Lysophosphatidylcholine acyltransferase 3-dependent phospholipid remodeling regulates lipid homeostasis and inflammation
Phospholipids (PLs) are important structural components of biological membranes and precursors of numerous signaling molecules. The fatty acyl composition of PLs determines the biophysical characteristics of membranes. Multiple lines of evidence demonstrated that changes in fatty acyl composition could potentially affect the properties of proteins associated with membranes and influence the biological processes that occur on membranes. However, there is little understanding of how regulatory pathways control PL fatty acyl composition in vivo or how such regulation dictates physiological responses. In this work, we investigated the regulation of membrane fatty acyl composition by the Liver X Receptor (LXR)-Lysophosphatidylcholine Acyltranferase 3 (Lpcat3) pathway and its physiological or pathological relevance in lipid homeostasis and metabolic diseases.
In chapter 2, we define a nuclear receptor pathway for the dynamic modulation of membrane composition in response to changes in cellular lipid metabolism. Ligand activation of LXR preferentially drives the incorporation of polyunsaturated fatty acids into PLs through induction of the remodeling enzyme Lpcat3. Promotion of Lpcat3 activity decreases endoplasmic reticulum (ER) stress induced by saturated free fatty acids in vitro or by obesity and hepatic lipid accumulation in vivo. Conversely, Lpcat3 knockdown in liver exacerbates ER stress and inflammation. Mechanistically, Lpcat3 modulates inflammation both by regulating c-Src (Proto-oncogene tyrosine-protein kinase Src) and JNK (c-Jun N-terminal kinases) activation through changes in membrane composition and by affecting substrate availability for inflammatory mediator production. These results outline an endogenous mechanism for the preservation of membrane homeostasis during lipid stress and identify Lpcat3 as an important mediator of LXRs effects on metabolism.
In chapter 3, we show that Lpcat3 is a critical determinant of triglyceride 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 massive enterocyte lipid accumulation and reduced plasma triglycerides. Mice lacking Lpcat3 in the liver show reduced plasma triglycerides, hepatosteatosis, and secrete lipid-poor very low density lipoprotein (VLDL) lacking arachidonoyl PLs. Mechanistic studies indicate that Lpcat3 activity controls 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.