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Lipoprotein Response to Diets High in Soy or Animal Protein With and Without Isoflavones in Moderately Hypercholesterolemic Subjects
- Alice H. Lichtenstein,
- Susan M. Jalbert,
- Herman Adlercreutz,
- Barry R. Goldin,
- Helen Rasmussen,
- Ernst J. Schaefer and
- Lynne M. Ausman
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 22, Issue 111 November 2002

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Objective— The objective of this study was to assess the independent effect of soy relative to common sources of animal protein and soy-derived isoflavones on blood lipids.Methods and Results— Forty-two subjects with LDL cholesterol levels ≥3.36 mmol/L were fed each of four diets in randomized order for 6 weeks per phase. Diets contained a minimum of 25 g animal protein or isolated soy protein/4.2 MJ, with each containing trace amounts or 50 mg of isoflavones/4.2 MJ. Soy protein had a modest effect on total, LDL and HDL cholesterol, and triglyceride concentrations (−2%, P=0.017; −2%, P=0.042; +3%; P=0.034, −11%, P<0.001, respectively). Soy protein had no significant effect on plasma lipids in individuals with LDL cholesterol <4.14 mmol/L and significantly reduced total and LDL cholesterol and triglyceride concentrations in individuals with LDL cholesterol ≥4.14 mmol/L (−4%, P=0.001; −5%, P=0.003; −15%, P<0.001, respectively). No significant effect of isoflavones on plasma lipid levels was observed either constituent to the soy protein or supplemental to the animal protein.Conclusions— Although potentially helpful when used to displace products containing animal fat from the diet, the regular intake of relatively high levels of soy protein (>50 g/day) had only a modest effect on blood cholesterol levels and only in subjects with elevated LDL cholesterol levels (≥4.14 mmol/L). Soy-derived isoflavones had no significant effect.
Apolipoprotein A5, a Newly Identified Gene That Affects Plasma Triglyceride Levels in Humans and Mice
- Len A. Pennacchio and
- Edward M. Rubin
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 23, Issue 41 April 2003

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Apolipoprotein A5 (APOA5) is a newly described member of the apolipoprotein gene family whose initial discovery arose from comparative sequence analysis of the mammalian APOA1/C3/A4 gene cluster. Functional studies in mice indicated that alteration in the level of APOA5 significantly affected plasma triglyceride concentrations. Mice that overexpressed human APOA5 displayed significantly reduced triglycerides, whereas mice that lacked apoa5 had a large increase in this lipid parameter. Studies in humans have also suggested an important role for APOA5 in determining plasma triglyceride concentrations. In these experiments, polymorphisms in the human gene were found to define several common haplotypes that were associated with significant changes in triglyceride concentrations in multiple populations. Several separate clinical studies have provided consistent and strong support for the effect with 24% of whites, 35% of blacks, and 53% of Hispanics who carry APOA5 haplotypes associated with increased plasma triglyceride levels. In summary, APOA5 represents a newly discovered gene involved in triglyceride metabolism in both humans and mice whose mechanism of action remains to be deciphered.
Small, Dense LDL and Elevated Apolipoprotein B Are the Common Characteristics for the Three Major Lipid Phenotypes of Familial Combined Hyperlipidemia
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 23, Issue 71 July 2003

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Objective— Familial combined hyperlipidemia (FCHL) is associated with variable lipid and lipoprotein phenotypes arbitrarily defined as type IIa, IIb, and IV based on plasma total cholesterol and triglyceride levels. This study sought to characterize consistent lipoprotein and lipid abnormalities across the 3 lipoprotein phenotypes in 62 patients with documented FCHL (IIa [n=14], IIb [n=19], and IV [n=29]) and 44 healthy individuals.Methods and Results— The lipoprotein cholesterol distribution was determined over 38 fractions obtained by density gradient ultracentrifugation. As expected, FCHL patients with hypertriglyceridemia (IIb and IV) had higher cholesterol levels in VLDL than IIa, whereas IIa showed higher cholesterol in the big, buoyant LDL and in HDL. LDL cholesterol was higher in IIb than IV; most of the increase in LDL cholesterol was associated with big, buoyant LDL rather than small, dense LDL (sdLDL). The differences in lipoproteins between phenotypes were attributable to changes in VLDL and big, buoyant LDL levels. Comparison of the FCHL patients with healthy individuals showed a significant elevation in plasma apolipoprotein B levels and sdLDL in all 3 FCHL phenotypes.Conclusions— Although triglyceride and cholesterol levels are variable by lipoprotein phenotype, sdLDL and elevated plasma apolipoprotein B levels are consistent characteristics of FCHL shared by the 3 different lipoprotein phenotypes.
Analysis of Apolipoprotein A5, C3, and Plasma Triglyceride Concentrations in Genetically Engineered Mice
- Nadine Baroukh,
- Eric Bauge,
- Jennifer Akiyama,
- Jessie Chang,
- Veena Afzal,
- Jean-Charles Fruchart,
- Edward M. Rubin,
- Jamila Fruchart-Najib and
- Len A. Pennacchio
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 24, Issue 71 July 2004

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Objective— Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are strongly altered by changes in the expression of either of these 2 genes. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. These similar findings raised the issue of the relationship between these 2 genes and altered triglycerides.Methods and Results— To address this issue, we generated independent lines of mice that either overexpressed (“double transgenic”) or completely lacked (“double knockout”) both apolipoprotein genes. We report that both “double transgenic” and “double knockout” mice display normal triglyceride concentrations compared with overexpression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the “double transgenic” mice are ≈500-fold lower than human ApoCIII levels, supporting ApoAV as a potent triglyceride modulator despite its low concentration.Conclusions— Together, these data support that APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner.To address the relationship between the apolipoprotein A5 and C3 genes, we generated independent lines of mice that either overexpressed or completely lacked both genes. We report both lines display normal triglyceride concentrations compared with overexpression or deletion of either gene alone. Together, these data support that APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner.
Variation in the Lamin A/C Gene: Associations With Metabolic Syndrome
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 24, Issue 91 September 2004

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Objective— Metabolic syndrome is associated with increased risk for cardiovascular disease and type 2 diabetes mellitus (T2DM). The lamin A/C (LMNA) gene, mutations of which cause rare syndromes of severe insulin resistance and dyslipidemia, is located on chromosome 1q21-q24, a region linked to T2DM in several genome wide scans, including in the Old Order Amish. To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components.Methods and Results— We performed DNA sequence analysis of LMNA. Six single-nucleotide polymorphisms (SNPs) were identified: c.141889C>T (intron 3), c.141906G>T (intron 3), A287A (c.141253T>C; exon 5), c.140353G>A (intron 6), c.139418C>T (intron 8), and H566H (c. 138747C>T; exon 10). In 971 participants from the Amish Family Diabetes Study, the H566H polymorphism of LMNA was associated with metabolic syndrome diagnosed according to National Cholesterol Education Program ATP III criteria and also higher mean fasting triglyceride and lower mean high-density lipoprotein-cholesterol concentrations. However, no differences in allele frequencies were observed for any SNP among participants with T2DM or impaired glucose homeostasis (IGH) and normoglycemic controls. Haplotype analysis showed that >87% of individuals carried 1 of 2 common LMNA haplotypes. There were no significant differences in haplotype frequencies among subjects with metabolic syndrome T2DM, IGH, and controls.Conclusion— Sequence variation in LMNA may confer modest susceptibility for development of metabolic syndrome and dyslipidemia in the Amish.To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components, we performed DNA analysis of polymorphisms in LMNA. The H566H polymorphism was associated with metabolic syndrome and also higher mean fasting triglyceride and lower mean HDL-cholesterol concentrations in the Old Order Amish.
Identification of Unique Lipoprotein Subclasses for Visceral Obesity by Component Analysis of Cholesterol Profile in High-Performance Liquid Chromatography
- Mitsuyo Okazaki,
- Shinichi Usui,
- Masato Ishigami,
- Naohiko Sakai,
- Tadashi Nakamura,
- Yuji Matsuzawa and
- Shizuya Yamashita
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 25, Issue 31 March 2005

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Objective— The contribution of visceral fat accumulation to the development of coronary heart disease was previously reported, but the relation between visceral fat accumulation and serum lipoprotein subclasses was unknown.Methods and Results— We examined the relation of lipoprotein subclasses with visceral fat accumulation in 62 male subjects (aged 22 to 67 years) with visceral fat syndrome or obesity. Cholesterol levels in very low–density, low-density, and high-density lipoprotein subclasses (VLDL, LDL, and HDL) were determined by computer-assisted high-performance liquid chromatography. Subcutaneous fat area and visceral fat area were measured by computed tomographic scanning. There was no significant correlation between the subcutaneous fat area and the cholesterol levels in all lipoprotein subclasses. In contrast, the visceral fat area was correlated positively (P<0.002) with VLDL and LDL subclasses, except for large LDL, but negatively (P<0.001) with those in large and medium HDL subclasses. The observed positive correlations of small and very small LDL subclasses remained significant (P<0.005) after adjustment for serum cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol, respectively, but a significant negative correlation (P<0.005) of large LDL was obtained after adjustment for LDL cholesterol.Conclusion— These findings indicate that this simple high-performance liquid chromatography method may be applied for easy detection and evaluation of abnormal distribution of lipoprotein subclasses.Different contribution of visceral fat accumulation to each of the lipoprotein subclasses was clearly demonstrated in men with visceral fat accumulation. The high-performance liquid chromatography method described in this study might therefore be a useful tool.
Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans
- John S. Millar,
- Margaret E. Brousseau,
- Margaret R. Diffenderfer,
- P. Hugh,
- R. Barrett,
- Francine K. Welty,
- Aisha Faruqi,
- Megan L. Wolfe,
- Chorthip Nartsupha,
- Andres G. Digenio,
- James P. Mancuso,
- Gregory G. Dolnikowski,
- Ernst J. Schaefer and
- Daniel J. Rader
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 26, Issue 61 June 2006

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Objective— Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins.Methods and Results— Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production.Conclusions— These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.The CETP inhibitor torcetrapib reduces apoB-containing lipoproteins in plasma. Torcetrapib alone reduces VLDL, IDL, and LDL apoB100 pool size primarily through increased apoB100 clearance. In contrast, addition of torcetrapib to background treatment with atorvastatin was associated with enhanced VLDL apoB100 clearance and reduced production of IDL and LDL apoB100.
Hyperinsulinemia Is Associated With Increased Production Rate of Intestinal Apolipoprotein B-48–Containing Lipoproteins in Humans
- Hélène Duez,
- Benoît Lamarche,
- Kristine D. Uffelman,
- René Valero,
- Jeffrey S. Cohn and
- Gary F. Lewis
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 26, Issue 61 June 2006

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Objectives— Whereas postprandial hyperlipidemia is a well-described feature of insulin-resistant states and type 2 diabetes, no previous studies have examined intestinal lipoprotein production rates (PRs) in relation to hyperinsulinemia or insulin resistance in humans.Methods and Results— Apolipoprotein B-48 (apoB-48)–containing lipoprotein metabolism was examined in the steady-state fed condition with a 15-hour primed constant infusion of [D3]-l-leucine in 14 nondiabetic men with a broad range of body mass index (BMI) and insulin sensitivity. To examine the relationship between indices of insulin resistance and intestinal lipoprotein PR data were analyzed in 2 ways: by correlation and by comparing apoB-48 PRs in those whose fasting plasma insulin concentrations were above or below the median for the 14 subjects studied (60 pmol/L). ApoB-48 PR was significantly higher in hyperinsulinemic, insulin-resistant subjects (1.73±0.39 versus 0.88±0.13 mg/kg per day; P<0.05) and correlated with fasting plasma insulin concentrations (r=0.558; P=0.038), despite great heterogeneity in apoB-48 kinetic parameters, particularly among the obese subjects. There was no significant difference in clearance of apoB-48 between the 2 groups, nor was there a significant correlation between apoB-48 fractional clearance rate and fasting insulin or homeostasis model assessment-insulin resistance.Conclusions— These are the first human data to conclusively demonstrate that intestinal apoB-48–containing triglyceride-rich lipoprotein PR is increased in hyperinsulinemic, insulin-resistant humans. Intestinal lipoprotein particle overproduction is a newly described feature of insulin resistance in humans.In the present study, we investigated whether intestinal lipoprotein particle production rate is related to indices of insulin resistance in humans. ApoB-48–containing lipoprotein metabolism was examined in 14 nondiabetic men with a broad range of BMI and insulin sensitivity. We demonstrate that intestinal apoB-48–containing TRL production rate is increased in hyperinsulinemic, insulin-resistant humans.
Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor δ Agonist
- Dennis L. Sprecher,
- Christine Massien,
- Greg Pearce,
- Andrew N. Billin,
- Itay Perlstein,
- Timothy M. Willson,
- David G. Hassall,
- Nicolas Ancellin,
- Scott D. Patterson,
- David C. Lobe and
- Tony G. Johnson
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 27, Issue 21 February 2007

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Objectives— Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)δ expression. In parallel, PPARδ agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models.Methods and Results— Healthy volunteers were allocated placebo (n=6) or PPARδ agonist (GW501516) at 2.5 mg (n=9) or 10 mg (n=9), orally, once-daily for 2 weeks while hospitalized and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (P=0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (P=0.02). HDLc was enhanced in both treatment groups (2.5 mg P=0.004, 10 mg P<0.001) when compared with the decrease in the placebo group (−11.5±1.6%, P=0.002). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addition to a 2-fold increase in ABCA1 (P=0.002). However, LpL expression remained unchanged.Conclusions— This is the first report of a PPARδ agonist administered to man. In this small study, GW501516 significantly influenced HDLc and TGs in healthy volunteers. Enhanced in vivo serum fat clearance, and the first demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression, suggests peripheral fat utilization and lipidation as potential mechanisms toward these HDL:TG effects.A specific PPARδ agonist was administered to human volunteers for the first time, revealing a decline in serum TG, an improvement in TG-clearance post-fat feeding, and an elevation in HDLc compared with placebo. Consistent with these findings, in vitro PPARδ-treated human skeletal muscle cells induced fatty acid oxidation, and upregulated ABCA1 expression.
Angiopoietin-Like Protein3 Regulates Plasma HDL Cholesterol Through Suppression of Endothelial Lipase
- Mitsuru Shimamura,
- Morihiro Matsuda,
- Hiroaki Yasumo,
- Mitsuyo Okazaki,
- Kazunori Fujimoto,
- Keita Kono,
- Tetsuya Shimizugawa,
- Yosuke Ando,
- Ryuta Koishi,
- Takafumi Kohama,
- Naohiko Sakai,
- Kazuaki Kotani,
- Ryutaro Komuro,
- Tatsuo Ishida,
- Kenichi Hirata,
- Shizuya Yamashita,
- Hidehiko Furukawa and
- Iichiro Shimomura
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 27, Issue 21 February 2007

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Objectives— A low level of high-density lipoprotein (HDL) in plasma has been recognized as an aspect of metabolic syndrome and as a crucial risk factor of cardiovascular events. However, the physiological regulation of plasma HDL levels has not been completely defined. Current studies aim to reveal the contribution of angiopoietin-like protein3 (angptl3), previously known as a plasma suppressor of lipoprotein lipase, to HDL metabolism.Methods and Results— Angptl3-deficient mice showed low plasma HDL cholesterol and HDL phospholipid (PL), and which were increased by ANGPTL3 supplementation via adenovirus. In vitro, ANGPTL3 inhibited the phospholipase activity of endothelial lipase (EL), which hydrolyzes HDL-PL and hence decreases plasma HDL levels, through a putative heparin-binding site in the N-terminal domain of ANGPTL3. Post-heparin plasma in Angptl3-knockout mice had higher phospholipase activity than did that in wild-type mice, suggesting that the activity of endogenous EL is elevated in Angptl3-deficient mice. Furthermore, we established an ELISA system for human ANGPTL3 and found that plasma ANGPTL3 levels significantly correlated with plasma HDL cholesterol and HDL-PL levels in human subjects.Conclusions— Angptl3 acts as an inhibitor of EL and may be involved in the regulation of plasma HDL cholesterol and HDL-PL levels in humans and rodents.Current studies investigated the potential involvement of angptl3, previously known as a plasma suppressor of lipoprotein lipase, in HDL metabolism and its effects on endothelial lipase (EL) activity. The results suggest that angptl3 should be involved in the regulation of plasma HDL levels through the inhibition of EL activity.
LDL Physical and Chemical Properties in Familial Combined Hyperlipidemia
- John E. Hokanson,
- Ronald M. Krauss,
- John J. Albers,
- Melissa A. Austin and
- John D. Brunzell
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 15, Issue 41 April 1995

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Abstract Familial combined hyperlipidemia (FCHL) is characterized by elevations of triglyceride and/or cholesterol within families and an elevation in apoB. Although small dense LDL has been consistently associated with hypertriglyceridemia, small dense LDL persists despite reductions in triglyceride after treatment with gemfibrozil in FCHL. The current study evaluated potential differences in the distribution and chemical composition of LDL species in patients with FCHL and normolipidemic control subjects. LDL from FCHL patients was characterized by a relative abundance of a discrete LDL species with a mean peak analytic ultracentrifuge flotation rate (S°_f) of 4.7±0.5 (SEM), a density of 1.041±0.001 g/mL, and a particle diameter of 250±1 Å as assessed by gradient gel electrophoresis. The major LDL species in the control subjects had a higher mean S°_f rate (6.3±0.4), was more buoyant (density, 1.037±0.001 g/mL), and was larger (diameter, 262±2 Å). In addition, in a series of six LDL fractions separated by equilibrium density gradient ultracentrifugation, particle diameters were significantly smaller in all fractions from FCHL patients compared with those from control subjects. LDL particles from patients contained less free cholesterol, cholesteryl ester, and phospholipid than LDL from control subjects. The amount of triglyceride per LDL particle, however, did not differ between FCHL patients and control subjects. Differences in flotation rate and mass of the major LDL species between patients and control subjects could not be fully accounted for by differences in plasma triglyceride levels. Thus, LDL particles from FCHL patients are smaller and more dense with less cholesterol and phospholipid. Many of these differences appear to be independent of plasma triglyceride. Differences in LDL physical and chemical properties may contribute to the increase in premature coronary disease in FCHL.
Evidence for Nonesterified Fatty Acids as Modulators of Neutral Lipid Transfers in Normolipidemic Human Plasma
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 15, Issue 91 September 1995

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Abstract The relations between the level of plasma nonesterified fatty acid (NEFA) and both the mass concentration and activity of the cholesteryl ester transfer protein (CETP) were studied in fasted normolipidemic subjects. Plasma NEFA correlated positively with both CETP mass concentration (r=.50; P<.01) and the transfer of cholesteryl ester from HDL toward plasma VLDL+LDL (CET_{HDL→VLDL+LDL} activity) (r=.46; P<.05) but not with the transfer of cholesteryl ester from LDL toward plasma HDL (CET_LDL→HDL activity) (r=−.05; NS). The high binding capacity of albumin for NEFA was used to investigate whether lipoprotein-bound NEFAs were implicated in the modulation of the cholesteryl ester transfer reaction. As compared with nonsupplemented controls, the addition of an excess of fatty acid–free albumin (8 g/L) to total normolipidemic plasmas reduced CET_{HDL→VLDL+LDL} activity (18.3±5.5% versus 9.8±3.1%; P<.0001) but not CET_LDL→HDL activity (22.3±4.5% versus 23.3±5.1%; NS). Moreover, CET_{HDL→VLDL+LDL} and CET_LDL→HDL activities correlated negatively when measured in native plasma (r=−.45; P<.05) but positively when measured in albumin-supplemented plasma (r=.40; P<.05). In long-term incubation experiments, lipoprotein-bound NEFA increased the net mass transfer of cholesteryl esters from HDL toward VLDL+LDL but reduced the net mass transfer of triglycerides in the opposite direction, from VLDL+LDL toward HDL. Taken together, data of the present study brought strong and concordant arguments in favor of a dual effect of plasma NEFA in modulating both the mass and the activity of CETP in vivo.
Increased Cholesteryl Ester Transfer Activity in Plasma From Analbuminemic Patients
- Sylvie Braschi,
- Laurent Lagrost,
- Emmanuel Florentin,
- Claude Martin,
- Anne Athias,
- Philippe Gambert,
- Michel Krempf,
- Christian Lallemant and
- Bernard Jacotot
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 16, Issue 31 March 1996

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Abstract Hypercholesterolemia associated with analbuminemia, an inherited disease manifesting low plasma albumin concentration, is characterized by enhanced LDL cholesterol levels and reduced HDL cholesterol levels. In addition, compared with normal counterparts, the esterified cholesterol:triglyceride ratio tends to be higher in analbuminemic apoB-containing lipoproteins and lower in analbuminemic HDL. The aim of the present study was to investigate the mechanism that may account for the association of a hypoalbuminemic state with alterations in the concentration and composition of plasma lipoprotein fractions. To this end, endogenous cholesterol esterification activity, phospholipid transfer activity, and cholesteryl ester transfer activity were measured in total plasma from three analbuminemic patients and five control subjects. Whereas endogenous cholesterol esterification and phospholipid transfer rates were not significantly affected in analbuminemia, the transfer of radiolabeled cholesteryl esters from HDL toward apoB-containing lipoproteins was constantly higher in analbuminemic plasmas than in normal control plasma (473.6±107.3%·h⁻¹·mL⁻¹ versus 227.5±84.0%·h⁻¹·mL⁻¹, respectively; P=.036). The rise in cholesteryl ester transfer protein (CETP) activity in analbuminemic plasma was due to a significant increase in the transfer of radiolabeled cholesteryl esters toward LDL but not toward the triglyceride-rich lipoproteins. The CETP mass was higher in analbuminemic patients than in control subjects, but the difference did not reach the significance level (5.18±0.82 mg/L versus 3.13±1.19 mg/L, respectively; P=.07). Since abnormally elevated nonesterified fatty acid (NEFA) levels were shown to be associated with analbuminemic lipoproteins, mostly LDL, the direct role of lipoprotein-bound NEFA in enhancing CETP activity was suspected. In support of this view, supplementation of total plasmas with fatty acid–poor albumin was shown to reduce CETP activity to a significantly greater extent in analbuminemic plasmas than in normal control plasma. It is concluded that hyperlipidemia associated with the hypoalbuminemic state can relate, at least in part, to the combined effect of CETP and NEFA in promoting the transfer of cholesteryl esters from the antiatherogenic HDL toward the proatherogenic apoB-containing lipoproteins.
Compositional Differences of LDL Particles in Normal Subjects With LDL Subclass Phenotype A and LDL Subclass Phenotype B
- Warren H. Capell,
- Alberto Zambon,
- Melissa A. Austin,
- John D. Brunzell and
- John E. Hokanson
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 16, Issue 81 August 1996

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A predominance of small LDL particles (subclass phenotype B), as determined by gradient-gel electrophoresis is found among patients with myocardial infarction. Despite physical differences in phenotype A and B particles, differences in lipid composition of particles in these phenotypes have yet to be reported in an unselected population of males and females. The present study used lipid/apoB ratios to analyze the amount of lipid per LDL particle, isolated by density-gradient ultracentrifugation, in 70 healthy subjects. Relative to apoB, the LDL particles from phenotype B subjects were found to contain less free cholesterol (0.391±0.05 versus 0.465±0.05; mean±SD; P<.001), phospholipid (1.26±0.2 versus 1.43±0.2; P<.001), and cholesteryl ester (1.97±0.1 versus 2.11±0.2; P<.001) than particles from phenotype A subjects. The amount of triglyceride per LDL particle did not differ between the two phenotypes (0.410±0.1 versus 0.406±0.1; P=NS) despite higher plasma triglyceride levels in the phenotype B subjects. LDL size and buoyancy were positively correlated with particle free cholesterol, phospholipid, and cholesteryl ester but not with particle triglyceride. These data suggest that the physical properties of LDL from subjects with phenotype A and B reflect their lipid composition. The compositional differences between LDL particles of the two phenotypes may provide new insight into the increased risk of myocardial infarction in subjects with small, dense LDL.
Apolipoprotein E Polymorphism and LDL Size in a Biethnic Population
- Steven M. Haffner,
- Michael P. Stern,
- Heikki Miettinen,
- David Robbins and
- Barbara V. Howard
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 16, Issue 91 September 1996

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Polymorphisms in the apolipoprotein E (apoE) phenotype (especially E₄) are associated with increased cardiovascular risk and particularly with increased concentrations of LDL cholesterol. Little is known, however, about whether alterations in LDL size are associated with the apoE₄ phenotype. LDL size was determined by gradient gel electrophoresis, and apoE phenotype was determined by isoelectric focus in 337 nondiabetic subjects from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors in Mexican Americans and non-Hispanic whites. ApoE₄ was associated not only with increases in LDL cholesterol concentrations but also with decreased LDL size. After adjustment for age, sex, body mass index, waist-to-hip ratio, triglyceride, HDL cholesterol, fasting insulin, and diabetic status, the apoE phenotype remained significantly related to LDL size (Å) in both men (apoE₂₃, 260.0; apoE₃₃, 256.3; and apoE₃₄, 252.6; P=.01) and women (apoE₂₃, 261.7; apoE₃₃, 257.9; and apoE₃₄, 256.7, P=.045). Variations in apoE phenotype are associated not only with changes in the absolute concentration of LDL cholesterol but also with changes in its composition. These changes are only partly explained by associations of apoE with insulin, triglyceride, and HDL cholesterol.
Relationship of LDL Size to Insulin Sensitivity in Normoglycemic Men
- Leena Mykkänen,
- Steven M. Haffner,
- David L. Rainwater,
- Pauli Karhapää,
- Heikki Miettinen and
- Markku Laakso
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 17, Issue 71 July 1997

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Abstract A preponderance of small, dense LDL has been suggested to be more atherogenic than larger, more buoyant LDL. Although several studies have suggested associations of small, dense LDL with hyperinsulinemia, few data are available on the relation of small, dense LDL to insulin resistance. We examined the association of LDL particle size determined by gradient gel electrophoresis with the rates of whole-body glu-cose uptake (WBGU) as determined by the hyperinsulinemic euglycemic clamp with indirect calorimetry in 87 Finnish normoglycemic men. LDL size was significantly positively correlated with the rates of WBGU (overall, r=.31, P<.01; oxidative, r=.23, P<.05; and nonoxidative, r=.31, P<.01). Rates of WBGU were also significantly lower in subjects with small LDL particles (≤26.0 nm) compared with those in sub-jects with larger LDL particles (>26.0 nm). This relation was not explained by obesity. Serum triglyceride concentrations were found to significantly affect the relationship of LDL particle size to WBGU. Specifically, LDL size was correlated with the rates of WBGU in men with mildly elevated triglyceride levels but not in men with low triglyceride levels. Serum VLDL triglyceride concentration was a substantially stronger determinant of LDL size than were the rates of WBGU. WBGU was not significantly related to LDL size when adjusted for triglycerides. We conclude that a preponderance of small, dense LDL particles is associated with insulin resistance and that serum triglyceride concentration modifies this relationship.
Association of Vitamin K–Dependent Coagulation Proteins and C4b Binding Protein With Triglyceride-Rich Lipoproteins of Human Plasma
- Ning Xu,
- Björn Dahlbäck,
- Ann-Kristin Öhlin and
- Åke Nilsson
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 18, Issue 11 January 1998

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Abstract—The triglyceride (TG) concentration in plasma is an independent risk factor for coronary heart disease. There is evidence that TG-rich lipoprotein (TGRLP), ie, chylomicrons (CMs), chylomicron remnants (CMRs), and VLDLs associate with factor VII and prothrombin and that the association enhances a platelet factor Xa–mediated prothrombin activation when the CM-prothrombin complex is exposed to platelets. In this study, we examined the association of the vitamin K–dependent coagulation factors VII, IX, X, and prothrombin, as well as the anticoagulation protein C and its cofactor protein S, in plasma lipoproteins obtained from human fasting and postprandial plasma. We also analyzed some other proteins that are related to the coagulation system but not to vitamin K–dependent proteins, including factor V, serum amyloid P component (SAP), C4b binding protein (C4BP), and thrombomodulin (TM), and as a control, Ig G. Human TGRLP (d<1.006 kg/L), LDL (d=1.006 to 1.063 kg/L), and HDL (d=1.063 to 1.210 kg/L) were separated from normal subjects both in fasting and 2 to 3 hours after the ingestion of a meal containing 100 g fat. The different coagulation proteins, SAP, C4BP, TM, and Ig G were determined by SDS-polyacrylamide gel electrophoresis combined with Western blotting, using specific polyclonal or monoclonal antibodies, and were visualized by peroxidase staining. All the vitamin K–dependent proteins associate with TGRLP in both fasting and postprandial plasma, but not with LDL or HDL. Factor V, SAP, TM, and Ig G were not found in any lipoprotein classes. C4BP, which is a regulatory protein of the classic pathway of the complement system and which binds protein S in vivo to regulate blood coagulation, was present in TGRLP, especially postprandial, but not in LDL or HDL. The amounts of prothrombin, protein S, and C4BP in postprandial TGRLP were larger than those in fasting TGRLP. Vitamin K–dependent procoagulation and anticoagulation proteins, as well as C4BP, could be associated with TGRLP in vivo. If the association enhances prothrombin activation, this effect may thus be counteracted by simultaneous binding of protein S.
Cholesterol Metabolism and Efflux in Human THP-1 Macrophages
- Leonard Kritharides,
- Aimee Christian,
- Genevieve Stoudt,
- Dianne Morel and
- George H. Rothblat
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 18, Issue 101 October 1998

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Abstract—This study has investigated in detail factors regulating accumulation, esterification, and mobilization of cholesterol in human THP-1 macrophages. Human THP-1 monocytes were differentiated into macrophages and then cholesterol enriched by exposure to acetylated LDL (AcLDL), together with [³H]free cholesterol (FC). Although THP-1 macrophages accumulated FC and esterified cholesterol (EC), assessed by both mass and radioactivity, cellular EC always demonstrated a much lower specific activity (cpm/μg) than did cellular FC, and several potential causes of this finding were investigated. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) during loading decreased cell [³H]EC by 95±1.4% but decreased cell EC mass by only 66.0±4.0%, indicating that some intracellular undegraded AcLDL-derived EC was present in these cells. Esterification of [³H]oleate to EC in THP-1 cells loaded with AcLDL was 2.0 nmol · mg⁻¹ · h⁻¹, consistent with previous literature. However, EC, triglyceride, and phospholipid fractions respectively contained 1.0±0.07%, 80.0±0.5%, and 18.9±0.3% of cell [³H]oleate, indicating triglycerides were much more metabolically active than EC. In addition, the mass of triglyceride in THP-1 macrophages exceeded that of EC both before and after exposure to AcLDL. Esterification of nonlipoprotein-derived cholesterol was compared in THP-1 cells and nonhuman Fu5AH, CHO, and RAW macrophage cells. Whereas the nonhuman cell lines all esterified over 30% of 2-hydroxypropyl-β-cyclodextrin (hp-β-CD)–delivered cholesterol within 6 hours, THP-1 cells esterified <8.0% of incorporated cholesterol. Kinetics of cholesterol efflux from AcLDL-loaded THP-1 cells were first investigated after loading with only FC, and interactions between efflux and EC hydrolysis were further assessed after loading cells with both EC and FC. Over 24 hours, human apolipoprotein (apo) A-I, apoHDL reconstituted with phosphatidylcholine, and HDL₃ respectively removed 46.6±3.7%, 61.3±3.4%, and 76.4±10.1% of [³H]FC from FC-enriched THP-1 cells. Cholesterol efflux to apoA-I was saturated by 24 hours and was enhanced by using apoA-I–phospholipid instead of pure apoA-I. Kinetic modeling identified that 97% of effluxed FC derived from a slow pool, with a T_1/2 ranging from 27.7 hours for HDL to 69.3 hours for apoA-I. Although efflux enhanced net clearance of EC, hydrolysis of EC during concurrent inhibition of ACAT was unaffected by cholesterol efflux. Supplementation of THP-1 cultures with cAMP to stimulate hormone-sensitive lipase did not significantly enhance net hydrolysis of EC or cholesterol efflux. In conclusion, human THP-1 macrophages contain a large and metabolically active pool of triglyceride and a relatively inactive pool of EC. The low specific activity of EC relative to FC is contributed to by reduced esterification of FC, slow hydrolysis of EC, and accumulated lipoprotein EC. The relative inactivity of the EC pool may further contribute to already impaired cholesterol efflux from these cells. Net cholesterol efflux from human macrophages is achieved by pure apoA-I and is substantially further enhanced by the presence of phospholipid in acceptor particles.
Independent Effects of Apo E Phenotype and Plasma Triglyceride on Lipoprotein Particle Sizes in the Fasting and Postprandial States
- Anthony M. Dart and
- Bridget Cooper
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 19, Issue 101 October 1999

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Abstract—LDL particle sizes and Apo E phenotypes were determined in 212 subjects of whom 51 had angina. LDL diameter was significantly less in subjects with an ε2 allele (24.76±0.08 vs 24.94±0.02 nm, P=0.02), and this was evident for both E2/E3 (24.77±0.09 nm) and E2/E4 (24.69±0.08 nm) phenotypes. Although there was a negative relation between LDL diameter and plasma triglyceride, the effect of apo E2 was still evident with adjustment for triglyceride. In multiple regression analysis, the significant determinants of LDL diameter were gender (with females having larger particles than males), body mass index, and the presence (or absence) of E2. HDL particle sizes and compositions were determined on fasting samples and, additionally, 5 and 8 hours after a fat-rich meal for 48 coronary heart disease cases and 49 control subjects. Fasting HDL particle sizes were not related to the presence of E2 but were significantly smaller for subjects possessing an ε4 allele (8.09±0.08 vs 8.39±0.05 nm, P=0.003) and were negatively related to plasma triglyceride. However, the effect of E4 persisted after adjustment for triglyceride. In a multiple regression analysis, the only significant determinant of fasting HDL diameter was the presence (or absence) of E4 with fasting plasma triglyceride just failing to reach significance (P=0.06). There was a postprandial increase in HDL diameter that was less marked in subjects with coronary heart disease. The postprandial increase in HDL diameter was of sufficient magnitude to result in size reclassification of HDL particles. The influence of E4 was also evident at both postprandial time points. Compositional analysis demonstrated that the increase in HDL diameters postprandially could be attributed to triglyceride enrichment, with an accompanying fall in cholesterol ester content. Phospholipid changes postprandially were biphasic with an initial fall followed by a rise in concentration. The increase in triglyceride content was significantly less in those subjects with angina despite an equivalent rise in plasma triglyceride. The present study demonstrates significant, but different, effects of variation in apo E phenotype on the particle sizes of both HDL and LDL. Such effects were still evident with adjustment for differences in plasma triglyceride and suggests that variation in apo E phenotype exerts effects on lipoprotein particle sizes by mechanisms additional to those dependent on change in plasma triglyceride.
A Hepatic Lipase Gene Promoter Polymorphism Attenuates the Increase in Hepatic Lipase Activity With Increasing Intra-abdominal Fat in Women
- Molly C. Carr,
- John E. Hokanson,
- Samir S. Deeb,
- Jonathan Q. Purnell,
- Ellen S. Mitchell and
- John D. Brunzell
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 19, Issue 111 November 1999

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Abstract—High hepatic lipase (HL) activity is associated with an atherogenic lipoprotein profile of small, dense LDL particles and lower HDL₂-C. Intra-abdominal fat (IAF) is positively associated with HL activity. A hepatic lipase gene (LIPC) promoter variant (G→A⁻²⁵⁰) is associated with lower HL activity, higher HDL₂-C, and less dense LDL particles. To determine whether the LIPC promoter polymorphism acts independently of IAF to regulate HL, 57 healthy, premenopausal women were studied. The LIPC promoter A allele was associated with significantly lower HL activity (GA/AA=104±34 versus GG=145±57 nmoles · mL⁻¹ · min⁻¹, P=0.009). IAF was positively correlated with HL activity (r=0.431, P<0.001). Multivariate analysis revealed a strong relationship between both the LIPC promoter genotype (P=0.001) and IAF (P<0.001) with HL activity. The relationship between IAF and HL activity for carriers and noncarriers of the A allele was curvilinear with the carriers having a lower apparent maximum level of plasma HL activity compared with noncarriers (138 versus 218 nmoles · mL⁻¹ · min⁻¹, P<0.001). In addition, the LIPC A allele was associated with a significantly higher HDL₂-C (GA/AA=16±7 versus GG=11±5 mg/dL, P=0.003). We conclude that the LIPC promoter A allele attenuates the increase in HL activity due to IAF in premenopausal women.

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