Glycerolipid Synthesis and Lipid Droplet Formation in the Endoplasmic Reticulum

Abstract

More than 60 years ago, Eugene Kennedy and coworkers elucidated the endoplasmic reticulum (ER)-based pathways of glycerolipid synthesis, including the synthesis of phospholipids and triacylglycerols (TGs). The reactions of the Kennedy pathway were identified by studying the conversion of lipid intermediates and the isolation of biochemical enzymatic activities, but the molecular basis for most of these reactions was unknown. With recent progress in the cell biology, biochemistry, and structural biology in this area, we have a much more mechanistic understanding of this pathway and its reactions. In this review, we provide an overview of molecular aspects of glycerolipid synthesis, focusing on recent insights into the synthesis of TGs. Further, we go beyond the Kennedy pathway to describe the mechanisms for storage of TG in cytosolic lipid droplets and discuss how overwhelming these pathways leads to ER stress and cellular toxicity, as seen in diseases linked to lipid overload and obesity.

Figure 1.

Biochemistry of the early steps of the Kennedy pathway of glycerolipid synthesis. In the first steps of glycerolipid synthesis, fatty acyl-CoAs are sequentially added to a glycerol-3-phosphate backbone. The phosphate group is removed to form diacylglycerol. In the final step shown, triacylglycerols are formed from diacylglycerol and acyl-CoA substrates. Multiple enzymes catalyze each step in this pathway. See text for details.

Figure 2.

The endoplasmic reticulum (ER)-based Kennedy pathway of glycerolipid synthesis. An overview of the pathway of the early steps of glycerophospholipid synthesis in the ER is shown. Several structures that are available or predicted (lipin, DGAT1, and DGAT2) are shown at the ER membrane. Blue oval represents GPAT3 or GPAT4 with activator CHP-1 (dark blue oval); red oval, acylglycerol phosphate acyltransferase (AGPAT). Reactions of the CDP-DAG pathway and the last steps of the Kennedy pathway to synthesize phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are shown schematically in gray. See text for details.

Figure 3.

Model for CoA:diacylglycerol acyltransferase 1 (DGAT1)-mediated triacylglycerol (TG) synthesis and liquid droplet (LD) formation at LD assembly complexes (LDACs). DGAT1 dimers synthesize TG from DAG and fatty acyl-CoA substrates. The product, TG, is released into the membrane where it rapidly diffuses. LDACs provide a space for TGs to interact with each other, rather than membrane phospholipids, thus catalyzing oil phase transition. As the nascent LD forms, it is released toward the cytoplasm by an opening of the seipin transmembrane segments in the LDAC.