The Aryl hydrocarbon receptor is activated by modified low-density lipoprotein

Abstract

Endogenous activation of the aryl hydrocarbon receptor (AHR) is required for normal vascular development. This biology led us to investigate the interplay between the AHR and vascular physiology by using an in vitro model of fluid shear stress. Using this system, we show that fluid flow induces a robust AHR-mediated increase in CYP1 expression. Furthermore, we demonstrate that incubation with sheared bovine or human sera is sufficient for AHR activation, indicating that direct cellular exposure to shear stress is not required for this response. Fractionation of sera by size and density revealed the AHR-activating factor to be low-density lipoprotein (LDL). Purified LDL (0.1 mg/ml) from sheared sera induces a 6-fold increase in AHR-mediated signaling as compared with LDL purified from static sera. Similar results were obtained by exposing a purified fraction of LDL to fluid flow, suggesting that shear stress is capable of directly modifying LDL structure and/or function. In addition, we show that LDL can be converted to an AHR-activating species by conventional methods of lipoprotein modification, such as NaOCl oxidation. Finally, we demonstrate that an increased level of AHR-activating LDL is present in the sera of AHR null mice as compared with heterozygous littermates, suggesting a role for the Ahr locus in the physiological response to modified LDL in vivo. Overall, these data demonstrate a previously undescribed relationship between LDL modification and AHR biology and provide a potential explanation for the vascular abnormalities observed in AHR null mice.AHR ͉ cyp1a1 ͉ cyp1b1 ͉ shear stress T he aryl hydrocarbon receptor (AHR) is a ligand activated basic-helix-loop-helix (bHLH) transcription factor that belongs to the PAS (Per-Arnt-Sim) family of nuclear sensors (1). The AHR binds to numerous environmental contaminants including tetrachlorodibenzo-p-dioxin (TCDD), benzo[a]pyrene, and coplanar polychlorinated biphenyls (2). Upon binding these xenobiotic ligands, the AHR translocates to the nucleus and dimerizes with a second bHLH-PAS protein known as the Ah receptor nuclear translocator (ARNT). The AHR-ARNT complex can then bind to dioxin response elements (DREs) found upstream of target genes, leading to their transcriptional up-regulation. The CYP1 family of cytochrome P450s, CYP1A1, CYP1A2 and CYP1B1, as well as the phase II enzymes GST-A1 and NQO1 are among the genes that are regulated by the AHR (2, 3). The enzymes encoded by these genes display metabolic activity toward many AHR ligands, prompting the idea that this pathway represents an adaptive response to xenobiotic exposure (2, 3).In addition to its role in the metabolic response to xenobiotics, the AHR also has an important role in vascular development. Mice that harbor a null allele at the Ahr locus display a number of vascular phenotypes. These include a patent ductus venosus (DV), persistent hyaloid arteries in the eye, decreased hepatic perfusion, a confused vascularization in the corneal limbus, and cardiac hypertrophy (4-6). Experiments usi...

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