title: Side chain oxygenated cholesterol regulates cellular cholesterol homeostasis through direct sterol-membrane interactions.
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-hydroxycholesterol. 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 endoplasmic 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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Gale
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Westover
authors.forename: Nicole
authors.initials: N
authors.lastname: Dudley
authors.forename: Kathiresan
authors.initials: K
authors.lastname: Krishnan
authors.forename: Sean
authors.initials: S
authors.lastname: Merlin
authors.forename: David E
authors.initials: DE
authors.lastname: Scherrer
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Zhai
authors.forename: Howard L
authors.initials: HL
authors.lastname: Brockman
authors.forename: Rhoderick E
authors.initials: RE
authors.lastname: Brown
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
authors.forename: Paul
authors.initials: P
authors.lastname: Schlesinger
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006888:Hydroxycholesterols / Q000378:metabolism* / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D006888:Hydroxycholesterols; C007997:25-hydroxycholesterol; D006903:Hydroxymethylglutaryl CoA Reductases