Chylomicron remnant clearance from the plasma is normal in familial hypercholesterolemic homozygotes with defined receptor defects.

Abstract

The retinyl palmitate fat tolerance test was used to measure chylomicron remnant clearance in 10 normal subjects (apolipoprotein E Iapo El isotypes 3 or 4 only), 6 normolipidemic apo E2/2 homozygotes and 5 familial hypercholesterolemic homozygotes. Skin fibroblasts with fully upregulated LDL receptors from the latter subjects degraded rabbit "25I-jBVLDL in vitro at rates ranging from < 10-48% of normal. Experiments in vivo revealed no significant differences between the normal and homozygous familial hypercholesterolemic (FHH) subjects in chylomicron remnant clearance assessed on the basis of "areas under the curves" for retinyl palmitate levels present in postprandial serum, chylomicron remnants (Sf. < 1,000), or chylomicrons (Sf. > 1,000). Remnant clearance was greatly decreased at all times in the apo E2/2 homozygotes, indicative of an important degree of flux control exerted by a receptor-mediated step involving apo E as ligand. The absence of any excess remnant accumulation in FHH subjects with varying "impairment" of LDL receptor-mediated degradation of apo Econtaining lipoproteins, permits the conclusion that chylomicron remnants are initially cleared from the plasma by apo E-recognizing receptors which are genetically distinct from

High Dose of Simvastatin Normalizes Postprandial Remnant-Like Particle Response in Patients With Heterozygous Familial Hypercholesterolemia

“…Studies involving postprandial lipoprotein remnants with REs as a marker in homozygous or heterozygous FH patients revealed either abnormalities 12,38 or a normal removal of chylomicron remnants. 13,31 We confirmed an earlier report by Castro Cabezas et al 12 that postprandial chylomicron remnants reflected by REs in the SfϽ1000 fraction were elevated in heterozygous FH patients compared with matched control subjects. In the fasting state and the early postprandial period (first 3 hours after a meal), smaller sized chylomicrons (considered to be atherogenic) are secreted.…”

“…9 -11 Castro Cabezas et al 12 have demonstrated a small but significant postprandial increase in retinyl palmitate concentration in the chylomicron remnant fraction (Svedberg flotation unit [Sf]Ͻ1000) in heterozygous FH patients compared with normolipidemic control subjects. However, Rubinsztein et al 13 did not observe any accumulation of vitamin A-labeled chylomicrons, IDLsized remnants, or chylomicron remnants in homozygous FH patients. Additionally, Kowal et al 14 reported that only 5% of the binding capacity of the LDL receptor was needed to remove chylomicron particles, suggesting only a minor role for the LDL receptor in the removal process of lipoprotein remnants.…”

Postprandial lipoprotein metabolism and atherosclerosis

“…remnants is controversial, because humans with homozygous familial hypercholesterolaemia (FH) seem to clear chylomicron remnants without any gross abnormality [56]. The Watanabe heritable hyperlipidaemic rabbit (WHHL) is an homozygous FH model which also seems to retain the capacity of clearing intestinal lipoproteins [57].…”

Blockade of the α2‐Macroglobulin Receptor/Low‐Density‐Lipoprotein‐Receptor‐Related Protein on Rat Liver Parenchymal Cells by the 39‐kDa Receptor‐Associated Protein Leaves the Interaction of β‐Migrating very‐Low‐Density Lipoprotein with the Lipoprotein Remnant Receptor Unaffected

“…In contrast, Kita et al (1982) found no uptake of abnormal lipoprotein remnants in the Watanabe heritable hyper-lipidaemic rabbit, an animal with dysfunctional LDL receptors. Similarly in humans, the lack of LDL receptors does not lead to a pathological change in the metabolism of dietary fat (Rubinsztein et al, 1990).…”