Side chain oxygenated cholesterol regulates cellular cholesterol homeostasis through direct sterol-membrane interactions

Sarah E. Gale, Emily J. Westover, Nicole Dudley, Kathiresan Krishnan, Sean Merlin, David E. Scherrer, Xianlin Han, Xiuhong Zhai, Howard L. Brockman, Rhoderick E Brown, Douglas F. Covey, Jean E. Schaffer, Paul Schlesinger, Daniel S. Ory

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Abstract

Side chain oxysterols exert cholesterol homeostatic effects by suppression of sterol regulatory element-binding protein maturation and promoting degradation of hydroxymethylglutaryl- CoA reductase. To examine whether oxysterol-membrane interactions contribute to the regulation of cellular cholesterol homeostasis, we synthesized the enantiomer of 25-hydroxycho- lesterol. Using this unique oxysterol probe, we provide evidence that oxysterol regulation of cholesterol homeostatic responses is not mediated by enantiospecific oxysterol-protein interactions. We show that side chain oxysterols, but not steroid ring- modified oxysterols, exhibit membrane expansion behavior in phospholipid monolayers and bilayers in vitro. This behavior is non-enantiospecific and is abrogated by increasing the saturation of phospholipid acyl chain constituents. Moreover, we extend these findings into cultured cells by showing that exposure to saturated fatty acids at concentrations that lead to endo- plasmic reticulum membrane phospholipid remodeling inhibits oxysterol activity. These studies implicate oxysterol-membrane interactions in acute regulation of sterol homeostatic responses and provide new insights into the mechanism through which oxysterols regulate cellular cholesterol balance.

Original languageEnglish (US)
Pages (from-to)1755-1764
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number3
DOIs
StatePublished - Jan 16 2009

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    Gale, S. E., Westover, E. J., Dudley, N., Krishnan, K., Merlin, S., Scherrer, D. E., Han, X., Zhai, X., Brockman, H. L., Brown, R. E., Covey, D. F., Schaffer, J. E., Schlesinger, P., & Ory, D. S. (2009). Side chain oxygenated cholesterol regulates cellular cholesterol homeostasis through direct sterol-membrane interactions. Journal of Biological Chemistry, 284(3), 1755-1764. https://doi.org/10.1074/jbc.M807210200