Activation of liver X receptors prevents statin-induced death of 3T3-L1 preadipocytes

Lise Madsen; Rasmus K. Petersen; Knut R. Steffensen; Lone M. Pedersen; Philip Hallenborg; Tao Ma; Livar Frøyland; Stein Ove Døskeland; Jan-Åke Gustafsson; Karsten Kristiansen

doi:10.1074/jbc.M800720200

Activation of liver X receptors prevents statin-induced death of 3T3-L1 preadipocytes

Lise Madsen, Rasmus K. Petersen, Knut R. Steffensen, Lone M. Pedersen, Philip Hallenborg, Tao Ma, Livar Frøyland, Stein Ove Døskeland, Jan-Åke Gustafsson, Karsten Kristiansen

5 Citations (Scopus)

Abstract

The biological functions of liver X receptors (LXRs) alpha and beta have primarily been linked to pathways involved in fatty acid and cholesterol homeostasis. Here we report a novel role of LXR activation in protecting cells from statin-induced death. When 3T3-L1 preadipocytes were induced to differentiate by standard isobutylmethylxanthine/dexamethasone/insulin treatment in the presence of statins, they failed to differentiate and underwent massive apoptosis. The simultaneous addition of selective LXR agonists prevented the statin-induced apoptosis. By using mouse embryo fibroblasts from wild-type (LXRalpha+/+/LXRbeta+/+), LXRalpha knock-out mice (LXRalpha(-/-)/LXRbeta+/+), LXRbeta knock-out mice (LXRalpha+/-/LXRbeta(-/-)), and LXR double knock-out mice (LXRalpha(-/-)/LXRbeta(-/-)) as well as 3T3-L1 cells transduced with retroviruses expressing either wild-type LXRalpha or a dominant negative version of LXRalpha, we demonstrate that the response to LXR agonists is LXR-dependent. Interestingly, LXR-mediated rescue of statin-induced apoptosis was not related to up-regulation of genes previously shown to be involved in the antiapoptotic action of LXR. Furthermore, forced expression of Bcl-2 did not prevent statin-induced apoptosis; nor did LXR action depend on protein kinase B, whose activation by insulin was impaired in statin-treated cells. Rather, LXR-dependent rescue of statin-induced apoptosis in 3T3-L1 preadipocytes required NF-kappaB activity, since expression of a dominant negative version of IkappaBalpha prevented LXR agonist-dependent rescue of statin-induced apoptosis. Thus, the results presented in this paper provide novel insight into the action of statins on and LXR-dependent inhibition of apoptosis.

Original language	English
Journal	Journal of Biological Chemistry
Volume	283
Issue number	33
Pages (from-to)	22723-22736
Number of pages	14
ISSN	1083-351X
DOIs	https://doi.org/10.1074/jbc.M800720200
Publication status	Published - 2008
Externally published	Yes

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@article{1047aff0f75411ddbf70000ea68e967b,

title = "Activation of liver X receptors prevents statin-induced death of 3T3-L1 preadipocytes",

abstract = "The biological functions of liver X receptors (LXRs) alpha and beta have primarily been linked to pathways involved in fatty acid and cholesterol homeostasis. Here we report a novel role of LXR activation in protecting cells from statin-induced death. When 3T3-L1 preadipocytes were induced to differentiate by standard isobutylmethylxanthine/dexamethasone/insulin treatment in the presence of statins, they failed to differentiate and underwent massive apoptosis. The simultaneous addition of selective LXR agonists prevented the statin-induced apoptosis. By using mouse embryo fibroblasts from wild-type (LXRalpha+/+/LXRbeta+/+), LXRalpha knock-out mice (LXRalpha(-/-)/LXRbeta+/+), LXRbeta knock-out mice (LXRalpha+/-/LXRbeta(-/-)), and LXR double knock-out mice (LXRalpha(-/-)/LXRbeta(-/-)) as well as 3T3-L1 cells transduced with retroviruses expressing either wild-type LXRalpha or a dominant negative version of LXRalpha, we demonstrate that the response to LXR agonists is LXR-dependent. Interestingly, LXR-mediated rescue of statin-induced apoptosis was not related to up-regulation of genes previously shown to be involved in the antiapoptotic action of LXR. Furthermore, forced expression of Bcl-2 did not prevent statin-induced apoptosis; nor did LXR action depend on protein kinase B, whose activation by insulin was impaired in statin-treated cells. Rather, LXR-dependent rescue of statin-induced apoptosis in 3T3-L1 preadipocytes required NF-kappaB activity, since expression of a dominant negative version of IkappaBalpha prevented LXR agonist-dependent rescue of statin-induced apoptosis. Thus, the results presented in this paper provide novel insight into the action of statins on and LXR-dependent inhibition of apoptosis.",

author = "Lise Madsen and Petersen, {Rasmus K.} and Steffensen, {Knut R.} and Pedersen, {Lone M.} and Philip Hallenborg and Tao Ma and Livar Fr{\o}yland and D{\o}skeland, {Stein Ove} and Jan-{\AA}ke Gustafsson and Karsten Kristiansen",

note = "Keywords: 3T3 Cells; Adipocytes; Animals; Apoptosis; Cell Death; Cell Differentiation; Crosses, Genetic; DNA-Binding Proteins; Embryo, Mammalian; Fibroblasts; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear",

year = "2008",

doi = "10.1074/jbc.M800720200",

language = "English",

volume = "283",

pages = "22723--22736",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

number = "33",

}

TY - JOUR

T1 - Activation of liver X receptors prevents statin-induced death of 3T3-L1 preadipocytes

AU - Madsen, Lise

AU - Petersen, Rasmus K.

AU - Steffensen, Knut R.

AU - Pedersen, Lone M.

AU - Hallenborg, Philip

AU - Ma, Tao

AU - Frøyland, Livar

AU - Døskeland, Stein Ove

AU - Gustafsson, Jan-Åke

AU - Kristiansen, Karsten

N1 - Keywords: 3T3 Cells; Adipocytes; Animals; Apoptosis; Cell Death; Cell Differentiation; Crosses, Genetic; DNA-Binding Proteins; Embryo, Mammalian; Fibroblasts; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear

PY - 2008

Y1 - 2008

N2 - The biological functions of liver X receptors (LXRs) alpha and beta have primarily been linked to pathways involved in fatty acid and cholesterol homeostasis. Here we report a novel role of LXR activation in protecting cells from statin-induced death. When 3T3-L1 preadipocytes were induced to differentiate by standard isobutylmethylxanthine/dexamethasone/insulin treatment in the presence of statins, they failed to differentiate and underwent massive apoptosis. The simultaneous addition of selective LXR agonists prevented the statin-induced apoptosis. By using mouse embryo fibroblasts from wild-type (LXRalpha+/+/LXRbeta+/+), LXRalpha knock-out mice (LXRalpha(-/-)/LXRbeta+/+), LXRbeta knock-out mice (LXRalpha+/-/LXRbeta(-/-)), and LXR double knock-out mice (LXRalpha(-/-)/LXRbeta(-/-)) as well as 3T3-L1 cells transduced with retroviruses expressing either wild-type LXRalpha or a dominant negative version of LXRalpha, we demonstrate that the response to LXR agonists is LXR-dependent. Interestingly, LXR-mediated rescue of statin-induced apoptosis was not related to up-regulation of genes previously shown to be involved in the antiapoptotic action of LXR. Furthermore, forced expression of Bcl-2 did not prevent statin-induced apoptosis; nor did LXR action depend on protein kinase B, whose activation by insulin was impaired in statin-treated cells. Rather, LXR-dependent rescue of statin-induced apoptosis in 3T3-L1 preadipocytes required NF-kappaB activity, since expression of a dominant negative version of IkappaBalpha prevented LXR agonist-dependent rescue of statin-induced apoptosis. Thus, the results presented in this paper provide novel insight into the action of statins on and LXR-dependent inhibition of apoptosis.

AB - The biological functions of liver X receptors (LXRs) alpha and beta have primarily been linked to pathways involved in fatty acid and cholesterol homeostasis. Here we report a novel role of LXR activation in protecting cells from statin-induced death. When 3T3-L1 preadipocytes were induced to differentiate by standard isobutylmethylxanthine/dexamethasone/insulin treatment in the presence of statins, they failed to differentiate and underwent massive apoptosis. The simultaneous addition of selective LXR agonists prevented the statin-induced apoptosis. By using mouse embryo fibroblasts from wild-type (LXRalpha+/+/LXRbeta+/+), LXRalpha knock-out mice (LXRalpha(-/-)/LXRbeta+/+), LXRbeta knock-out mice (LXRalpha+/-/LXRbeta(-/-)), and LXR double knock-out mice (LXRalpha(-/-)/LXRbeta(-/-)) as well as 3T3-L1 cells transduced with retroviruses expressing either wild-type LXRalpha or a dominant negative version of LXRalpha, we demonstrate that the response to LXR agonists is LXR-dependent. Interestingly, LXR-mediated rescue of statin-induced apoptosis was not related to up-regulation of genes previously shown to be involved in the antiapoptotic action of LXR. Furthermore, forced expression of Bcl-2 did not prevent statin-induced apoptosis; nor did LXR action depend on protein kinase B, whose activation by insulin was impaired in statin-treated cells. Rather, LXR-dependent rescue of statin-induced apoptosis in 3T3-L1 preadipocytes required NF-kappaB activity, since expression of a dominant negative version of IkappaBalpha prevented LXR agonist-dependent rescue of statin-induced apoptosis. Thus, the results presented in this paper provide novel insight into the action of statins on and LXR-dependent inhibition of apoptosis.

U2 - 10.1074/jbc.M800720200

DO - 10.1074/jbc.M800720200

M3 - Journal article

C2 - 18487205

SN - 0021-9258

VL - 283

SP - 22723

EP - 22736

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 33

ER -

Activation of liver X receptors prevents statin-induced death of 3T3-L1 preadipocytes

Abstract

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