Silencing of Lipid Metabolism Genes through IRE1α-Mediated mRNA Decay Lowers Plasma Lipids in Mice

被引：245

作者：

So, Jae-Seon ^{[1
]}

Hur, Kyu Yeon ^{[1
]}

Tarrio, Margarite ^{[2
]}

Ruda, Vera ^{[3
,4
,5
]}

Frank-Kamenetsky, Maria ^{[6
]}

Fitzgerald, Kevin ^{[6
]}

Koteliansky, Victor ^{[6
]}

Lichtman, Andrew H. ^{[2
]}

Iwawaki, Takao ^{[7
,8
,9
]}

Glimcher, Laurie H. ^{[1
,10
,11
]}

Lee, Ann-Hwee ^{[1
,10
]}

机构：

[1] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[3] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[5] Harvard Univ, Sch Med, Boston, MA 02114 USA

[6] Alnylam Pharmaceut, Cambridge, MA 02142 USA

[7] RIKEN, Iwawaki Initiat Res Unit, Wako, Saitama 3510198, Japan

[8] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan

[9] Gunma Univ, Adv Sci Res Leaders Dev Unit, Gunma 3718511, Japan

[10] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[11] Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA

来源：

CELL METABOLISM | 2012年 / 16卷 / 04期

关键词：

UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; BOX-BINDING PROTEIN-1; FATTY LIVER-DISEASE; ER STRESS; TRANSMEMBRANE PROTEIN; INSULIN-RESISTANCE; KINASE ACTIVATION; LDL-CHOLESTEROL; MOUSE MODELS;

D O I：

10.1016/j.cmet.2012.09.004

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

XBP1 is a key regulator of the unfolded protein response (UPR), which is involved in a wide range of physiological and pathological processes. XBP1 ablation in liver causes profound hypolipidemia in mice, highlighting its critical role in lipid metabolism. XBP1 deficiency triggers feedback activation of its upstream enzyme IRE1 alpha, instigating regulated IRE1-dependent decay (RIDD) of cytosolic mRNAs. Here, we identify RIDD as a crucial control mechanism of lipid homeostasis. Suppression of RIDD by RNA interference or genetic ablation of IRE1 alpha reversed hypolipidemia in XBP1-deficient mice. Comprehensive microarray analysis of XBP1 and/or IRE1 alpha-deficient liver identified genes involved in lipogenesis and lipoprotein metabolism as RIDD substrates, which might contribute to the suppression of plasma lipid levels by activated IRE1 alpha. Ablation of XBP1 ameliorated hepatosteatosis, liver damage, and hypercholesterolemia in dyslipidemic animal models, suggesting that direct targeting of either IRE1 alpha or XBP1 might be a feasible strategy to treat dyslipidemias.

引用

页码：487 / 499

页数：13

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