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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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Loss of Lpcat3 in liver does not alter membrane structure in ER and mitochondria.(A) EM of imidazole-stained liver sections. Arrowheads indicate nascent lipoprotein particles in smooth ER lumen. (B) EM of imidazole-stained liver sections. Mitochondria are shown. (C) EM of imidazole-stained liver sections. Rough ER is shown.DOI:http://dx.doi.org/10.7554/eLife.06557.020
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fig9s1: Loss of Lpcat3 in liver does not alter membrane structure in ER and mitochondria.(A) EM of imidazole-stained liver sections. Arrowheads indicate nascent lipoprotein particles in smooth ER lumen. (B) EM of imidazole-stained liver sections. Mitochondria are shown. (C) EM of imidazole-stained liver sections. Rough ER is shown.DOI:http://dx.doi.org/10.7554/eLife.06557.020

Mentions: To obtain further insight into the nature of the lipoprotein production defect in L-Lpcat3 KO mice, we examined liver samples by EM. Nascent lipoproteins, ranging between 0.05 and 0.11 microns in diameter, were easily visualized in the Golgi apparatus and secretory vesicles of control mice (Figure 9). Lipoprotein particles were also present in Golgi and secretory vesicles of L-Lpcat3 KO mice, however they were markedly smaller, ranging between 0.03 to 0.08 microns in diameter (Figure 9). We also observed small lipoprotein particles in the ER in mice of both genotypes (Figure 9—figure supplement 1). We did not find differences in the morphology of Golgi, ER or mitochondria between control and L-Lpcat3 KO livers, suggesting that loss of arachidonoyl PLs does not dramatically alter membrane structure in these organelles (Figure 9—figure supplement 1).10.7554/eLife.06557.019Figure 9.Reduced nascent lipoprotein particle size in the lumen of Golgi and secretory vesicles in Lpcat3-deficient 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)

Loss of Lpcat3 in liver does not alter membrane structure in ER and mitochondria.(A) EM of imidazole-stained liver sections. Arrowheads indicate nascent lipoprotein particles in smooth ER lumen. (B) EM of imidazole-stained liver sections. Mitochondria are shown. (C) EM of imidazole-stained liver sections. Rough ER is shown.DOI:http://dx.doi.org/10.7554/eLife.06557.020
© Copyright Policy
Related In: Results  -  Collection

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

fig9s1: Loss of Lpcat3 in liver does not alter membrane structure in ER and mitochondria.(A) EM of imidazole-stained liver sections. Arrowheads indicate nascent lipoprotein particles in smooth ER lumen. (B) EM of imidazole-stained liver sections. Mitochondria are shown. (C) EM of imidazole-stained liver sections. Rough ER is shown.DOI:http://dx.doi.org/10.7554/eLife.06557.020
Mentions: To obtain further insight into the nature of the lipoprotein production defect in L-Lpcat3 KO mice, we examined liver samples by EM. Nascent lipoproteins, ranging between 0.05 and 0.11 microns in diameter, were easily visualized in the Golgi apparatus and secretory vesicles of control mice (Figure 9). Lipoprotein particles were also present in Golgi and secretory vesicles of L-Lpcat3 KO mice, however they were markedly smaller, ranging between 0.03 to 0.08 microns in diameter (Figure 9). We also observed small lipoprotein particles in the ER in mice of both genotypes (Figure 9—figure supplement 1). We did not find differences in the morphology of Golgi, ER or mitochondria between control and L-Lpcat3 KO livers, suggesting that loss of arachidonoyl PLs does not dramatically alter membrane structure in these organelles (Figure 9—figure supplement 1).10.7554/eLife.06557.019Figure 9.Reduced nascent lipoprotein particle size in the lumen of Golgi and secretory vesicles in Lpcat3-deficient 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