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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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Chronic deletion of Lpcat3 does not induce unfolded protein response downstream gene expression.(A) Gene expression in livers of Lpcat3fl/fl (F/F) and Lpcat3fl/flAlbumin-Cre (L-KO) mice fed on a chow diet was analyzed by Affymetrix arrays. Select ER stress marker genes are presented by heatmap. Samples from 5 mice/group were pool for analysis. (B) Gene expression in livers of Lpcat3fl/fl (F/F) and Lpcat3fl/flAlbumin-Cre (L-KO) mice fed on a western diet was analyzed by Affymetrix arrays. Select ER stress marker genes are presented by heatmap. Samples from 5 mice/group were pool for analysis.DOI:http://dx.doi.org/10.7554/eLife.06557.017
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fig7s1: Chronic deletion of Lpcat3 does not induce unfolded protein response downstream gene expression.(A) Gene expression in livers of Lpcat3fl/fl (F/F) and Lpcat3fl/flAlbumin-Cre (L-KO) mice fed on a chow diet was analyzed by Affymetrix arrays. Select ER stress marker genes are presented by heatmap. Samples from 5 mice/group were pool for analysis. (B) Gene expression in livers of Lpcat3fl/fl (F/F) and Lpcat3fl/flAlbumin-Cre (L-KO) mice fed on a western diet was analyzed by Affymetrix arrays. Select ER stress marker genes are presented by heatmap. Samples from 5 mice/group were pool for analysis.DOI:http://dx.doi.org/10.7554/eLife.06557.017

Mentions: We previously reported that acute knockdown of Lpcat3 expression in livers of genetically obese mice exacerbated lipid-induced ER stress (Rong et al., 2013). Genetic deletion of Lpcat3 from liver did not lead to increased mRNA expression of ER stress markers in mice fed chow or western diet (Figure 7—figure supplement 1). These observations suggest that there may be compensatory responses in membrane composition that prevent induction of the ER stress response in the setting of chronic Lpcat3 deletion. In support of this idea, we observed a prominent increase in the abundance of oleoyl-PC species in L-Lpcat3 mice (Figure 5). We cannot exclude the possibility that ER stress may be increased in L-Lpcat3 mice in the setting of genetic obesity or other causes of severe lipotoxicity.


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)

Chronic deletion of Lpcat3 does not induce unfolded protein response downstream gene expression.(A) Gene expression in livers of Lpcat3fl/fl (F/F) and Lpcat3fl/flAlbumin-Cre (L-KO) mice fed on a chow diet was analyzed by Affymetrix arrays. Select ER stress marker genes are presented by heatmap. Samples from 5 mice/group were pool for analysis. (B) Gene expression in livers of Lpcat3fl/fl (F/F) and Lpcat3fl/flAlbumin-Cre (L-KO) mice fed on a western diet was analyzed by Affymetrix arrays. Select ER stress marker genes are presented by heatmap. Samples from 5 mice/group were pool for analysis.DOI:http://dx.doi.org/10.7554/eLife.06557.017
© Copyright Policy
Related In: Results  -  Collection

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

fig7s1: Chronic deletion of Lpcat3 does not induce unfolded protein response downstream gene expression.(A) Gene expression in livers of Lpcat3fl/fl (F/F) and Lpcat3fl/flAlbumin-Cre (L-KO) mice fed on a chow diet was analyzed by Affymetrix arrays. Select ER stress marker genes are presented by heatmap. Samples from 5 mice/group were pool for analysis. (B) Gene expression in livers of Lpcat3fl/fl (F/F) and Lpcat3fl/flAlbumin-Cre (L-KO) mice fed on a western diet was analyzed by Affymetrix arrays. Select ER stress marker genes are presented by heatmap. Samples from 5 mice/group were pool for analysis.DOI:http://dx.doi.org/10.7554/eLife.06557.017
Mentions: We previously reported that acute knockdown of Lpcat3 expression in livers of genetically obese mice exacerbated lipid-induced ER stress (Rong et al., 2013). Genetic deletion of Lpcat3 from liver did not lead to increased mRNA expression of ER stress markers in mice fed chow or western diet (Figure 7—figure supplement 1). These observations suggest that there may be compensatory responses in membrane composition that prevent induction of the ER stress response in the setting of chronic Lpcat3 deletion. In support of this idea, we observed a prominent increase in the abundance of oleoyl-PC species in L-Lpcat3 mice (Figure 5). We cannot exclude the possibility that ER stress may be increased in L-Lpcat3 mice in the setting of genetic obesity or other causes of severe lipotoxicity.

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