title: Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion.
abstract: The role of specific phospholipids (PLs) in lipid transport has been difficult to assess due to an inability to selectively manipulate membrane composition in vivo. Here we show that the phospholipid remodeling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3) is a critical determinant of triglyceride (TG) secretion due to its unique ability to catalyze the incorporation of arachidonate into membranes. Mice lacking Lpcat3 in the intestine fail to thrive during weaning and exhibit enterocyte lipid accumulation and reduced plasma TGs. Mice lacking Lpcat3 in the liver show reduced plasma TGs, hepatosteatosis, and secrete lipid-poor very low-density lipoprotein (VLDL) lacking arachidonoyl PLs. Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells, suggesting a biophysical basis for the requirement of arachidonoyl PLs in lipidating lipoprotein particles. These data identify Lpcat3 as a key factor in lipoprotein production and illustrate how manipulation of membrane composition can be used as a regulatory mechanism to control metabolic pathways.
authors: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
authors: Xin
authors: X
authors: Rong
authors: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
authors: Bo
authors: B
authors: Wang
authors: Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, United States.
authors: Merlow M
authors: MM
authors: Dunham
authors: Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, United States.
authors: Per Niklas
authors: PN
authors: Hedde
authors: Electron Microscopy Core, Gladstone Institute of Cardiovascular Disease, San Francisco, United States.
authors: Jinny S
authors: JS
authors: Wong
authors: Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, United States.
authors: Enrico
authors: E
authors: Gratton
authors: Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors: Stephen G
authors: SG
authors: Young
authors: Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, United States.
authors: David A
authors: DA
authors: Ford
authors: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
authors: Peter
authors: http://orcid.org/0000-0003-1259-0477
authors: P
authors: Tontonoz
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D001947:Breeding; D004032:Diet; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D022781:Hepatocytes / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL; D008099:Liver / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001055:Apolipoproteins B; D008079:Lipoproteins, VLDL; D000071518:Liver X Receptors; D008244:Lysophosphatidylcholines; D008563:Membrane Lipids; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D014280:Triglycerides; D016718:Arachidonic Acid; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C000600794:LPCAT3 protein, mouse
keywords: cell biology; human biology; lipoprotein; medicine; mouse; nuclear receptor; phospholipid