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Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion.

Rong X, Wang B, Dunham MM, Hedde PN, Wong JS, Gratton E, Young SG, Ford DA, Tontonoz P - Elife (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.

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.

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Lpcat3 is required for the incorporation of arachidonate into phosphatidylethanolamine in mouse liver.(A–B) ESI-MS/MS analysis of the abundance of phosphatidlyethanolamine (PE) species in livers from Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a chow diet (A) and a western diet (B).DOI:http://dx.doi.org/10.7554/eLife.06557.014
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fig5s1: Lpcat3 is required for the incorporation of arachidonate into phosphatidylethanolamine in mouse liver.(A–B) ESI-MS/MS analysis of the abundance of phosphatidlyethanolamine (PE) species in livers from Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a chow diet (A) and a western diet (B).DOI:http://dx.doi.org/10.7554/eLife.06557.014

Mentions: We also analyzed the effect of western diet on hepatic phospholipid composition in the presence and absence of Lpcat3. The diet increased the abundance of certain PC species, such as 16:0, 18:1 PC, presumably reflecting the abundance of oleate in the western diet. However, we observed the same prominent deficits in 16:0, 20:4 PC and 18:0, 20:4 PC on western diet as we observed on chow diet, with no change in total levels of PC (Figure 5B). In addition, there were reductions in 16:1, 18:2 PC and 18:1, 20:4 PC in western diet-fed Lpcat3 KO livers compared to controls. Severe reductions of phosphatidlyethanolamine (PE) species containing arachidonate chains were also observed in L-Lpcat3 KO mice on both chow and western diets (Figure 5—figure supplement 1). Interestingly, 16:0, 20:4 PE and 18:0, 20:4 PE are particularly abundant PE species in liver on western diet, and reductions in their levels was sufficient to reduce total PE levels.


Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion.

Rong X, Wang B, Dunham MM, Hedde PN, Wong JS, Gratton E, Young SG, Ford DA, Tontonoz P - Elife (2015)

Lpcat3 is required for the incorporation of arachidonate into phosphatidylethanolamine in mouse liver.(A–B) ESI-MS/MS analysis of the abundance of phosphatidlyethanolamine (PE) species in livers from Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a chow diet (A) and a western diet (B).DOI:http://dx.doi.org/10.7554/eLife.06557.014
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400582&req=5

fig5s1: Lpcat3 is required for the incorporation of arachidonate into phosphatidylethanolamine in mouse liver.(A–B) ESI-MS/MS analysis of the abundance of phosphatidlyethanolamine (PE) species in livers from Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a chow diet (A) and a western diet (B).DOI:http://dx.doi.org/10.7554/eLife.06557.014
Mentions: We also analyzed the effect of western diet on hepatic phospholipid composition in the presence and absence of Lpcat3. The diet increased the abundance of certain PC species, such as 16:0, 18:1 PC, presumably reflecting the abundance of oleate in the western diet. However, we observed the same prominent deficits in 16:0, 20:4 PC and 18:0, 20:4 PC on western diet as we observed on chow diet, with no change in total levels of PC (Figure 5B). In addition, there were reductions in 16:1, 18:2 PC and 18:1, 20:4 PC in western diet-fed Lpcat3 KO livers compared to controls. Severe reductions of phosphatidlyethanolamine (PE) species containing arachidonate chains were also observed in L-Lpcat3 KO mice on both chow and western diets (Figure 5—figure supplement 1). Interestingly, 16:0, 20:4 PE and 18:0, 20:4 PE are particularly abundant PE species in liver on western diet, and reductions in their levels was sufficient to reduce total PE levels.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.

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.

Show MeSH