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

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

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.

Original language	English
Pages (from-to)	910-918
Number of pages	9
Journal	Cell Metabolism
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2014.10.001
State	Published - Nov 4 2014

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Inc.

Funding

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.

Funders	Funder number
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

Cite this

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

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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",

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year = "2014",

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

language = "English",

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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, no. 5, pp. 910-918. https://doi.org/10.1016/j.cmet.2014.10.001

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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

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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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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