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.
Highlights
Phospholipids (PLs) are important components of biological membranes and serve as precursors for the generation of diverse signaling molecules (Spector and Yorek, 1985)
We demonstrate here that lysophosphatidylcholine acyltransferase 3 (Lpcat3) is uniquely required for the incorporation of arachidonic acid into membranes in vivo, and that an absence of arachidonoyl PLs profoundly affects lipid transport and lipoprotein production
Global Lpcat3−/− mice on a C57BL/6 background were born at the expected Mendelian frequency, and their weights were indistinguishable from week-old Lpcat3fl/fl (WT) mice at birth (Figure 1D, Table 1)
Summary
Phospholipids (PLs) are important components of biological membranes and serve as precursors for the generation of diverse signaling molecules (Spector and Yorek, 1985). In mammalian cells PLs synthesized de novo undergo further remodeling through deacylation by phospholipases and the subsequent and reacylation by lysophospholipid acyltransferases (Lpcats). Membrane PLs reach an equilibrium in which the majority of PL species contain a saturated acyl chain at the sn-1 position and an unsaturated chain at the sn-2 position. The Lpcat-dependent remodeling process is essential for the diversity and asymmetric distribution of acyl chains because the de novo PL synthesis pathway has little substrate specificity (Yamashita et al, 2014). We previously identified the sterol-activated nuclear receptor LXR as an integrator of cellular lipid levels and membrane PL composition. Cell-based assays suggest that Lpcat preferentially catalyzes the synthesis of phosphatidylcholine (PC) species containing an unsaturated
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