title: LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Rong
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Albert
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.forename: Mark A
authors.initials: MA
authors.lastname: Duerr
authors.forename: Brian T
authors.initials: BT
authors.lastname: Chamberlain
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Tarling
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ito
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Peter A
authors.initials: PA
authors.lastname: Edwards
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C543069:LPCAT3 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src)