Reduced VLDL clearance in Apoe-/-Npc1-/- mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels

被引：9

作者：

Ishibashi, Minako ^{[1
]}

Masson, David ^{[2
]}

Westerterp, Marit ^{[1
]}

Wang, Nan ^{[1
]}

Sayers, Scott ^{[1
]}

Li, Rong ^{[1
]}

Welch, Carrie L. ^{[1
]}

Tall, Alan R. ^{[1
]}

机构：

[1] Columbia Univ, Dept Med, Div Mol Med, New York, NY 10027 USA

[2] Univ Bourgogne, INSERM, Ctr Rech, UMR866,Fac Med,Inst Fed Rech Sante,STIC, Dijon, France

来源：

JOURNAL OF LIPID RESEARCH | 2010年 / 51卷 / 09期

基金：

美国国家卫生研究院;

关键词：

liver; Niemann-Pick disease; receptor; lipoprotein; atherosclerosis; nuclear receptor; INTRACELLULAR CHOLESTEROL TRAFFICKING; LIPOPROTEIN-LIPASE EXPRESSION; BINDING PROTEIN 1C; IN-VIVO; PLASMA-CHOLESTEROL; GENE-EXPRESSION; TRANSGENIC MICE; DEFICIENT MICE; LIVER-DISEASE; TARGET GENES;

D O I：

10.1194/jlr.M006163

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Niemann-Pick type C1 (NPC1) promotes the transport of LDL receptor (LDL-R)-derived cholesterol from late endosomes/lysosomes to other cellular compartments. NPC1-deficient cells showed impaired regulation of liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP) target genes. We observed that Apoe(-/-)Npc1(-/-) mice displayed a marked increase in total plasma cholesterol mainly due to increased VLDL, reflecting decreased clearance. Although nuclear SREBP-2 and Ldlr mRNA levels were increased in Apoe(-/-)Npc1(-/-) liver, LDL-R protein levels were decreased in association with marked induction of proprotein convertase subtilisin/kexin type 9 (Pcsk9) and inducible degrader of the LDL-R (Idol), both known to promote proteolytic degradation of LDL-R. While Pcsk9 is known to be an SREBP-2 target, marked up-regulation of IDOL in Apoe(-/-)Npc1(-/-) liver was unexpected. However, several other LXR target genes also increased in Apoe(-/-)Npc1(-/-) liver, suggesting increased synthesis of endogenous LXR ligands secondary to activation of sterol biosynthesis. In conclusion, we demonstrate that NPC1 deficiency has a major impact on VLDL metabolism in Apoe(-/-) mice through modulation of hepatic LDL-R protein levels. In contrast to modest induction of hepatic IDOL with synthetic LXR ligands, a striking up-regulation of IDOL in Apoe(-/-)Npc1(-/-) mice could indicate a role of endogenous LXR ligands in regulation of hepatic IDOL.-Ishibashi, M., D. Masson, M. Westerterp, N. Wang, S. Sayers, R. Li, C. L. Welch, and A. R. Tall. Reduced VLDL clearance in Apoe-(-/-)-Npc1(--/-)- mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels. J. Lipid Res. 2010. 51: 2655-2663.

引用

页码：2655 / 2663

页数：9

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