Subclasses of Low-Density Lipoprotein and Very Low-Density Lipoprotein in Familial Combined Hyperlipidemia: Relationship to Multiple Lipoprotein Phenotype

Abstract

Objective-The present study addresses the presence of distinct metabolic phenotypes in familial combined hyperlipidemia (FCHL) in relation to small dense low-density lipoprotein (sd LDL) and very low-density lipoprotein (VLDL) subclasses. Methods and Results-Hyperlipidemic FCHL relatives (nϭ72) were analyzed for LDL size by gradient gel electrophoresis. Pattern B LDL (sd LDL, particle size Ͻ258 Å) and pattern A LDL (buoyant LDL, particle size Ն258 Å) were defined. Analyses showed bimodal distribution of LDL size associated with distinct phenotypes. Subjects with predominantly large, buoyant LDL showed a hypercholesterolemic phenotype and the highest apo B levels. Subjects with predominantly sd LDL showed a hypertriglyceridemic, low high-density lipoprotein (HDL) cholesterol phenotype, with moderately elevated apoB, total cholesterol level, and LDL cholesterol level. Subjects with both buoyant LDL and sd LDL (pattern AB, nϭ7) showed an intermediate phenotype, with high normal plasma triglycerides. VLDL subfraction analysis showed that the sd LDL phenotype was associated with a 10-times higher number of VLDL1 particles of relatively lower apo AI and apo E content, as well as smaller VLDL2 particles, in combination with increased plasma insulin concentration in comparison to pattern A. Key Words: sd LDL Ⅲ apolipoprotein B Ⅲ triglycerides Ⅲ insulin resistance Ⅲ VLDL F amilial combined hyperlipidemia (FCHL) is a metabolic disease, delineated as a genetic disorder of lipid metabolism almost 3 decades ago. 1 It is associated with a 2-to 5-fold increased risk of premature coronary artery disease. 1,2 Despite recent progress, the genetic and metabolic backgrounds of FCHL have not been elucidated in detail. Subjects with FCHL present with a complex phenotype whose expression is influenced by genetic, metabolic, and environmental factors. [3][4][5][6] Affected FCHL relatives are viscerally obese, 2,4,7 hyperinsulinemic, 3 insulin-resistant, 5,7 and can show a number of abnormalities in lipid metabolism: hypercholesterolemia and/or hypertriglyceridemia, elevated apolipoprotein B (apoB) levels, small dense low-density lipoprotein (sd LDL), and decreased plasma high-density lipoprotein (HDL) cholesterol concentrations. Conclusions-TheVery low-density lipoprotein (VLDL) and LDL consist of distinct, physicochemically heterogenic subclasses. 8 A practical characterization of the LDL profile divides it into two major phenotypes: pattern A, characterized by a preponderance of large, buoyant particles, with peak particle diameter Ն258 Å, and pattern B, characterized by predominance of sd LDL particles, with peak particle diameter Ͻ258 Å. In the population, sd LDL phenotype and the concurrent metabolic abnormalities (relative hypertriglyceridemia and low HDL cholesterol) have been designated the atherogenic lipoprotein phenotype, 9 consistent with its association with an increased risk of coronary artery disease. 9,10 Furthermore, pattern B LDL has been recognized as a feature of the metabolic syndrome 11 and is characteristic for i...

Characterization of metabolic interrelationships and in silico phenotyping of lipoprotein particles using self-organizing maps

“…These fi ndings are also in line with studies showing that the delipidation of large VLDL can produce low levels of LDL ( 37 ) and that large VLDL is related to small dense LDL ( 32,38,39 ). In addition, the small dense LDL phenotype has been linked to increased production and decreased catabolism of VLDL particles ( 40 ).…”

“…It has been reported that small dense and large LDL particle distributions do not differ in plasma LDL-C concentration ( 30,31 ). On the other hand, large LDL particles have been connected to higher LDL-C concentrations than the predominance of small LDL particles ( 32 ). The binding of LDL particles to the LDL receptor has been shown to be reduced with dense as well as large LDL compared with LDL with intermediate particle sizes ( 33 ), indicating that Figs.…”

LDL particle size, fat distribution and insulin resistance in obese children

“…Therefore, it may be a good diagnostic criterion for FCHL (Working Committee on JAS Guideline for Diagnosis and Treatment of Hyperlipidemias, 2002). However, it was reported that hyperlipidemic FCHL subjects showed a bimodal distribution of LDL size, corresponding to distinct phenotypes (Georgieva et al, 2004). Subjects with nonsdLDL showed type IIa hyperlipidemia and high apoB levels.…”

Quantitative Trait Loci for Apolipoprotein B, Cholesterol, and Triglycerides in Familial Combined Hyperlipidemia Pedigrees

“…The putative gene in this region may have a pleiotropic effect on increased total serum cholesterol and apoB within FCHL pedigrees. In addition, VLDL subclasses have direct impacts on the plasma concentrations of LDL subclasses in FCHL, specifically VLDL1 and small dense LDL, 30 suggesting a VLDL-triglyceride pathway in FCHL. What is known about its biochemistry corresponds well with linkage and association results for apoA-CIII-AIV, apoAII, and apoB in FCHL.…”

“…What is known about its biochemistry corresponds well with linkage and association results for apoA-CIII-AIV, apoAII, and apoB in FCHL. 30 The USF-1 gene may also act in the VLDL-triglyceride pathway by stimulating lipogenesis, by fatty acid synthase, for export in VLDL, apoB, cholesterol, and triglycerides. 31 17q11 contains the gene for NOS2A, the inducible nitric oxide synthase, which we found to be downregulated in adipose tissue biopsy samples from FCHL subjects in comparison with age-, sex-, and body mass index-matched controls (data not shown).…”