The LXR-idol axis differentially regulates plasma LDL levels in primates and mice

Cynthia Hong; Stephanie M. Marshall; Allison L. McDaniel; Mark Graham; Joseph D. Layne; Lei Cai; Elena Scotti; Rima Boyadjian; Jason Kim; Brian T. Chamberlain; Rajendra K. Tangirala; Michael E. Jung; Loren Fong; Richard Lee; Stephen G. Young; Ryan E. Temel; Peter Tontonoz

doi:10.1016/j.cmet.2014.10.001

The LXR-idol axis differentially regulates plasma LDL levels in primates and mice

Cynthia Hong
, Stephanie M. Marshall
, Allison L. McDaniel
, Mark Graham
, Joseph D. Layne
, Lei Cai
, Elena Scotti
, Rima Boyadjian
, Jason Kim
, Brian T. Chamberlain
, Rajendra K. Tangirala
, Michael E. Jung
, Loren Fong
, Richard Lee
, Stephen G. Young
, Ryan E. Temel
, Peter Tontonoz

Producción científica: Article › revisión exhaustiva

83 Citas (Scopus)

Resumen

The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR-IDOL axis are both tissue and species specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues, but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans.

Idioma original	English
Páginas (desde-hasta)	910-918
Número de páginas	9
Publicación	Cell Metabolism
Volumen	20
N.º	5
DOI	https://doi.org/10.1016/j.cmet.2014.10.001
Estado	Published - nov 4 2014

Nota bibliográfica

Publisher Copyright:
© 2014 Elsevier Inc.

Financiación

We are grateful for the technical contributions of Kathryn L. Kelley and Janet K. Sawyer at Wake Forest University School of Medicine, Jon Salazar at UCLA, and Matthew Hallowell from Tulane University. This work was supported by NIH grants HL088528 and HL111932 (R.E.T.), HL066088 (P.T.), and HL090553 (S.G.Y. and P.T.) and by ADA grant 1-14-JF-33 (C.H.). P.T. in an Investigator of the Howard Hughes Medical Institute.

Financiadores	Número del financiador
National Institutes of Health (NIH)	HL090553, HL066088, HL111932
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)	R00HL088528
National Heart, Lung, and Blood Institute (NHLBI)
Aeronautical Development Agency India	1-14-JF-33
Aeronautical Development Agency India

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2014.10.001

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Hong, C., Marshall, S. M., McDaniel, A. L., Graham, M., Layne, J. D., Cai, L., Scotti, E., Boyadjian, R., Kim, J., Chamberlain, B. T., Tangirala, R. K., Jung, M. E., Fong, L., Lee, R., Young, S. G., Temel, R. E., & Tontonoz, P. (2014). The LXR-idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metabolism, 20(5), 910-918. https://doi.org/10.1016/j.cmet.2014.10.001

@article{e2f8b97f277848e68e6101a0f2be8731,

title = "The LXR-idol axis differentially regulates plasma LDL levels in primates and mice",

abstract = "The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR-IDOL axis are both tissue and species specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues, but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans.",

author = "Cynthia Hong and Marshall, \{Stephanie M.\} and McDaniel, \{Allison L.\} and Mark Graham and Layne, \{Joseph D.\} and Lei Cai and Elena Scotti and Rima Boyadjian and Jason Kim and Chamberlain, \{Brian T.\} and Tangirala, \{Rajendra K.\} and Jung, \{Michael E.\} and Loren Fong and Richard Lee and Young, \{Stephen G.\} and Temel, \{Ryan E.\} and Peter Tontonoz",

note = "Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",

year = "2014",

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doi = "10.1016/j.cmet.2014.10.001",

language = "English",

volume = "20",

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Hong, C, Marshall, SM, McDaniel, AL, Graham, M, Layne, JD, Cai, L, Scotti, E, Boyadjian, R, Kim, J, Chamberlain, BT, Tangirala, RK, Jung, ME, Fong, L, Lee, R, Young, SG, Temel, RE & Tontonoz, P 2014, 'The LXR-idol axis differentially regulates plasma LDL levels in primates and mice', Cell Metabolism, vol. 20, n.º 5, pp. 910-918. https://doi.org/10.1016/j.cmet.2014.10.001

TY - JOUR

T1 - The LXR-idol axis differentially regulates plasma LDL levels in primates and mice

AU - Hong, Cynthia

AU - Marshall, Stephanie M.

AU - McDaniel, Allison L.

AU - Graham, Mark

AU - Layne, Joseph D.

AU - Cai, Lei

AU - Scotti, Elena

AU - Boyadjian, Rima

AU - Kim, Jason

AU - Chamberlain, Brian T.

AU - Tangirala, Rajendra K.

AU - Jung, Michael E.

AU - Fong, Loren

AU - Lee, Richard

AU - Young, Stephen G.

AU - Temel, Ryan E.

AU - Tontonoz, Peter

PY - 2014/11/4

Y1 - 2014/11/4

N2 - The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR-IDOL axis are both tissue and species specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues, but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans.

AB - The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR-IDOL axis are both tissue and species specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues, but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans.

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JO - Cell Metabolism

JF - Cell Metabolism

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The LXR-idol axis differentially regulates plasma LDL levels in primates and mice

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Nota bibliográfica

Financiación

ASJC Scopus subject areas

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