Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion
Xin Rong,
Bo Wang,
Merlow M Dunham,
Per Niklas Hedde,
Jinny S Wong,
Enrico Gratton,
Stephen G Young,
David A Ford,
Peter Tontonoz
Affiliations
Xin Rong
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
Bo Wang
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
Merlow M Dunham
Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, United States; Center for Cardiovascular Research, Saint Louis University, St. Louis, United States
Per Niklas Hedde
Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, United States; Center for Complex Biological Systems, University of California, Irvine, Irvine, United States
Jinny S Wong
Electron Microscopy Core, Gladstone Institute of Cardiovascular Disease, San Francisco, United States
Enrico Gratton
Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, United States; Center for Complex Biological Systems, University of California, Irvine, Irvine, United States
Stephen G Young
Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, United States
David A Ford
Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, United States; Center for Cardiovascular Research, Saint Louis University, St. Louis, United States
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.
