The aryl hydrocarbon receptor is activated by modified low-density lipoprotein.
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.
McMillan
Brian J
BJ
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1400 University Avenue, Room 213, Madison, WI 53706, USA.
Bradfield
Christopher A
CA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001769:Blood; D002417:Cattle; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D008077:Lipoproteins, LDL; D018336:Receptors, Aryl Hydrocarbon; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1