L-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study.

Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease. There are currently limited therapeutic options to lower Lp(a) levels. L-Carnitine has been reported to reduce Lp(a) levels. The aim of this study was to compare the effect of L-carnitine/simvastatin co-administration with that of simvastatin monotherapy on Lp(a) levels in subjects with mixed hyperlipidemia and elevated Lp(a) concentration. Subjects with levels of low-density lipoprotein cholesterol (LDL-C) >160 mg/dL, triacylglycerol (TAG) >150 mg/dL and Lp(a) >20 mg/dL were included in this study. Subjects were randomly allocated to receive L-carnitine 2 g/day plus simvastatin 20 mg/day (N = 29) or placebo plus simvastatin 20 mg/day (N = 29) for a total of 12 weeks. Lp(a) was significantly reduced in the L-carnitine/simvastatin group [-19.4%, from 52 (20-171) to 42 (15-102) mg/dL; p = 0.01], but not in the placebo/simvastatin group [-6.7%, from 56 (26-108) to 52 (27-93) mg/dL, p = NS versus baseline and p = 0.016 for the comparison between groups]. Similar significant reductions in total cholesterol, LDL-C, apolipoprotein (apo) B and TAG were observed in both groups. Co-administration of L-carnitine with simvastatin was associated with a significant, albeit modest, reduction in Lp(a) compared with simvastatin monotherapy in subjects with mixed hyperlipidemia and elevated baseline Lp(a) levels.

Dietary fat clearance in type V hyperlipoproteinaemia secondary to a rare variant of human apolipoprotein E: the apolipoprotein E3 (Arg 136-->Ser)

This present case report describes two siblings with severe type V hyperlipoproteinaemia, diagnosed very early in life and due to the combination of the common apolipoprotein (Apo) E2 allele and rare mutant variant of ApoE, ApoE3 (Arg 136-->Ser). Phenotyping of ApoE falsely identified E2/E2 phenotype. The presence of mutated ApoE was suspected on an unusual restriction polymorphism of a Hha 1 restriction site and confirmed by sequence analysis of the cloned polymerase chain reaction fragment of exon 4 and familial segregation study. The severity of the hypertriacylglycerolaemia was modulated by the lipid content of the diet. A low-fat diet enriched in medium-chain triacylglycerol (TAG) decreased but did not normalize plasma TAG levels in both affected patients of the pedigree. A standardized lipid-enriched test meal showed a marked impairment of TAG-rich lipoprotein (TRL) clearance, especially the exogeneous TRL bearing ApoB-48 which still represented 79% of total TRL 7 h after the fat load. Finally, differences between the male and female siblings with the existence of a consanguine relationship in their parents suggested the involvement of other genetic factors in modulating the severity of phenotypic expression. This observation reinforces the usefulness of genotyping of ApoE for the characterization of genetic hypertriacylglycerolaemia and selection of the appropriate diet and treatment.

Xantomas: marcadores cutáneos de hiperlipidemias / Xanthomas: Cutaneous markers of hyperlipidemias

Se presenta una revisión sobre los xantomas cutáneos enfatizando su importancia como marcadores de padecimientos sistémicos principalmente de la hiperlipoproteinemias primarias y secundarias. Existe una estrecha relación entre el trastorno metabólico y tipo de lípido sérico elevado con las diferentes variedades de xantomas. Se destaca la necesidad del diagnóstico temprano de la dislipidemias por el riesgo de la enfermedad coronaria aterosclerosa en pacientes jóvenes

Hypertriglyceridemia: severe type V hyperlipidemia in a young woman.

We present a patient with the typical clinical and biochemical features of severe Type V hyperlipidemia associated with alcohol consumption and estrogen use. Prompt medical intervention resulted in normalization of her lipid profile. We review the lipoprotein composition, the role of lipoproteins in lipid transport with special emphasis on triglycerides, and the clinical features, pathogenesis, and management of Type V hyperlipidemia.

Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity.

Homozygosity for the apolipoprotein (apo) E variant apoE2(158 Arg----Cys) invariably gives rise to dysbetalipoproteinemia, and when associated with obesity or a gene for hyperlipidemia, results in type III hyperlipoproteinemia. The association of the E2/2 phenotype with type IV/V hyperlipoproteinemia rather than type III hyperlipoproteinemia in identical twin brothers led us to investigate the primary structure of their apoE. Lipoprotein electrophoresis on agarose gels confirmed the presence of increased very low density lipoproteins (VLDL) and chylomicrons but little, if any, beta-VLDL, indicating that these subjects did not have dysbetalipoproteinemia. When the apoE from these twins was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis on a system that can distinguish apoE2(158 Arg----Cys) from all other known apoE variants, it gave rise to two components. One had the unique mobility of apoE2(158 Arg----Cys), and one migrated in the position of the other variants of apoE (and normal apoE3), indicating that the brothers were heterozygous for apoE2(158 Arg----Cys) and a second apoE2 isoform. Cysteamine modification and isoelectric focusing showed that, like apoE2(158 Arg----Cys), the second apoE2 isoform also contained two cysteine residues. The structural mutation in the second apoE2 isoform was determined by peptide sequencing. Like normal apoE3, this variant had arginine at position 158, but differed from apoE3 by the substitution of cysteine for arginine at position 228. Total apoE isolated from the brothers had the same receptor-binding activity in a competitive binding assay as a 1:1 mixture of normal apoE3 and apoE2(158 Arg----Cys).(ABSTRACT TRUNCATED AT 250 WORDS)

A case of hypopituitarism and type V hyperlipidemia.

A 29-year-old woman developed hypopituitarism following removal of a pituitary chromophobe adenoma, and this was complicated by type V hyperlipidemia and obesity.

The pathogenesis of hyperlipoproteinaemia.

The hyperlipoproteinaemias are among the most commonly encountered metabolic derangements seen in clinical practice, and are important because of their frequent association with atherosclerotic vascular disease. Although their underlying biochemical defects are not yet completely elucidated, sufficient comprehension of normal lipoprotein metabolism has now been acquired to permit us to ascribe mechanisms to these clinical conditions as we know them. This article briefly summarises the plasma lipoprotein transport system and classifies the major primary lipoprotein disorders according to current understanding of the pathological changes responsible for their presentation.

Dual defect in metabolism of very-low-density lipoprotein triglycerides. Patients with type 5 hyperlipoproteinemia.

Transport of very-low-density lipoprotein (VLDL) triglycerides (TGs) were studied in eight patients with type 5 hyperlipoproteinemia (HLP). Results were compared to those from patients with type 4 HLP. Type 4 patients had either overproduction of VLDL TGs (nine patients) or defective clearance of VLDL TGs (eight patients). Patients with type 5 HLP were found to have increased production rates of VLDL TG, but also reduced fractional catabolic rates of VLDL TGs. Synthesis rates of VLDL TGs in type 5 were similar to those in type 4 patients with overproduction of VLDL TGs. The mean fractional catabolic rate in patients with type 5 HLP also were similar to those of type 4 patients with defective clearance. This study demonstrates that in most patients with type 5 HLP there is a dual defect in TG metabolism--overproduction of VLDL TGs and a clearance defect for TG-rich lipoproteins.

Hypertriglyceridemic very low density lipoproteins induce triglyceride synthesis and accumulation in mouse peritoneal macrophages.

Triglyceride-rich lipoproteins may be responsible for the lipid accumulation in macrophages that can occur in hypertriglyceridemia. Chylomicrons and very low density lipoproteins (VLDL, total and with flotation constant [S(f)] 100-400) from fasting hypertriglyceridemic subjects induced a massive accumulation of oil red O-positive inclusions in unstimulated peritoneal macrophages. Cell viability was not affected. The predominant lipid that accumulated in cells exposed to hypertriglyceridemic VLDL was triglyceride. Hypertriglyceridemic VLDL stimulated the incorporation of [(14)C]oleate into cellular triglyceride up to ninefold in 16 h, but not into cholesteryl esters. Mass increase in cellular triglyceride was 38-fold. The stimulation of cellular triglyceride formation was dependent on time, temperature, and concentration of hypertriglyceridemic VLDL. By contrast, VLDL, low density, and high density lipoproteins from fasting normolipemic subjects had no significant effect on oleate incorporation into neutral lipids or on visible lipid accumulation.(125)I-Hypertriglyceridemic VLDL (S(f) 100-400) were degraded by macrophages in a dose-dependent manner, with 50 and 100% saturation observed at 3 and 24 mug protein/ml (2.5 and 20 nM), respectively. Hypertriglyceridemic VLDL inhibited the internalization and degradation of (125)I-hypertriglyceridemic VLDL (4 nM) by 50% at 3 nM. Cholesteryl ester-rich VLDL from cholesterol-fed rabbits gave 50% inhibition at 5 nM. Low density lipoproteins (LDL) inhibited by 10% at 5 nM and 40% at 47 nM. Acetyl LDL at 130 nM had no effect. We conclude that the massive triglyceride accumulation produced in macrophages by hypertriglyceridemic VLDL is a direct consequence of uptake via specific receptors that also recognize cholesteryl ester-rich VLDL and LDL but are distinct from the acetyl LDL receptor. Uptake of these triglyceride-rich lipoproteins by monocyte-macrophages in vivo may play a significant role in the pathophysiology of atherosclerosis.

Kinetic bases of the primary hyperlipidaemias: studies of apolipoprotein B turnover in genetically defined subjects.

Autologous 131I-labelled very low density lipoprotein (VLDL) and 125I-labelled low density lipoprotein (LDL) were injected into seven normal subjects and into forty-three hyperlipidaemic patients, classified into groups on the basis of family studies and clinical findings, to quantitate VLDL and LDL apolipoprotein B kinetics. In normal subjects, mean VLDL-B peptide synthetic rate was 15 . 1 mg kg-1 day-1, mean LDL-B peptide synthetic rate 7 . 7 mg kg-1 day-1 and mean LDL-B fractional catabolic rate (FCR) 0 . 31 day-1. In heterozygous familial hypercholesterolaemia (n = 14) VLDL-B peptide production was normal in patients with normal triglyceride levels; in those with high triglyceride levels there was either VLDL overproduction or a catabolic defect. LDL-B peptide synthetic rates ranged from high normal to increased (8 . 5--18 . 0 mg kg-1 day-1) and LDL-B peptide FCR values were markedly reduced (0 . 14--0 . 28 day-1) confirming the presence of a defect in LDL catabolism but indicating over-production as well. In familial combined hyperlipidaemia (n = 11) VLDL-B peptide production ranged from normal to elevated (13 . 9--44 . 4 mg kg-1 day-1, mean 23 . 8 mg kg-1 day-1) correlating with the VLDl triglyceride level (i.e. with the phenotypic expression of the disorder). LDL-B peptide production ranged from high normal to markedly increased (8 . 9--19 . 5 mg kg-1 day-1, mean 12 . 2 mg kg-1 day-1) and correlated with LDL cholesterol levels (i.e. the phenotype), (r = +0 . 66, P < 0 . 05). Three patients with unclassified hypercholesterolaemia had increased LDL-B peptide synthetic rates. One patient with remnant hyperlipoproteinaemia (type III) had a high normal VLDL-B peptide synthetic rate, 17 . 3 mg kg-1 day-1, and a strikingly low FCR of VLDL-B. In familial hypertriglyceridaemia (three patients) there was a low VLDL-B peptide FCR. In unclassified hypertriglyceridaemia VLDL over-production was the finding in seven patients but four patients appeared to have catabolic defects only. Overall there were significant hyperbolic relationships between VLCL-B peptide FCR and VLDL-B peptide concentration (r = -0 . 78, P < 0 . 001, for the log/log relationship) and between LDL-B peptide FCR and LDL cholesterol (r = -0 . 88, P < 0 . 001 for the log/log relationship.)

Hypertriglyceridaemia associated with an abnormal triglyceride-rich lipoprotein carrying excess apolipoprotein C-III-2.

Two men aged 48 and 35 years with severe hypertriglyceridaemia, glucose intolerance, and a secondary anaemia had more apolipoprotein C-III-2 and less apo C-III-1 on their triglyceride-rich lipoproteins (d less than 1.006) than did types IV or V lipaemic controls. Although the patients' abnormal lipoproteins seemed to produce normal activation of lipoprotein lipase, they did not serve as an efficient substrate for purified lipoprotein lipase. Adipose tissue of case 1 had considerable lipoprotein-lipase activity and the hypertriglyceridaemia responded to dietary therapy (carbohydrate 180 g, fat 80 g, protein 60 g per day, and no alcohol). The haemolytic anaemia improved, but the patient remained glucose intolerant. The abnormal content of apo C-III-2 on the triglyceride-rich lipoproteins, rendering them resistant to clearance by lipoprotein lipase, is believed to have contributed to the patients' severe hypertriglyceridaemia.