TY - JOUR
T1 - 25-Hydroxycholesterol increases the availability of cholesterol in phospholipid membranes
AU - Olsen, Brett N.
AU - Schlesinger, Paul H.
AU - Ory, Daniel S.
AU - Baker, Nathan A.
N1 - Funding Information:
This work was supported by the National Institutes of Health (grants U54 CA11934205 and R01 GM069702 to N.A.B., and R01 HL067773 to D.S.O.). B.N.O. was supported by a Cellular and Molecular Biology Training Grant (NIH T32 GM007067). Computational resources were provided by the Texas Advanced Computing Center through Teragrid grants TG-MCB060053 and TG-MCA08X003, as well as the National Biomedical Computation Resource (NIH P41 RR0860516).
PY - 2011/2/16
Y1 - 2011/2/16
N2 - Side-chain oxysterols are enzymatically generated oxidation products of cholesterol that serve a central role in mediating cholesterol homeostasis. Recent work has shown that side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), alter membrane structure in very different ways from cholesterol, suggesting a possible mechanism for how these oxysterols regulate cholesterol homeostasis. Here we extend our previous work by using molecular-dynamics simulations of 25-HC and cholesterol mixtures in 1-palmitoyl-2-oleoyl- phosphatidylcholine bilayers to examine the combined effects of 25-HC and cholesterol in the same bilayer. 25-HC causes larger changes in membrane structure when added to cholesterol-containing membranes than when added to cholesterol-free membranes. We also find that the presence of 25-HC changes the position, orientation, and solvent accessibility of cholesterol, shifting it into the water interface and thus increasing its availability to external acceptors. This is consistent with experimental results showing that oxysterols can trigger cholesterol trafficking from the plasma membrane to the endoplasmic reticulum. These effects provide a potential mechanism for 25-HC-mediated regulation of cholesterol trafficking and homeostasis through modulation of cholesterol availability.
AB - Side-chain oxysterols are enzymatically generated oxidation products of cholesterol that serve a central role in mediating cholesterol homeostasis. Recent work has shown that side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), alter membrane structure in very different ways from cholesterol, suggesting a possible mechanism for how these oxysterols regulate cholesterol homeostasis. Here we extend our previous work by using molecular-dynamics simulations of 25-HC and cholesterol mixtures in 1-palmitoyl-2-oleoyl- phosphatidylcholine bilayers to examine the combined effects of 25-HC and cholesterol in the same bilayer. 25-HC causes larger changes in membrane structure when added to cholesterol-containing membranes than when added to cholesterol-free membranes. We also find that the presence of 25-HC changes the position, orientation, and solvent accessibility of cholesterol, shifting it into the water interface and thus increasing its availability to external acceptors. This is consistent with experimental results showing that oxysterols can trigger cholesterol trafficking from the plasma membrane to the endoplasmic reticulum. These effects provide a potential mechanism for 25-HC-mediated regulation of cholesterol trafficking and homeostasis through modulation of cholesterol availability.
UR - http://www.scopus.com/inward/record.url?scp=79951839943&partnerID=8YFLogxK
U2 - 10.1016/j.bpj.2010.12.3728
DO - 10.1016/j.bpj.2010.12.3728
M3 - Article
C2 - 21320439
AN - SCOPUS:79951839943
VL - 100
SP - 948
EP - 956
JO - Biophysical Journal
JF - Biophysical Journal
SN - 0006-3495
IS - 4
ER -