Limits...
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.

Show MeSH
Quantification of western blots.Immunoblot blot results of apoB-100 and apoB-48 proteins in (A) Figure 3B and (B) Figure 3C were quantified by densitometry.DOI:http://dx.doi.org/10.7554/eLife.06557.010
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4400582&req=5

fig3s1: Quantification of western blots.Immunoblot blot results of apoB-100 and apoB-48 proteins in (A) Figure 3B and (B) Figure 3C were quantified by densitometry.DOI:http://dx.doi.org/10.7554/eLife.06557.010

Mentions: To further explore a role for Lpcat3 in TG secretion, we challenged control and L-Lpcat3 KO mice with western diet (40% high fat and 0.2% cholesterol) for 9 weeks. Mice lacking hepatic Lpcat3 again showed lower total plasma TG levels (Figure 3A) and a striking loss of TG in the VLDL plasma lipoprotein fraction (Figure 3B, Figure 3—figure supplement 1A). In addition, these mice had increased levels of plasma apoB-100 compared to controls (Figure 3C, Figure 3—figure supplement 1B). Analysis of tissue lipids revealed prominent accumulation of hepatic TG and cholesterol in the liver of L-Lpcat3 KO mice (Figure 3D,E). We also challenged mice with a high-sucrose diet, which strongly stimulates hepatic lipid synthesis and secretion. On the high-sucrose diet, L-Lpcat3 KO mice exhibited hepatic TG accumulation (Figure 3F,G). The accumulation of hepatic TG in L-Lpcat3 KO mice in the setting of reduced plasma VLDL TG implied that Lpcat3 activity might be crucial for the assembly and secretion of TG-rich lipoproteins from the liver.10.7554/eLife.06557.009Figure 3.Dietary challenge accentuates metabolic phenotypes in liver-specific Lpcat3 knockout mice.


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)

Quantification of western blots.Immunoblot blot results of apoB-100 and apoB-48 proteins in (A) Figure 3B and (B) Figure 3C were quantified by densitometry.DOI:http://dx.doi.org/10.7554/eLife.06557.010
© Copyright Policy
Related In: Results  -  Collection

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

fig3s1: Quantification of western blots.Immunoblot blot results of apoB-100 and apoB-48 proteins in (A) Figure 3B and (B) Figure 3C were quantified by densitometry.DOI:http://dx.doi.org/10.7554/eLife.06557.010
Mentions: To further explore a role for Lpcat3 in TG secretion, we challenged control and L-Lpcat3 KO mice with western diet (40% high fat and 0.2% cholesterol) for 9 weeks. Mice lacking hepatic Lpcat3 again showed lower total plasma TG levels (Figure 3A) and a striking loss of TG in the VLDL plasma lipoprotein fraction (Figure 3B, Figure 3—figure supplement 1A). In addition, these mice had increased levels of plasma apoB-100 compared to controls (Figure 3C, Figure 3—figure supplement 1B). Analysis of tissue lipids revealed prominent accumulation of hepatic TG and cholesterol in the liver of L-Lpcat3 KO mice (Figure 3D,E). We also challenged mice with a high-sucrose diet, which strongly stimulates hepatic lipid synthesis and secretion. On the high-sucrose diet, L-Lpcat3 KO mice exhibited hepatic TG accumulation (Figure 3F,G). The accumulation of hepatic TG in L-Lpcat3 KO mice in the setting of reduced plasma VLDL TG implied that Lpcat3 activity might be crucial for the assembly and secretion of TG-rich lipoproteins from the liver.10.7554/eLife.06557.009Figure 3.Dietary challenge accentuates metabolic phenotypes in liver-specific Lpcat3 knockout mice.

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