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
The acute, transient effects of moderate exercise on plasma lipoprotein parameters were assessed in 12 healthy, normolipidemic male volunteers subjected to a 5.5-km run at a comfortable pace. The course was completed in 31.5 min (range 23-43 min) and elicited a significant increase in pulse rate and plasma lactate levels and a fall in diastolic blood pressure. Of the plasma lipid parameters, total phospholipid, apo B-associated phospholipid, plasma triglyceride, and free fatty acid levels increased substantially immediately after the run and, except for triglyceride, were still raised 2 h later. Lesser but also significant increases were also noted in high-density lipoprotein-cholesterol (HDL-C), HDL3-C, and HDL-phospholipid concentrations after the run. The increase in HDL-phospholipid persisted for 2 h but the others returned to basal levels. Apolipoprotein Al, lecithin: cholesterol acyltransferase activity, total cholesterol, low-density lipoprotein-cholesterol, and the free cholesterol:cholesterol ester ratio remained essentially unaltered by exercise. The results were compatible with an increased secretion of triglyceride and phospholipid-rich VLDL, followed by the rapid clearance of the triglyceride moiety from the plasma and some redistribution of surface components to the HDL fraction.
The metabolism of low density lipoproteins (LDL) was studied in cultured fibroblasts obtained from five local patients diagnosed, on the basis of clinical features and serum cholesterol concentrations, as having the homozygous form of familial hypercholesterolemia. LDL receptor function was assessed by measuring the binding, internalization, and degradation of 125I-labeled LDL, and by measuring the stimulation of cellular acyl-CoA cholesterol acyltransferase (ACAT) activity which followed exposure to LDL. Fibroblasts from two cases (CF and GM) showed receptor activities which were approximately 10% of the values obtained with normal cells, while ACAT stimulation by LDL was very low. These two patients were classified as homozygous for a receptor-defective abnormality. However, fibroblasts from the other three patients (JG, ES, and TT) showed greater than 25% of normal receptor activity, as assessed by 125I-LDL binding and catabolism. ACAT stimulation by LDL in cells from JG and ES was within the range of values shown by cells previously characterized as heterozygous for a receptor-negative mutation. Cells from ES behaved atypically: a low, but nonsaturable, activation by LDL was evident. ACAT stimulation by LDL was normal in cells from TT. Receptor activities of the cells from the available parents, assessed on the basis of LDL binding and degradation or of ACAT stimulation, were not clearly distinguishable from those of normal cells. These results add to the growing evidence of genetic heterogeneity underlying the clinical picture associated with familial hypercholesterolemia in different geographical distributions.
A previous study of the low density lipoprotein (LDL) receptor gene haplotype distribution in 12 unrelated South African patients with homozygous familial hypercholesterolaemia indicated the existence of several different receptor gene mutations in this patient pool. We have now screened these subjects for large insertion or deletion mutations at their receptor gene loci by restriction fragment size analysis using the Southern blot hybridization technique. We have detected a hitherto undescribed 2.5-kb deletion, which mapped to the central region of the gene, and most likely includes all of exons 7 and 8. The deletion was confined to two of the three so-called coloured individuals in this racially divided sample. Both probands were homozygous for the deletion with a strong possibility of consanguinity in one of the families. Mendelian inheritance was shown in both families and all carriers detected manifested elevated plasma LDL cholesterol levels. The origin of the deletion is unclear but may have been present in the indigenous Khoisan population or have been brought to South Africa by early European or Indonesian settlers.
Summary: Phytosterolaemia (P-sitosterolaemia), a rare, autosomal recessive disorder, has not hitherto been reported in Southern Africa. We report four new homozygous patients, from three unrelated families with significant 1-sitosterolaemia (6.6-11.3%), campesterolaemia (2.2-4.6%) and clearly detectable, though unquantified, levels of cholestanol. Three of the four patients had characteristic cutaneous and tendinous xanthomas within the first decade of life. The fourth patient, a 5 year old, was free of xanthomas despite persistently elevated concentrations of plant sterols in her plasma. All our patients were female bringing the male:female ratio in reported cases to 8:23. All were at or below the 50th percentile for height and weight, and presented at some stage with borderline, hypochromic anaemia associated with red cell abnormalities and thrombocytopaenia. The oldest patient showed suggestive clinical evidence of atherosclerosis affecting her aorta, ileofemoral bifurcation and possibly coronary arteries. All homozygotes responded to a diet restricted in phytosterols and the administration of cholestyramine with falls in plasma sterols of up to 68%.The recent discovery of a possible inherited defect in the synthesis of HMG CoA reductase in patients with phytosterolaemia makes this disorder a model system for studying the biological role ofthis enzyme in regulating the absorption and clearance of sterols other than cholesterol, and the factors governing the sterol composition of cell membranes.
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