Sphingomyelin phosphodiesterase-1 (SMPD1) coding variants do not contribute to low levels of high-density lipoprotein cholesterol.

Background: Niemann-Pick disease type A and B is caused by a deficiency of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. In Niemann-Pick patients, SMPD1 gene defects are reported to be associated with a severe reduction in plasma high-density lipoprotein (HDL) cholesterol.

Methods: Two common coding polymorphisms in the SMPD1 gene, the G1522A (G508R) and a hexanucleotide repeat sequence within the signal peptide region, were investigated in 118 unrelated subjects of French Canadian descent with low plasma levels of HDL-cholesterol (< 5th percentile for age and gender-matched subjects).

Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency.

Mutations in the ABCA1 gene cause defective cellular lipid efflux and severe familial HDL deficiency. We examined the prevalence of mutations at the ABCA1 gene in 58 unrelated probands of French-Canadian descent with HDL deficiency (HDL-C<5th percentile). A defective cellular cholesterol or phospholipid efflux (<75% and <70% of normal controls, respectively) was identified in 14/58 (24%) of subjects.

Effects of fenofibrate on apolipoprotein kinetics in patients with coexisting dysbetalipoproteinemia and heterozygous familial hypercholesterolemia.

Dysbetalipoproteinemia (dysb) and familial hypercholesterolemia (FH) are two genetic disorders giving rise to severe disturbances of lipid homeostasis and premature atherosclerosis. The co-occurrence of both metabolic abnormalities is very rare and is estimated to affect 1 individual per 2,500,000 in the general population. However, the relative contribution of these two dyslipidemias to the combined lipoprotein phenotype is unknown.

Effect of fenofibrate on plasma lipoprotein composition and kinetics in patients with complete hepatic lipase deficiency.

Objective: The goal of this study was to characterize the effect of microcoated fenofibrate (160 mg/day for 6 months) on plasma lipoprotein composition and kinetics in 2 patients with complete hepatic lipase (HL) deficiency.

Methods And Results: Fenofibrate treatment normalized the plasma lipoprotein profile of patients with complete HL deficiency, as evidenced by significant reductions in the plasma concentration of cholesterol (-49%) and triglycerides (-82%) and a significant increase in low-density lipoprotein (LDL) size (251.5+/-1.

Plasma metabolism of apoB-containing lipoproteins in patients with hepatic lipase deficiency.

The metabolism of apoB-containing lipoproteins was investigated in the fasted state in three complete and three partial hepatic lipase (HL)-deficient subjects as well as in seven normotriglyceridemic (NTG) and two hypertriglyceridemic (HTG) controls using a 12 h primed-constant infusion of L-[5,5,5-D(3)]-leucine. Two males with complete HL deficiency had increased plasma pool sizes of VLDL and IDL apoB-100 due to substantial reductions in fractional catabolic rate (FCR) of VLDL and IDL apoB-100 compared with both NTG and HTG controls. Reductions in LDL apoB-100 production rate (PR) were also observed in these two patients compared with NTG and HTG controls.

Evidence that hepatic lipase deficiency in humans is not associated with proatherogenic changes in HDL composition and metabolism.

The aim of the present study was to characterize the composition and metabolism of HDL in subjects with complete hepatic lipase (HL) deficiency. Analyses were carried out in three complete and three partial HL-deficient subjects as well as in eight normotriglyceridemic (NTG) and two hypertriglyceridemic controls. Complete HL deficiency was associated with hypertriglyceridemia and with a 3.

Increased production of VLDL apoB-100 in subjects with familial hypercholesterolemia carrying the same null LDL receptor gene mutation.

Early radiokinetic studies revealed that the classical metabolic defect in patients with familial hypercholesterolemia (FH) is hypocatabolism of LDL due to decreased LDL receptor activity. However, recent studies have suggested that hepatic oversecretion of apolipoprotein B-100 (apoB-100)-containing lipoproteins could also contribute to the markedly elevated plasma concentrations of LDL-cholesterol found in FH. The aim of this study was to examine the kinetics of apoB-100 labeled with a stable isotope (l-[5,5,5-D(3)] leucine) in five normolipidemic controls and in seven well-characterized FH subjects that included six FH heterozygotes and one FH homozygote carrying the same null LDL receptor gene mutation.

Characterization of a novel mutation causing hepatic lipase deficiency among French Canadians.

Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides (TGs) and cholesterol. The aim of the present study was to characterize the molecular defect leading to severe HL deficiency in a Québec-based kindred. In the proband and two of her brothers, the very low to undetectable HL activity resulted from compound heterozygosity for two rare HL gene mutations, a previously unknown missense mutation in exon 5 designated A174T and the previously reported T383M mutation in exon 8 of the HL gene.

Characterization of LDL particle size among carriers of a defective or a null mutation in the lipoprotein lipase gene: the Québec LIPD Study.

Objective: The objective of the present study was to compare the impact of the null P207L and defective D9N mutations in the LPL gene on LDL particle size among heterozygous carriers.

Methods And Results: LDL particle size was measured on whole plasma by 2% to 16% non-denaturing polyacrylamide gradient gel electrophoresis in a cohort of 206 heterozygous carriers of either the P207L or the D9N mutation. The P207L carriers (N=88) presented with a more atherogenic lipoprotein-lipid profile compared with the D9N carriers (N=118).

Determinants of HDL particle size in patients with the null (P207L) or defective (D9N) mutation in the lipoprotein lipase gene: the Québec LipD Study.

The aim of the present study was to examine the impact of the defective D9N and the null P207L mutations in the lipoprotein lipase (LPL) gene on high density lipoprotein (HDL) particle size in relation to specific environmental factors such as obesity, gender and menopausal status. Analyses were carried out in 118 heterozygous carriers of the D9N mutation and 88 heterozygous for the P207L mutation. HDL particle size was measured on whole plasma by non-denaturing 4-30% polyacrylamide gradient gel electrophoresis.