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.
|Number of pages
|Published - Nov 4 2014
Bibliographical noteFunding 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.
© 2014 Elsevier Inc.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology