Subclasses of low-density lipoprotein and very low-density lipoprotein in familial combined hyperlipidemia: relationship to multiple lipoprotein phenotype.

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 (n=72) were analyzed for LDL size by gradient gel electrophoresis. Pattern B LDL (sd LDL, particle size <258 A) and pattern A LDL (buoyant LDL, particle size > or =258 A) 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, n=7) 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. CONCLUSIONS: The present observations underscore the importance of the VLDL triglyceride metabolic pathway in FCHL as an important determinant of the phenotypic heterogeneity of the disorder.

Lipoprotein secretion by intestinal Caco-2 cells is affected differently by trans and cis unsaturated fatty acids: effect of carbon chain length and position of the double bond.

The effects of trans fatty acids on intestinal lipoprotein secretion were determined in polarized Caco-2 cells. Palmitic acid (16:0), palmitoleic acid (c-16:1delta9), and palmitelaidic acid (t-16:1delta9), as well as stearic acid (18:0), oleic acid (c-18:1delta9), c-vaccenic acid (c-18:1delta11), elaidic acid (t-18:1delta9), and t-vaccenic acid (t-18:1delta11) were studied. Compared with 18:0 (control), c- and t-18:1delta9 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-18:1delta11 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 C16 fatty acids were not comparable: t-16:1delta9 did not affect triacylglycerol and apo B secretion (compared with 16:0, as control) whereas c-16:1delta9 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.

Participation of the microsomal triglyceride transfer protein in lipoprotein assembly in Caco-2 cells: interaction with saturated and unsaturated dietary 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 mM 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 mm 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 < 1.006 g/ml).