Pla2g12b Drives Expansion of Triglyceride-Rich Lipoproteins

Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins (TRLs). Yet, how triglycerides are loaded onto TRLs remains largely unknown. Mutations in Phospholipase A2 group 12B (PLA2G12B) have been shown to disrupt TRL homeostasis, but its’ mechanistic role in this process remains unclear. By characterizing secreted triglyceride-rich lipoproteins and their precursors within the ER, we discover that PLA2G12B channels lipids within the ER lumen into nascent TRLs. This activity promotes efficient lipid secretion while preventing excess accumulation of intracellular lipids. We characterize the functional domains, subcellular localization, and interacting partners of PLA2G12B, demonstrating that PLA2G12B is calcium dependent, and tightly associated with the ER membrane. We also detect profound resistance to atherosclerosis in PLA2G12B mutant mice, suggesting an evolutionary tradeoff between triglyceride transport and cardiovascular disease risk. Here we identify PLA2G12B as a key driver of triglyceride incorporation into vertebrate lipoproteins.