LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition.
LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition.
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DOI：
10.1016/j.cmet.2013.10.002
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发表时间：
2013-11-05
期刊：
影响因子：
29
通讯作者：
Tontonoz P
中科院分区：
文献类型：
--
作者：
Rong X;Albert CJ;Hong C;Duerr MA;Chamberlain BT;Tarling EJ;Ito A;Gao J;Wang B;Edwards PA;Jung ME;Ford DA;Tontonoz P
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 LXR preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids through induction of the remodeling enzyme Lpcat3. Promotion of Lpcat3 activity ameliorates ER stress induced by saturated free fatty acids in vitro or by obesity and hepatic lipid accumulation in vivo. Conversely, Lpcat3 knockdown in liver exacerbates ER stress and inflammation. Mechanistically, Lpcat3 modulates inflammation both by regulating c-Src and JNK 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 LXRs effects on metabolism.
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