Delayed chylomicron remnant clearance in subjects with heterozygous familial hypercholesterolaemia

To study the role of the LDL receptor in the clearance of chylomicron remnants in humans.

Chylomicron remnant clearance was studied in five untreated subjects with heterozygous familial hypercholesterolaemia (FH) and nine normolipidaemic controls, by oral retinyl palmitate-fat loading tests. Fasting plasma triglycerides (TG), which are important determinators of chylomicron and remnant clearance, were not significantly different between FH (1.76+/-0.32 mmol L(-1), mean+/-SEM) and controls (1.26+/-0.18 mmol L(-1). Chylomicrons (Sf > 1000) and their remnants (Sf < 1000) were separated by flotation and their clearance was estimated by calculating the area under the 24 h-retinyl palmitate curve (AUC-RP). The factors determining chylomicron and remnant clearance were studied by univariate and multiple regression analysis.

Triglyceride clearance in plasma, Sf > 1000 fractions and Sf < 1000 fractions was not significantly different between FH subjects and controls. In subjects with heterozygous FH, chylomicron remnant clearance was two-fold delayed (AUC-RP, 49.39+/-11.61 h.mg L(-1) compared to controls (27.45+/-3.95 h.mg L(-1); P = 0.048). Moreover, 28.4% higher fasting plasma TG in FH resulted in 44.4% higher areas under the remnant-curves compared to controls. The clearance of chylomicron RP was associated to plasma apo E (beta = 0.73, P = 0.011), plasma LDL cholesterol (beta = 0.62, P = 0.018) and plasma TG (beta = 0.58, P = 0.029). The clearance of remnant RP was associated to the diagnosis (FH vs. non-FH), but not to the well-known determinants of remnant clearance like plasma TG.

The clearance of chylomicrons and large remnants isolated in the Sf > fraction depends primarily on the apo B, E (LDL) receptor and to a lesser extent on plasma triglycerides. The clearance of smaller chylomicron remnants isolated in the Sf < 1000 depends to a large extent on the apo B, E (LDL) receptor.