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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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Schematic illustration of the role of the LXR-Lpcat3 pathway in VLDL lipidation.Activation of LXRs promotes the incorporation of arachidonate into intracellular membranes through the induction of Lpcat3 expression. This change in membrane composition creates a dynamic membrane environment that facilitates the transfer of TG synthesized on ER and/or in cytosolic LD to nascent apoB–containing lipoproteins particles, leading to the efficient lipidation of apoB–containing lipoproteins.DOI:http://dx.doi.org/10.7554/eLife.06557.023
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fig12: Schematic illustration of the role of the LXR-Lpcat3 pathway in VLDL lipidation.Activation of LXRs promotes the incorporation of arachidonate into intracellular membranes through the induction of Lpcat3 expression. This change in membrane composition creates a dynamic membrane environment that facilitates the transfer of TG synthesized on ER and/or in cytosolic LD to nascent apoB–containing lipoproteins particles, leading to the efficient lipidation of apoB–containing lipoproteins.DOI:http://dx.doi.org/10.7554/eLife.06557.023

Mentions: This work illustrates how manipulation of membrane composition can be used as regulatory mechanism to control metabolic pathways. A model for Lpcat3 action is presented in Figure 12. Lpcat3 is not only a required component of lipoprotein production; it is also a regulated one. The fact that Lpcat3 expression is dynamically regulated by LXRs in liver and intestine strongly suggests that the level of Lpcat3 enzymatic activity has evolved to respond to dietary and metabolic demands. LXR is transcriptionally activated as cellular cholesterol levels rise. Thus, the LXR-Lpcat3 pathway provides a mechanism to integrate sterol metabolism and membrane PL composition. We speculate that Lpcat3 expression is induced in response to lipid loading in order to increase ER/Golgi membrane flexibility and to facilitate efficient TG secretion (thereby unloading cells of excess lipids). In support of this idea, we found that the ability of pharmacologic LXR agonist to stimulate hepatic VLDL production was impaired in the genetic absence of Lpcat3.10.7554/eLife.06557.023Figure 12.Schematic illustration of the role of the LXR-Lpcat3 pathway in VLDL lipidation.


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)

Schematic illustration of the role of the LXR-Lpcat3 pathway in VLDL lipidation.Activation of LXRs promotes the incorporation of arachidonate into intracellular membranes through the induction of Lpcat3 expression. This change in membrane composition creates a dynamic membrane environment that facilitates the transfer of TG synthesized on ER and/or in cytosolic LD to nascent apoB–containing lipoproteins particles, leading to the efficient lipidation of apoB–containing lipoproteins.DOI:http://dx.doi.org/10.7554/eLife.06557.023
© Copyright Policy
Related In: Results  -  Collection

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

fig12: Schematic illustration of the role of the LXR-Lpcat3 pathway in VLDL lipidation.Activation of LXRs promotes the incorporation of arachidonate into intracellular membranes through the induction of Lpcat3 expression. This change in membrane composition creates a dynamic membrane environment that facilitates the transfer of TG synthesized on ER and/or in cytosolic LD to nascent apoB–containing lipoproteins particles, leading to the efficient lipidation of apoB–containing lipoproteins.DOI:http://dx.doi.org/10.7554/eLife.06557.023
Mentions: This work illustrates how manipulation of membrane composition can be used as regulatory mechanism to control metabolic pathways. A model for Lpcat3 action is presented in Figure 12. Lpcat3 is not only a required component of lipoprotein production; it is also a regulated one. The fact that Lpcat3 expression is dynamically regulated by LXRs in liver and intestine strongly suggests that the level of Lpcat3 enzymatic activity has evolved to respond to dietary and metabolic demands. LXR is transcriptionally activated as cellular cholesterol levels rise. Thus, the LXR-Lpcat3 pathway provides a mechanism to integrate sterol metabolism and membrane PL composition. We speculate that Lpcat3 expression is induced in response to lipid loading in order to increase ER/Golgi membrane flexibility and to facilitate efficient TG secretion (thereby unloading cells of excess lipids). In support of this idea, we found that the ability of pharmacologic LXR agonist to stimulate hepatic VLDL production was impaired in the genetic absence of Lpcat3.10.7554/eLife.06557.023Figure 12.Schematic illustration of the role of the LXR-Lpcat3 pathway in VLDL lipidation.

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