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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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Analysis of cholesteryl ester and lysoPC species in L-Lpcat3 KO mice.(A–B) ESI-MS/MS analysis of the abundance of cholesteryl ester (A) and lysophosphatidylcholine (LysoPC) (B) species in livers of Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a chow diet (n ≥ 5/group). (C–D) ESI-MS/MS analysis of the abundance of cholesteryl ester (C) and lysophosphatidylcholine (LysoPC) (D) species in livers of Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a western diet (n ≥ 5/group). Statistical analysis was performed using Student's t-test. Values are means ± SEM. *p < 0.05; **p < 0.01.DOI:http://dx.doi.org/10.7554/eLife.06557.015
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fig6: Analysis of cholesteryl ester and lysoPC species in L-Lpcat3 KO mice.(A–B) ESI-MS/MS analysis of the abundance of cholesteryl ester (A) and lysophosphatidylcholine (LysoPC) (B) species in livers of Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a chow diet (n ≥ 5/group). (C–D) ESI-MS/MS analysis of the abundance of cholesteryl ester (C) and lysophosphatidylcholine (LysoPC) (D) species in livers of Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a western diet (n ≥ 5/group). Statistical analysis was performed using Student's t-test. Values are means ± SEM. *p < 0.05; **p < 0.01.DOI:http://dx.doi.org/10.7554/eLife.06557.015

Mentions: Interestingly, the severe loss of arachidonate in livers of Lpcat3 KO mice on chow diet was observed in PLs, but not in TG (Figure 5D) nor in cholesterol esters (Figure 6A). There was an increase in total cholesterol ester and a number of cholesterol ester species in L-Lpcat3 KO mice, consistent with the histologic evidence of increased neutral lipid content in the liver (Figure 2). There was no accumulation of the major lipid substrates of Lpcat3 (16:0 lysoPC and 18:0 lysoPC) in L-Lpcat3 KO mice (Figure 6B), suggesting these precursors are efficiently shuttled into alternative pathways in the absence of Lpcat3. Broadly similar results were obtained from mice fed western diet, although we did observe modestly lower levels of 20:4 lysoPC (Figure 6C,D).10.7554/eLife.06557.015Figure 6.Analysis of cholesteryl ester and lysoPC species in L-Lpcat3 KO 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)

Analysis of cholesteryl ester and lysoPC species in L-Lpcat3 KO mice.(A–B) ESI-MS/MS analysis of the abundance of cholesteryl ester (A) and lysophosphatidylcholine (LysoPC) (B) species in livers of Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a chow diet (n ≥ 5/group). (C–D) ESI-MS/MS analysis of the abundance of cholesteryl ester (C) and lysophosphatidylcholine (LysoPC) (D) species in livers of Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a western diet (n ≥ 5/group). Statistical analysis was performed using Student's t-test. Values are means ± SEM. *p < 0.05; **p < 0.01.DOI:http://dx.doi.org/10.7554/eLife.06557.015
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Analysis of cholesteryl ester and lysoPC species in L-Lpcat3 KO mice.(A–B) ESI-MS/MS analysis of the abundance of cholesteryl ester (A) and lysophosphatidylcholine (LysoPC) (B) species in livers of Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a chow diet (n ≥ 5/group). (C–D) ESI-MS/MS analysis of the abundance of cholesteryl ester (C) and lysophosphatidylcholine (LysoPC) (D) species in livers of Lpcat3fl/fl (Flox/Flox) and Lpcat3fl/flAlbumin-Cre (L-Lpcat3 KO) mice fed on a western diet (n ≥ 5/group). Statistical analysis was performed using Student's t-test. Values are means ± SEM. *p < 0.05; **p < 0.01.DOI:http://dx.doi.org/10.7554/eLife.06557.015
Mentions: Interestingly, the severe loss of arachidonate in livers of Lpcat3 KO mice on chow diet was observed in PLs, but not in TG (Figure 5D) nor in cholesterol esters (Figure 6A). There was an increase in total cholesterol ester and a number of cholesterol ester species in L-Lpcat3 KO mice, consistent with the histologic evidence of increased neutral lipid content in the liver (Figure 2). There was no accumulation of the major lipid substrates of Lpcat3 (16:0 lysoPC and 18:0 lysoPC) in L-Lpcat3 KO mice (Figure 6B), suggesting these precursors are efficiently shuttled into alternative pathways in the absence of Lpcat3. Broadly similar results were obtained from mice fed western diet, although we did observe modestly lower levels of 20:4 lysoPC (Figure 6C,D).10.7554/eLife.06557.015Figure 6.Analysis of cholesteryl ester and lysoPC species in L-Lpcat3 KO 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
Related in: MedlinePlus