Side chain oxygenated cholesterol regulates cellular cholesterol homeostasis
through direct sterol-membrane interactions.
Authors Gale SE, Westover EJ, Dudley N, Krishnan K, Merlin S, Scherrer DE, Han X, Zhai
X, Brockman HL, Brown RE, Covey DF, Schaffer JE, Schlesinger P, Ory DS
Submitted By Jean Schaffer on 3/31/2010
Status Published
Journal The Journal of biological chemistry
Year 2009
Date Published 1/16/2009
Volume : Pages 284 : 1755 - 1764
PubMed Reference 18996837
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.

Investigators with authorship
Jean SchafferWashington University in St Louis