Cholesterol Metabolite Contributes to Buildup of Atherosclerotic Plaques

A recent paper described the mechanism by which the cholesterol metabolite 27-hydroxycholesterol (27HC) contributes to the development of the fatty plaques that characterize atherosclerosis.

27HC is an abundant oxysterol metabolized by an enzyme encoded by the CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) gene. This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases, which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. This enzyme likely plays a minor role in total bile acid synthesis, but may also be involved in the development of atherosclerosis, neurosteroid metabolism, and sex hormone synthesis.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) used mouse and culture models to determine how 27HC modulated lipid metabolism. Results published in the June 2014 online edition of the journal Cell Metabolism revealed that in a mouse model (apoe−/−) where 27HC was elevated due to the genetically engineered deletion of CYP7B1, development of atherosclerosis was promoted without altering lipid status while estrogen-related atheroprotection was weakened.

27HC was found to upregulate proinflammatory genes and increase adhesion via the estrogen receptor in monocytes and macrophages. In endothelial cells, 27HC was also pro-adhesive via the estrogen receptor, and in contrast to estrogen, which inhibited NF-kappaB activation, 27HC stimulated NF-kappaB activation.

"When 27HC is present, estrogen's protective effects are only observed at very high levels of the hormone," said senior author Dr. Philip W. Shaul, professor of pediatrics at the University of Texas Southwestern Medical Center. "This result may explain why hormone therapy with estrogen does not provide cardiovascular benefit in women with preexisting atherosclerosis, in which 27HC is abundant in the vascular wall. Although statins have had a dramatic impact on cardiovascular health by lowering cholesterol, we still need complementary methods to combat atherosclerosis. Targeting 27HC, either by lowering the levels of this compound or by inhibiting its actions, could potentially provide a complementary approach to preventing vascular disease."

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University of Texas Southwestern Medical Center