Journal
ELIFE
Volume 4, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.06557
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NHLBI NIH HHS [HL090553, P01 HL090553, HL030568, HL074214, P01 HL030568, R01 HL074214] Funding Source: Medline
- NIDDK NIH HHS [P30 DK063491, DK063491] Funding Source: Medline
- NIGMS NIH HHS [GM076516, P50 GM076516, P41 GM103540, GM103540] Funding Source: Medline
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The role of specific phospholipids 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 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 triglycerides. Mice lacking Lpcat3 in the liver show reduced plasma triglycerides, hepatosteatosis, and secrete lipid-poor VLDL lacking arachidonoyl phospholipids. Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells, suggesting a biophysical basis for the requirement of arachidonoyl phospholipids 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.
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