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...

The effects of trans fatty acids on intestinal lipoprotein secretion were determined in polarized Caco-2 cells. Palmitic acid (16:0), palmitoleic acid (c-16:1⌬9), and palmitelaidic acid (t-16:1⌬9), as well as stearic acid (18:0), oleic acid (c-18:1⌬9), c-vaccenic acid (c-18:1⌬11), elaidic acid (t-18:1⌬9), and t-vaccenic acid (t-18:1⌬11) were studied. Compared with 18:0 (control), c-and t-18:1⌬9 increased triacylglycerol secretion (2.7-and 3.6-fold, respectively) as well as apolipoprotein (apo) B-48 and apo B-100 secretion (both 1.6-fold compared with 18:0); c-and t-18:1⌬11 caused a modest 1.7-fold increase in triacylglycerol secretion with no significant effect on secretion of apo B. Thus, the position of the double bond in the 18:1 isomers, but not its geometrical configuration, affected lipoprotein secretion by Caco-2 cells. In contrast, the effects of the geometrical isomers (cis and trans) of C 16 fatty acids were not comparable: t-16:1⌬9 did not affect triacylglycerol and apo B secretion (compared with 16:0, as control) whereas c-16:1⌬9 was a potent stimulator of secretion of triacylglycerol (2.4-fold higher than 16:0), apo B-48 (1.3-fold higher than 16:0), and apo B-100 (1.5-fold higher than 16:0). We conclude that the carbon chain length of fatty acids, as well as the position of double bonds and their stereochemical configuration, are important determinants of the unique effects of various species of dietary trans fatty acids on lipoprotein secretion and composition in Caco-2 cells.Am J Clin Nutr 1998;68:561-7. KEY WORDSIntestine, apolipoprotein B, Caco-2 cells, cis fatty acids, trans fatty acids, lipoproteins, diet, triacylglycerol, chylomicrons, in vitro study INTRODUCTIONSynthesis of chylomicrons in the enterocyte represents the initial step in the cascade of metabolic events that connects dietary fat intake with plasma lipid and lipoprotein profiles and the possible development of coronary artery disease (CAD) (1, 2). Postprandial lipemia is determined by the contribution of chylomicrons containing triacylglycerol from dietary sources as well as that of VLDLs that carry liver-derived triacylglycerols. Various dietary fatty acids are known to have specific effects on plasma triacylglycerol concentrations (3, 4), reflecting interference with intestinal chylomicron assembly and metabolism. One specific class of dietary fatty acids that has received growing attention in the past decades is that of the trans fatty acids. trans Fatty acids are known to cause changes in plasma lipids and lipoprotein phenotypes, but the mechanisms involved are unknown. The major dietary sources of trans fatty acids are partly hydrogenated vegetable oils, mainly elaidic acid (t-18:1⌬9). Additional sources are animal and dairy fats [palmitelaidic acid (t-16:1⌬9) and tvaccenic acid (t-18:1⌬11)] and partly hydrogenated fish oils (very-long-chain trans fatty acids, ie, > C 22 ). Because humans cannot synthesize trans fatty acids (5, 6), all trans fatty acids are derived from nutritional sources. Dietary trans fatty acids ...

This study was designed to gain insight into the role of microsomal triglyceride transfer protein (MTP) in the association of apolipoprotein (apo) B with lipid during intestinal lipoprotein assembly. The MTP-inhibiting compound BMS-200150 (Jamil et al. 1996. Proc. Natl. Acad. Sci. USA 93: 11991-11995) was used to inhibit the lipid transfer activity of MTP in Caco-2 cells. MTP inhibition reduced the number of apoB-containing lipoproteins that were secreted from the cells. Secretion of apoB-100 appeared to be more sensitive to BMS-200150 than apoB-48 secretion, which appeared to be relatively insensitive. BMS-200150 caused a decrease in the triglyceride content of the secreted lipoproteins, compared with control incubations without MTP inhibition. This indicated that, in Caco-2 cells, MTP is not only involved in the first step of lipoprotein synthesis, i.e., the rescue of apoB from intracellular degradation through early lipidation of the protein, but also in further steps involving the association of lipoproteins with triglycerides. When 0.5 m M oleic acid (18:1) was used to stimulate cellular lipid synthesis, secreted lipoproteins were predominantly of chylomicron/VLDL density and their secretion could be efficiently inhibited with BMS-200150. With 0.5 m M palmitic acid (16:0), lipoproteins of distinct densities (i.e., chylomicron/VLDL and IDL/LDL) were secreted by Caco-2 cells, as reported before (van Greevenbroek et al. 1995. J. Lipid Res. 36: 13-24). Secretion of the lipoproteins at chylomicron/VLDL density was strongly reduced by inhibition of MTP activity by BMS-200150, whereas the IDL/LDL density lipoproteins were relatively insensitive.In conclusion, specific inhibition of MTP activity in Caco-2 cells with BMS-200150 resulted in reduced secretion of apoB-containing lipoproteins (predominantly apoB-100) by Caco-2 cells and furthermore reduced the triglyceride content of these lipoproteins. MTP inhibition preferentially reduced the secretion of triglyceride-rich lipoproteins (d Ͻ 1.006 g/ml).-van Greevenbroek, M. M. J., M. G. Robertus-Teunissen, D. W. Erkelens, and T. W. A. de Bruin. Participation of the microsomal triglyceride transfer protein in lipoprotein assembly in Caco-2 cells: interaction with saturated and unsaturated dietary fatty acids.

The reduction in the frequency of rejection episodes several months after heart transplantation (HTX) correlates with the development of donor-specific nonresponsiveness. This is reflected in a reduced frequency of donor-specific cytotoxic T cells (CTL) in the peripheral blood. We investigated whether the reduced CTL frequency and the incidence of rejection episodes coincided with a change in the frequency of either IL-2- or IL-4-producing helper T lymphocytes (HTL). We measured the frequency of HTL before and at several time points after HTX in the blood of ten recipients, using limiting dilution analysis for IL-2 and IL-4. In most patients, HTL frequencies dropped immediately after transplantation, but returned to pre-HTX values later after transplantation. No consistent decrease or increase in frequencies was observed long after HTX. In contrast to IL-2, the HTL frequencies for IL-4 before transplantation were significantly higher in patients without post-HTX rejection episodes requiring treatment than in patients with such episodes. This phenomenon was observed for the in vitro responses towards both donor and third-party cells. In conclusion, relatively high frequencies of IL-4-producing T cells may have a beneficial effect on the outcome of human heart transplantation, because they are associated with a reduced incidence of rejection episodes after transplantation.