Glycerolipid Synthesis and Lipid Droplet Formation in the Endoplasmic Reticulum

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.

Automated summary

More than 60 years ago, the pathways of glycerolipid synthesis in the endoplasmic reticulum (ER) were elucidated, but the molecular basis for most of these reactions remained unknown. Recent progress in cell biology, biochemistry, and structural biology has provided a more mechanistic understanding of this pathway. This review provides an overview of molecular aspects of glycerolipid synthesis, focusing on the synthesis of triacylglycerols (TGs), and discusses the mechanisms for storage of TG in cytosolic lipid droplets and the implications for ER stress and cellular toxicity.