ER quality control: how cells detoxify their own membrane from lipid stress

The endoplasmic reticulum (ER) is the principal site of glycerolipid synthesis in eukaryotic cells. The continuous production of lipid intermediates, including phosphatidic acid (PA), diacylglycerol (DAG), and triacylglycerol (TAG), destabilizes the ER membrane when they accumulate. To maintain bilayer integrity, cells deploy two sequential strategies: enzymatic conversion of these intermediates into membrane-compatible phospholipids, and their physical sequestration into lipid droplets (LDs), ER-derived organelles whose biogenesis is actively regulated by the seipin complex. LD growth is further sustained by the relocalization of TAG-synthesizing enzymes to the LD surface and by bridge-like lipid transfer proteins at ER-LD contact sites. When these mechanisms are overwhelmed, the accumulation of non-bilayer lipids drives ER stress and lipotoxicity, thereby contributing to the development of metabolic diseases. Here, we review the molecular logic of ER lipid quality control, from intermediate-driven membrane stress to the regulated responses that neutralize it.