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 journalArticlepeer-review

68 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 languageEnglish
Pages (from-to)910-918
Number of pages9
JournalCell Metabolism
Volume20
Issue number5
DOIs
StatePublished - Nov 4 2014

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2014 Elsevier Inc.

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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