TY - JOUR
T1 - The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha
AU - Umetani, Michihisa
AU - Ghosh, Pritam
AU - Ishikawa, Tomonori
AU - Umetani, Junko
AU - Ahmed, Mohamed
AU - Mineo, Chieko
AU - Shaul, Philip W.
N1 - Funding Information:
This work was supported by National Institutes of Health grants HL087564 (P.W.S.), P03DK079328 (M.U.), and T32 HL098040 (P.G.); American Diabetes Association Grant 7-11-JF-46 (M.U.); and by the Associates First Capital Corporation Distinguished Chair in Pediatrics (P.W.S.).
PY - 2014/7/1
Y1 - 2014/7/1
N2 - Oxysterols are cholesterol metabolites that serve multiple functions in lipid metabolism, including as liver X receptor (LXR) ligands. 27-hydroxycholesterol (27HC) is an abundant oxysterol metabolized by CYP7B1. How 27HC impacts vascular health is unknown. We show that elevations in 27HC via cyp7b1 deletion promote atherosclerosis in apoe-/- mice without altering lipid status; furthermore, estrogen-related atheroprotection is attenuated. In wild-type mice, leukocyte-endothelial cell adhesion is increased by 27HC via estrogen receptor (ER)-dependent processes. In monocytes/ macrophages, 27HC upregulates proinflammatory genes and increases adhesion via ERα. In endothelial cells, 27HC is also proadhesive via ERα, and in contrast to estrogen, which blunts NF-κB activation, 27HC stimulates NF-κB activation via Erk1,2 and JNK-dependent IκBα degradation. Whereas 27HC administration to apoe-/- mice increases atherosclerosis, apoe-/-;erα-/- are unaffected. Thus, 27HC promotes atherosclerosis via proinflammatory processes mediated by ERα, and it attenuates estrogen-related atheroprotection. Strategies to lower 27HC may complement approaches targeting cholesterol to prevent vascular disease.
AB - Oxysterols are cholesterol metabolites that serve multiple functions in lipid metabolism, including as liver X receptor (LXR) ligands. 27-hydroxycholesterol (27HC) is an abundant oxysterol metabolized by CYP7B1. How 27HC impacts vascular health is unknown. We show that elevations in 27HC via cyp7b1 deletion promote atherosclerosis in apoe-/- mice without altering lipid status; furthermore, estrogen-related atheroprotection is attenuated. In wild-type mice, leukocyte-endothelial cell adhesion is increased by 27HC via estrogen receptor (ER)-dependent processes. In monocytes/ macrophages, 27HC upregulates proinflammatory genes and increases adhesion via ERα. In endothelial cells, 27HC is also proadhesive via ERα, and in contrast to estrogen, which blunts NF-κB activation, 27HC stimulates NF-κB activation via Erk1,2 and JNK-dependent IκBα degradation. Whereas 27HC administration to apoe-/- mice increases atherosclerosis, apoe-/-;erα-/- are unaffected. Thus, 27HC promotes atherosclerosis via proinflammatory processes mediated by ERα, and it attenuates estrogen-related atheroprotection. Strategies to lower 27HC may complement approaches targeting cholesterol to prevent vascular disease.
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U2 - 10.1016/j.cmet.2014.05.013
DO - 10.1016/j.cmet.2014.05.013
M3 - Article
C2 - 24954418
AN - SCOPUS:84904043004
SN - 1550-4131
VL - 20
SP - 172
EP - 182
JO - Cell Metabolism
JF - Cell Metabolism
IS - 1
ER -