LXRs Regulate ER Stress and Inflammation through Dynamic Modulation of Membrane Phospholipid Composition

被引：266

作者：

Rong, Xin ^{[1
,2
]}

Albert, Carolyn J. ^{[7
,8
]}

Hong, Cynthia ^{[1
,2
]}

Duerr, Mark A. ^{[7
,8
]}

Chamberlain, Brian T. ^{[3
,4
]}

Tarling, Elizabeth J. ^{[5
]}

Ito, Ayaka ^{[1
,2
]}

Gao, Jie ^{[1
,2
]}

Wang, Bo ^{[1
,2
]}

Edwards, Peter A. ^{[5
,6
]}

Jung, Michael E. ^{[3
,4
]}

Ford, David A. ^{[7
,8
]}

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, Calif NanoSyst Inst, Los Angeles, CA 90095 USA

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

[5] Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA

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

[7] St Louis Univ, Dept Biochem & Mol Biol, St Louis, MO 63104 USA

[8] St Louis Univ, Cardiovasc Res Ctr, St Louis, MO 63104 USA

来源：

CELL METABOLISM | 2013年 / 18卷 / 05期

关键词：

ENDOPLASMIC-RETICULUM STRESS; LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE 3; UNFOLDED PROTEIN RESPONSE; INSULIN-RESISTANCE; CHOLESTEROL; METABOLISM; OBESITY; RECEPTORS; MACROPHAGES; IDENTIFICATION;

D O I：

10.1016/j.cmet.2013.10.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The fatty acyl composition of phospholipids determines the biophysical character of membranes and impacts the function of membrane proteins. Here, we define a nuclear receptor pathway for the dynamic modulation of membrane composition in response to changes in cellular lipid metabolism. Ligand activation of liver X receptors (LXRs) preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids through induction of the remodeling enzyme Lpcat3. Promotion of Lpcat3 activity ameliorates endoplasmic reticulum (ER) stress induced by saturated free fatty acids in vitro or by hepatic lipid accumulation in vivo. Conversely, Lpcat3 knockdown in liver exacerbates ER stress and inflammation. Mechanistically, Lpcat3 modulates inflammation both by regulating inflammatory kinase activation through changes in membrane composition and by affecting substrate availability for inflammatory mediator production. These results outline an endogenous mechanism for the preservation of membrane homeostasis during lipid stress and identify Lpcat3 as an important mediator of LXR effects on metabolism.

引用

页码：685 / 697

页数：13

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