Structure of triglyceride-rich human low-density lipoproteins according to cryoelectron microscopy

Low-density lipoprotein (LDL) particles from normolipidemic individuals contain a cholesteryl ester-rich core that undergoes a thermal transition from a liquid crystalline to an isotropic liquid phase between 20 and 35 degrees C. LDL from hypertriglyceridemic patients or prepared in vitro by the exchange of very low-density lipoprotein for LDL cholesteryl esters is triglyceride-rich, does not have a thermal transition above 0 degrees C, and exhibits impaired binding to the LDL receptor on normal human skin fibroblasts. Cryoelectron microscopy of LDL quick-frozen from 10 (core-frozen) and 40 degrees C (core-melted) revealed ellipsoidal particles with internal striations and round particles devoid of striations, respectively. Cryoelectron microscopy of triglyceride-rich LDL prepared in vitro revealed particles similar to the core-melted normolipidemic LDL, i.e., round particles without striations. These data suggest that the LDL core in the liquid crystalline phase is characterized by the appearance of striations, whereas LDL with a core that is an isotropic liquid lacks striations. It is suggested that freezing the LDL core into a liquid crystalline phase imposes structural constraints that force LDL from a sphere without partitions to an ellipsoid with partitions. We further suggest that the striation-defined lamellae are a structural feature of a liquid crystalline neutral lipid core that is a determinant of normal binding to the LDL receptor and that conversion of the neutral lipid core of LDL to the isotropic liquid phase via an increase in the temperature or via the addition of triglyceride partially ablates the receptor binding determinants on the LDL surface. This effect is likely achieved through changes in the conformation of apo-B-100. These data suggest that the physical state of the LDL core determines particle shape, surface structure, and metabolic fate.