Remnants of triglyceride-rich lipoproteins containing apolipoprotein (apo) B-48 accumulate in apo E-deficient mice, causing pronounced hypercholesterolemia. Mice doubly deficient in apo E and hepatic lipase have more pronounced hypercholesterolemia, even though remnants do not accumulate appreciably in mice deficient in hepatic lipase alone. Here we show that the doubly deficient mice manifest a unique lamellar hyperlipoproteinemia, characterized by vesicular particles 600 Å-1,300 Å in diameter. As seen by negative-staining electron microscopy, these lipoproteins also contain an electron-lucent region adjacent to the vesicle wall, similar to the core of typical lipoproteins. Correlative chemical analysis indicates that the vesicle wall is composed of a 1:1 molar mixture of cholesterol and phospholipids, whereas the electron-lucent region appears to be composed of cholesteryl esters (about 12% of the particle mass). Like the spherical lipoproteins of doubly deficient mice, the vesicular particles contain apo B-48, but they are particularly rich in apo A-IV. We propose that cholesteryl esters are removed from spherical lipoproteins of these mice by scavenger receptor B1, leaving behind polar lipid-rich particles that fuse to form vesicular lipoproteins. Hepatic lipase may prevent such vesicular lipoproteins from accumulating in apo E-deficient mice by hydrolyzing phosphatidyl choline as scavenger receptor B1 removes the cholesteryl esters and by gradual endocytosis of lipoproteins bound to hepatic lipase on the surface of hepatocytes.Chylomicrons transport dietary fat and cholesterol into the blood and are metabolized in two discrete steps (1). First, chylomicron triglycerides and phospholipids are partially removed in extrahepatic tissues by lipoprotein lipase to yield chylomicron remnants (CR); second, the remnants are adsorbed onto hepatic parenchymal cells and undergo receptormediated endocytosis. Binding of CR to hepatocytes is mediated chiefly by the low-density lipoprotein (LDL) receptor and hepatic lipase (HL) (1). The LDL receptor-related protein can also bind CR that have been enriched with apolipoprotein (apo) E. Endocytosis of CR, leading to lysosomal catabolism, is primarily mediated by the LDL receptor. The LDL receptor and LDL receptor-related protein bind CR by means of apo E. Thus, apo E-deficient mice (2, 3) and humans (4) manifest massive accumulation of CR. Although CR clearance is impaired in HL-deficient mice (5), and conversion of very low-density lipoprotein (VLDL) remnants to LDL and LDL concentrations are reduced in HL-deficient humans (6) and mice (5), accumulation of remnant lipoproteins is limited (5-7). Recently, Mezdour et al. (8) have reported that mice doubly deficient in apo E and HL have considerably higher levels of cholesterol in lipoproteins with remnant characteristics than mice deficient only in apo E. Here we show that the doubly deficient mice uniquely manifest a pronounced lamellar hyperlipoproteinemia, in which lipoprotein particles resembling liposomes accumula...