levels and the development of atherosclerosis were assessed. FINDINGS: Mice lacking hepatocyte-specific Ahr did not exhibit significant differences in lipid levels or atherosclerosis. In contrast, male mice lacking Ahr in intestinal epithelial cells (IECs) showed significant changes in intestinal and systemic lipid levels, which coincided with altered RNA transcription and intestinal kinase activity, whereas female mice were unaffected. Interestingly, female mice showed reduced circulating leukocyte counts, whereas males were unaffected. Combined, these alterations resulted in decreased atherosclerosis development in both sexes. INTERPRETATION: This study reveals a major impact of intestinal epithelial cell-specific Ahr on lipid metabolism, with effects on atherosclerosis development, particularly in male mice, whereas atherosclerosis development in female intestinal epithelial cell-specific Ahr-deficient mice is accompanied by reduced circulating leukocytes, thereby suggesting apparent sex dimorphism.