High Density Lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy

Laxman Yetukuri, I. Huopaniemi, Artturi Koivuniemi, M. Maranghi, A. Hiukka, Heli Nygren, S. Kaski, M.-R. Taskinen, I. Vattulainen, M. Jauhiainen, Matej Orešič (Corresponding Author)

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Abstract

In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.
Original languageEnglish
Article numbere23589
Number of pages12
JournalPLoS ONE
Volume6
Issue number8
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Fenofibrate
high density lipoprotein
HDL Lipoproteins
Apolipoprotein A-II
drugs
therapeutics
Pharmaceutical Preparations
homocysteine
Homocysteine
Therapeutics
Lipids
lysophosphatidylcholine
sphingomyelins
Lysophosphatidylcholines
ethanolamine
Sphingomyelins
molecular dynamics
Apolipoprotein A-I
Molecular Dynamics Simulation
endpoints

Cite this

Yetukuri, Laxman ; Huopaniemi, I. ; Koivuniemi, Artturi ; Maranghi, M. ; Hiukka, A. ; Nygren, Heli ; Kaski, S. ; Taskinen, M.-R. ; Vattulainen, I. ; Jauhiainen, M. ; Orešič, Matej. / High Density Lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy. In: PLoS ONE. 2011 ; Vol. 6, No. 8.
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abstract = "In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.",
author = "Laxman Yetukuri and I. Huopaniemi and Artturi Koivuniemi and M. Maranghi and A. Hiukka and Heli Nygren and S. Kaski and M.-R. Taskinen and I. Vattulainen and M. Jauhiainen and Matej Orešič",
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Yetukuri, L, Huopaniemi, I, Koivuniemi, A, Maranghi, M, Hiukka, A, Nygren, H, Kaski, S, Taskinen, M-R, Vattulainen, I, Jauhiainen, M & Orešič, M 2011, 'High Density Lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy', PLoS ONE, vol. 6, no. 8, e23589. https://doi.org/10.1371/journal.pone.0023589

High Density Lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy. / Yetukuri, Laxman; Huopaniemi, I.; Koivuniemi, Artturi; Maranghi, M.; Hiukka, A.; Nygren, Heli; Kaski, S.; Taskinen, M.-R.; Vattulainen, I.; Jauhiainen, M.; Orešič, Matej (Corresponding Author).

In: PLoS ONE, Vol. 6, No. 8, e23589, 2011.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - High Density Lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy

AU - Yetukuri, Laxman

AU - Huopaniemi, I.

AU - Koivuniemi, Artturi

AU - Maranghi, M.

AU - Hiukka, A.

AU - Nygren, Heli

AU - Kaski, S.

AU - Taskinen, M.-R.

AU - Vattulainen, I.

AU - Jauhiainen, M.

AU - Orešič, Matej

PY - 2011

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N2 - In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.

AB - In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.

U2 - 10.1371/journal.pone.0023589

DO - 10.1371/journal.pone.0023589

M3 - Article

VL - 6

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 8

M1 - e23589

ER -