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.
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Marshall
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Allison L
authors.initials: AL
authors.lastname: McDaniel
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.affiliation: Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Layne
authors.affiliation: Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Scotti
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Boyadjian
authors.affiliation: Division of Endocrinology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kim
authors.affiliation: California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Chamberlain
authors.affiliation: Division of Endocrinology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Tangirala
authors.affiliation: California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Loren
authors.initials: L
authors.lastname: Fong
authors.affiliation: Cardiovascular Antisense Drug Discovery Group, Isis Pharmaceuticals, Carlsbad, CA 92010, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: ryan.temel@uky.edu.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Temel
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: ptontonoz@mednet.ucla.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000097:blood* / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D008078:Cholesterol, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; C403126:MYLIP protein, human; C542022:Mylip protein, mouse; D044767:Ubiquitin-Protein Ligases