The LXR-Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

被引：75

作者：

Hong, Cynthia ^{[1
,2
]}

Marshall, Stephanie M. ^{[8
]}

McDaniel, Allison L. ^{[8
]}

Graham, Mark ^{[9
]}

Layne, Joseph D. ^{[10
]}

Cai, Lei ^{[10
]}

Scotti, Elena ^{[1
,2
]}

Boyadjian, Rima ^{[1
,2
]}

Kim, Jason ^{[3
]}

Chamberlain, Brian T. ^{[4
,5
]}

Tangirala, Rajendra K. ^{[3
]}

Jung, Michael E. ^{[4
,5
]}

Fong, Loren ^{[6
]}

Lee, Richard ^{[9
]}

Young, Stephen G. ^{[6
,7
]}

Temel, Ryan E. ^{[8
,10
]}

Tontonoz, Peter ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Dept Med, Div Endocrinol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA

[8] Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Sect Lipid Sci, Winston Salem, NC 27157 USA

[9] ISIS Pharmaceut, Cardiovasc Antisense Drug Discovery Grp, Carlsbad, CA 92010 USA

[10] Univ Kentucky, Saha Cardiovasc Res Ctr, Lexington, KY 40536 USA

来源：

CELL METABOLISM | 2014年 / 20卷 / 05期

关键词：

LOW-DENSITY-LIPOPROTEIN; EXPRESSION IN-VITRO; LIVER-X-RECEPTORS; TRANSGENIC MICE; PHARMACOLOGICAL ACTIVATION; LYSOSOMAL DEGRADATION; CHOLESTEROL; IDENTIFICATION; REDUCTION; CLATHRIN;

D O I：

10.1016/j.cmet.2014.10.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：910 / 918

页数：9

共 30 条

[1]

Mutations in PCSK9 cause autosomal dominant hypercholesterolemia [J].

Abifadel, M ;

Varret, M ;

Rabès, JP ;

Allard, D ;

Ouguerram, K ;

Devillers, M ;

Cruaud, C ;

Benjannet, S ;

Wickham, L ;

Erlich, D ;

Derré, A ;

Villéger, L ;

Farnier, M ;

Beucler, I ;

Bruckert, E ;

Chambaz, J ;

Chanu, B ;

Lecerf, JM ;

Luc, G ;

Moulin, P ;

Weissenbach, J ;

Prat, A ;

Krempf, M ;

Junien, C ;

Seidah, NG ;

Boileau, C .

NATURE GENETICS, 2003, 34 (02) :154-156

[2]

AGELLON LB, 1991, J BIOL CHEM, V266, P10796

[3]

The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [J].

Brown, MS ;

Goldstein, JL .

CELL, 1997, 89 (03) :331-340

[4]

A RECEPTOR-MEDIATED PATHWAY FOR CHOLESTEROL HOMEOSTASIS [J].

BROWN, MS ;

GOLDSTEIN, JL .

SCIENCE, 1986, 232 (4746) :34-47

[5]

FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors [J].

Calkin, Anna C. ;

Goult, Benjamin T. ;

Zhang, Li ;

Fairall, Louise ;

Hong, Cynthia ;

Schwabe, John W. R. ;

Tontonoz, Peter .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (50) :20107-20112

[6]

Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial [J].

Chasman, Daniel I. ;

Giulianini, Franco ;

MacFadyen, Jean ;

Barratt, Bryan J. ;

Nyberg, Fredrik ;

Ridker, Paul M. .

CIRCULATION-CARDIOVASCULAR GENETICS, 2012, 5 (02) :257-264

[7]

Collins J.L., 2002, U.S. patent, Patent No. [2002/024632, 2002024632]

[8]

Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines [J].

Collins, JL ;

Fivush, AM ;

Watson, MA ;

Galardi, CM ;

Lewis, MC ;

Moore, LB ;

Parks, DJ ;

Wilson, JG ;

Tippin, TK ;

Binz, JG ;

Plunket, KD ;

Morgan, DG ;

Beaudet, EJ ;

Whitney, KD ;

Kliewer, SA ;

Willson, TM .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (10) :1963-1966

[9]

Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles [J].

Grefhorst, A ;

Elzinga, BM ;

Voshol, PJ ;

Plösch, T ;

Kok, T ;

Bloks, VW ;

van der Sluijs, FH ;

Havekes, LM ;

Romijn, JA ;

Verkade, HJ ;

Kuipers, F .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (37) :34182-34190

[10]

Constitutive activation of LXR in macrophages regulates metabolic and inflammatory gene expression: identification of ARL7 as a direct target [J].

Hong, Cynthia ;

Walczak, Robert ;

Dhamko, Helena ;

Bradley, Michelle N. ;

Marathe, Chaitra ;

Boyadjian, Rima ;

Salazar, Jon V. ;

Tontonoz, Peter .

JOURNAL OF LIPID RESEARCH, 2011, 52 (03) :531-539

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