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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 LXR-dependent VLDL TG secretion from liver.Plasma lipoprotein profile from flox/flox and L-Lpcat3 mice gavaged with LXR agonist GW 3965 (20 mg/kg) for 2 days. Pooled plasma (5 mice/group) was analyzed by FPLC. Increases in VLDL TG were calculated based on the area under the curve.DOI:http://dx.doi.org/10.7554/eLife.06557.022
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fig11: Lpcat3 is required for LXR-dependent VLDL TG secretion from liver.Plasma lipoprotein profile from flox/flox and L-Lpcat3 mice gavaged with LXR agonist GW 3965 (20 mg/kg) for 2 days. Pooled plasma (5 mice/group) was analyzed by FPLC. Increases in VLDL TG were calculated based on the area under the curve.DOI:http://dx.doi.org/10.7554/eLife.06557.022

Mentions: Finally, as LXR agonists have previously been reported to promote hepatic TG secretion (Schultz et al., 2000), we tested the requirement for Lpcat3 induction in this effect. Control and L-Lpcat3 KO mice were treated for 2 days with the LXR agonist GW3965 (20 mpk/day) by oral gavage. The TG levels in fractionated plasma were then determined after 6 hr fast. In line with prior studies, treatment of control mice with LXR agonist led to a prominent (95%) increase in plasma VLDL TG levels (Figure 11). By contrast, treatment of L-Lpcat3 KO mice with LXR agonist had a much more modest effect (45% increase). These data suggest that induction of Lpcat3 expression plays an important role in the control of hepatic VLDL production by LXRs.10.7554/eLife.06557.022Figure 11.Lpcat3 is required for LXR-dependent VLDL TG secretion from liver.


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 LXR-dependent VLDL TG secretion from liver.Plasma lipoprotein profile from flox/flox and L-Lpcat3 mice gavaged with LXR agonist GW 3965 (20 mg/kg) for 2 days. Pooled plasma (5 mice/group) was analyzed by FPLC. Increases in VLDL TG were calculated based on the area under the curve.DOI:http://dx.doi.org/10.7554/eLife.06557.022
© Copyright Policy
Related In: Results  -  Collection

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

fig11: Lpcat3 is required for LXR-dependent VLDL TG secretion from liver.Plasma lipoprotein profile from flox/flox and L-Lpcat3 mice gavaged with LXR agonist GW 3965 (20 mg/kg) for 2 days. Pooled plasma (5 mice/group) was analyzed by FPLC. Increases in VLDL TG were calculated based on the area under the curve.DOI:http://dx.doi.org/10.7554/eLife.06557.022
Mentions: Finally, as LXR agonists have previously been reported to promote hepatic TG secretion (Schultz et al., 2000), we tested the requirement for Lpcat3 induction in this effect. Control and L-Lpcat3 KO mice were treated for 2 days with the LXR agonist GW3965 (20 mpk/day) by oral gavage. The TG levels in fractionated plasma were then determined after 6 hr fast. In line with prior studies, treatment of control mice with LXR agonist led to a prominent (95%) increase in plasma VLDL TG levels (Figure 11). By contrast, treatment of L-Lpcat3 KO mice with LXR agonist had a much more modest effect (45% increase). These data suggest that induction of Lpcat3 expression plays an important role in the control of hepatic VLDL production by LXRs.10.7554/eLife.06557.022Figure 11.Lpcat3 is required for LXR-dependent VLDL TG secretion from liver.

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