Delayed chylomicron remnant clearance in subjects with heterozygous familial hypercholesterolaemia

Abstract

Objectives. To study the role of the LDL receptor in the clearance of chylomicron remnants in humans. Design. 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 Ϯ 0.32 mmol L Ϫ1 , mean Ϯ SEM) and controls (1.26 Ϯ 0.18 mmol L Ϫ1 ). Chylomicrons (Sf Ͼ 1000) and their remnants (Sf Ͻ 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. Results. Triglyceride clearance in plasma, Sf Ͼ 1000 fractions and Sf Ͻ 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 Ϯ 11.61 h.mg L Ϫ1 ) compared to controls (27.45 Ϯ 3.95 h.mg L Ϫ1 ; 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 (␤ = 0.73, P = 0.011), plasma LDL cholesterol (␤ = 0.62, P = 0.018) and plasma TG (␤ = 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. Conclusions. The clearance of chylomicrons and large remnants isolated in the Sf Ͼ 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 Ͻ 1000 depends to a large extent on the apo B, E (LDL) receptor.

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.…”

“…8 Animal studies have shown that a deficiency in the LDL receptor is associated with a delayed chylomicron remnant removal. 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.…”

Postprandial lipaemia in familial combined hyperlipidaemia

“…Since FCHL and the metabolic syndrome share so many clinical characteristics and metabolic disturbances [5,17,18], it has always been difficult to separate the two disorders. One of the striking differences may be the mode of inheritance and the effects of environmental factors on the expression of the two phenotypes.…”

“…FCHL (familial combined hyperlipidaemia) is the most frequent familial dyslipidaemia resulting in premature atherosclerosis [1][2][3][4][5]. Several reports have suggested that FCHL is a monogenic disorder with different modifying genes [6][7][8].…”

“…The diagnosis of FCHL is based on clinical criteria, such as the presence of 'multiple type hyperlipidaemia' [1][2][3][4][5], a positive family history of premature coronary heart disease and increased plasma apoB levels, reflecting overproduction of VLDL (very-low-density lipoprotein) [12,13]. Other metabolic characteristics in FCHL are impaired chylomicron remnant clearance [14,15], high levels of small, dense LDL (low-density lipoprotein) [16], the presence of insulin resistance [17,18], disturbed postprandial NEFA [non-esterified ('free') fatty acid] metabolism [19,20] and impaired NEFA up- [20], resulting in enhanced NEFA flux to the liver [19,20].…”