BACKGROUND

Lipoprotein distribution of non-cholesterol sterols was studied to evaluate in which lipoproteins they are carried in type 2 diabetes with body weight ranging from normal to overweight.

METHODS

Serum and lipoprotein squalene and non-cholesterol sterols were quantitated with gas-liquid chromatography in 33 diabetic subjects separated into normal (BMI < or = 25 kg/m2, n=10) and overweight (BMI>> 25 kg/m2, n=23) groups.

RESULTS

Two-thirds of the non-cholesterol sterols were carried in LDL and one-fifth in HDL, whereas squalene was mainly in VLDL and LDL in both groups. In overweight versus normal weight subjects, the absorption marker concentrations and ratios to cholesterol in serum and lipoproteins were lower and those of synthesis higher. In both groups the synthesis and absorption markers were interrelated in all lipoproteins suggesting intact regulation of cholesterol metabolism. The absorption marker ratios to cholesterol were mostly carried in HDL (cholestanol) and IDL (campesterol and sitosterol), and synthesis markers in VLDL and IDL regardless of overweight. Synthesis marker ratios were underestimated in serum versus VLDL and IDL, and those of absorption markers in serum versus IDL and HDL (p<0.05 for all). Squalene was related to lathosterol in all lipoprotein fractions (e.g., in LDL r=+0.501, p<0.01) suggesting that in diabetes squalene, too, is an indicator of cholesterol synthesis.

CONCLUSIONS

The absorption sterols are carried in IDL and HDL, and the synthesis markers in VLDL and IDL regardless of weight. The lipoprotein squalene and non-cholesterol sterol ratios were under- or overestimated in serum, and whether their evaluation in lipoproteins versus in serum only gives better information on cholesterol metabolism should be investigated further also in normal population.

The effect of the dose of oyster mushroom in the diet (1.0, 2.5, and 5.0%) and of the period of application (8, 16, 28, and 52 wk) on cholesterol accumulation in blood and body organs was studied in weanling male Wistar rats fed a diet containing 0.3% cholesterol. Reduction of cholesterol in serum and body organs was found to be dependent on the amount of dietary oyster mushroom administered. A negative correlation between the mushroom dose and cholesterol level was found after 8 and 28 wk of feeding (r=-0.9821 and -0.9803, respectively; P < 0.02 for both cases). The dose of 1% oyster mushroom did not affect cholesterol levels in serum or body organs. A significant reduction of cholesterol levels was observed in serum (31-46%) and liver (25-30%) at a dose of 5% of oyster mushroom for all periods. Reduced cholesterol content in very low-density lipoproteins (VLDL) was also observed at this level. The highest dose of oyster mushroom induced a decrease in conjugated diene levels in erythrocytes and an increase in the levels of reduced glutathione in the liver and stimulated the activities of catalase and glutathione peroxidase in the liver in the final period of the experiment.

Since distinct cholesterol and triglyceride concentrations in major lipoproteins and their subclasses may be related to atherosclerosis, we investigated the relationship of cholesterol and triglyceride concentrations in lipoprotein subclasses and the severity of carotid intima-media thickness (IMT), a surrogate marker of subclinical atherosclerosis. We studied 116 apparently healthy Japanese men (53 ± 9 years) without a history of cardiovascular diseases who were not taking any medication. Carotid IMT was measured by means of high-resolution vascular ultrasound. Plasma cholesterol and triglyceride concentrations in major lipoproteins and their subclasses were determined by HPLC with gel permeation columns. By univariate analyses, carotid IMT was the most closely related to age (r = 0.528, P < 0.001), followed by smoking habit expressed as pack-year cigarette consumption (r = 0.409, P < 0.001). In addition to total cholesterol and LDL cholesterol, carotid IMT was significantly associated with cholesterol and triglyceride concentrations in several LDL and VLDL subclasses. Stepwise multiple linear regression analysis revealed that age (β = 0.436, P < 0.001), smoking (pack-years) (β = 0.225, P = 0.007), and large LDL cholesterol (β = 0.175, P = 0.023) were independent predictors of determining carotid IMT (adjusted R(2) = 0.347, P < 0.001). These results indicate that large LDL cholesterol is an important, independent determinant of carotid IMT in healthy men.

Expression of the very low density lipoprotein receptor (VLDL-R) is barely detectable in liver, but occurs in adipose tissue, skeletal muscle, heart, and placenta, where it is postulated to supply triglyceride to tissues that utilize fatty acids. To investigate its tissue-specific expression, cell lines were transfected with luciferase reporter gene constructs driven by the 5'-flanking region of the VLDL-R gene. Transcriptional activity of a 4.2-kb promoter fragment was 5-fold higher in BeWo placental cells than in Huh-7 hepatoma cells, consistent with relative endogenous expression of the VLDL-R. By deletion analysis, DNase I protection assays and site-directed mutagenesis, two regulatory elements were essential for maximal promoter activity in BeWo cells: footprint site D (-856 to -830) and an inverted CCAAT box (-703 to -707). Mutation of either element reduced promoter activity by 60% in BeWo cells, but had little effect in Huh-7 cells, suggesting that these elements direct cell-type specific transcription. Electrophoretic mobility-shift assays with BeWo nuclear extracts revealed that the inverted CCAAT box binds transcription factor NF-Y, and site D binds CCAAT/enhancer-binding protein b (C/EBPbeta) and minor amounts of C/EBPalpha and C/EBPdelta. Overexpression of a dominant negative NF-YA vector confirmed involvement of NF-Y in the regulation of the VLDL-receptor gene through the CCAAT box. However overexpression of C/EBP could not stimulate transcription from the VLDL-receptor promoter nor from site D fused to a heterologous promoter, suggesting that the simultaneous binding of an accessory factor(s) may be necessary for C/EBP transactivation via the D site.

Niemann-Pick type C1 (NPC1) promotes the transport of LDL receptor (LDL-R)-derived cholesterol from late endosomes/lysosomes to other cellular compartments. NPC1-deficient cells showed impaired regulation of liver_X receptor (LXR) and sterol regulatory element-binding protein (SREBP) target genes. We observed that Apoe(-/-)Npc1(-/-) mice displayed a marked increase in total plasma cholesterol mainly due to increased VLDL, reflecting decreased clearance. Although nuclear SREBP-2 and Ldlr mRNA levels were increased in Apoe(-/-)Npc1(-/-) liver, LDL-R protein levels were decreased in association with marked induction of proprotein convertase subtilisin/kexin type 9 (Pcsk9) and inducible degrader of the LDL-R (Idol), both known to promote proteolytic degradation of LDL-R. While Pcsk9 is known to be an SREBP-2 target, marked upregulation of IDOL in Apoe(-/-)Npc1(-/-) liver was unexpected. However, several other LXR target genes also increased in Apoe(-/-)Npc1(-/-) liver, suggesting increased synthesis of endogenous LXR ligands secondary to activation of sterol biosynthesis. In conclusion, we demonstrate that NPC1 deficiency has a major impact on VLDL metabolism in Apoe(-/-) mice through modulation of hepatic LDL-R protein levels. In contrast to modest induction of hepatic IDOL with synthetic LXR ligands, a striking upregulation of IDOL in Apoe(-/-)Npc1(-/-) mice could indicate a role of endogenous LXR ligands in regulation of hepatic IDOL.

The binding of human 125I-labeled HDL3 (high-density lipoproteins, rho 1.125-1.210 g/cm3) to a crude membrane fraction prepared from bovine liver closely fit the paradigm expected of a ligand binding to a single class of identical and independent sites, as demonstrated by computer-assisted binding analysis. The dissociation constant (Kd), at both 37 and 4 degrees C, was 2.9 micrograms protein/ml (approx. 2.9 X 10(-8) M); the capacity of the binding sites was 490 ng HDL3 (approx. 4.9 pmol) per mg membrane protein at 37 degrees C and 115 at 4 degrees C. Human low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) also bound to these sites (Kd = 41 micrograms protein/ml, approx. 6.7 X 10(-8) M for LDL, and Kd = 5.7 micrograms protein/ml, approx. 7.0 X 10(-9) M for VLDL), but this observation must be considered in light of the fact that the normal circulating concentrations of these lipoproteins are much lower than those of HDL. The binding of 125I-labeled HDL3 to these sites was inhibited only slightly by 1 M NaCl, suggesting the presence of primarily hydrophobic interactions at the recognition site. The binding was not dependent on divalent cations and was not displaceable by heparin; the binding sites were sensitive to both trypsin and pronase. Of exceptional note was the finding that various subclasses of human HDL (including subclasses of immunoaffinity-isolated HDL) displaced 125I-labeled HDL3 from the hepatic HDL binding sites with different apparent affinities, indicating that these sites are capable of recognizing highly specific structural features of ligands. In particular, apolipoprotein A-I-containing lipoproteins with prebeta electrophoretic mobility bound to these sites with a strikingly lower affinity (Kd = 130 micrograms protein/ml) than did the other subclasses of HDL.

BACKGROUND

Inflammation and oxidative stress are associated with cardiovascular diseases and underlying atherosclerosis. The high density lipoprotein (HDL)-associated paraoxonase-1 (PON1) enzyme is known to be involved in the protection of serum lipids from such oxidation. Nonetheless, the disturbances of lipid profile during nematode-infected model have not yet been studied. Therefore, we aimed to explore the effects of Nippostrongylus brasiliensis infection in male Wistar rats, a model of human gastrointestinal nematode infections, on hepatic PON1 synthesis and the levels of lipid parameters.

METHODS

Nippostrongylus brasiliensis-infected rats fed standard and high-fat diets. Serum paraoxonase and arylesterase activities were measured on day 0, 2, 4, 7, and 14 post-infection (PI). Hepatic PONs and pro-inflammatory cytokines mRNA expression levels were evaluated in a standard diet-fed groups, and the disturbances in lipid profile as well as the levels of thiobarbituric acid reactive species (TBARS) and oxidized-LDL (Ox-LDL) were measured in high-fat diet-fed groups.

RESULTS

We found that N. brasiliensis-infected rats fed the standard diet show a significant reduction in serum PON1 activity and down-regulation of hepatic PON1 mRNA expression as well as up-regulation of hepatic IL-1β, IL-β receptor (R), TNF-α, and TNFRRNA expressions in association with hepatic recruitments of Kupffer cells and neutrohils. In the presence of the high-fat diet, N. brasiliensis infection increases serum triglycerides, total cholesterol, LDL/VLDL, TBARS and Ox-LDL as well as decreases serum HDL coinciding with a maximum serum PON1 reduction.

CONCLUSIONS

Nippostrongylus brasiliensis infection can induce atherogenic lipid profile and reduce serum PON1 activity.

BACKGROUND

Cellular cholesterol efflux is a key step in reverse cholesterol transport and may depend on the metabolism of apolipoprotein (apo) B-100, apoA-I, and apoA-II.

OBJECTIVE

We examined the associations between cholesterol efflux and plasma concentrations and kinetics of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL)-apoB-100, high-density lipoprotein (HDL)-apoA-I, and HDL-apoA-II in men. DESIGN, SUBJECTS, AND METHODS: Thirty men were recruited from the community with a wide range of body mass index. The capacity of plasma and HDL to efflux cholesterol was measured ex vivo. Apolipoprotein kinetics were measured using stable isotope techniques and multicompartmental modeling.

RESULTS

Cholesterol efflux to whole plasma was correlated with plasma levels of cholesterol, triglyceride, apoB-100, insulin, cholesteryl ester transfer protein, and lecithin-cholesterol acyltransferase, body mass index and waist circumference (P < 0.05 in all). Cholesterol efflux was inversely correlated with the fractional catabolic rate (FCR) of VLDL (r = -0.728), IDL (r = -0.662), and LDL-apoB-100 (r = -0.479) but positively correlated with the FCR (r = 0.438) and production rate (r = 0.468) of HDL-apoA-II. In multiple regression analysis, the concentration and FCR of VLDL-apoB-100 (β-coefficient = 0.708 and -0.518, respectively) and IDL-apoB-100 (β-coefficient = 0.354 and -0.447, respectively) were independent predictors of cholesterol efflux. The association of cholesterol efflux with apoB-100 metabolism was diminished after removal of apoB-100-containing lipoproteins from plasma prior to efflux. All associations, except for cholesteryl ester transfer protein, were lost when cholesterol efflux to isolated HDL was tested.

CONCLUSIONS

The plasma concentration and kinetics of apoB-100-containing lipoproteins are significant predictors of the capacity of whole plasma to effect cellular cholesterol efflux.

Type 2 diabetes mellitus (T2DM) is associated with increased plasma triglyceride (TG) concentrations, but African Americans (AA) have lower plasma TG than Caucasians (CC). We evaluated the hypothesis that obese AA women have lower plasma TG than obese CC women do because of differences in lipid kinetics. Eleven AA and 11 CC obese women with T2DM, matched on body mass index (BMI) (AA = 37 ± 1, CC = 37 ± 1 kg/m(2)), age, duration of diabetes, percentage body fat, and insulin sensitivity (S(I), determined by an intravenous glucose tolerance test), were studied. Plasma TG concentration (AA = 1.14 ± 0.11, CC = 1.88 ± 0.18 mmol/l), FFA rate of appearance (R(a)) into plasma (AA = 419 ± 27, CC = 503 ± 31 µmol·min(-1)), and total VLDL-TG secretion rate (AA = 18 ± 2, CC = 29 ± 4 µmol·min(-1)) were lower in AA than CC women (all P < 0.05). In contrast, plasma total apolipoprotein (apo)B-100 concentration (AA = 1,542 ± 179, CC = 1,620 ± 118 nmol/l) and VLDL-apoB-100 secretion rate (AA = 1.3 ± 0.1, CC = 1.3 ± 0.1 nmol·min(-1)) were similar in both groups, so the molar ratio of VLDL-TG secretion rate to VLDL-apoB-100 secretion rate was lower in AA women than in CC women. VLDL-TG concentration was lower in AA women due to lower total VLDL-TG secretion rate. However, the VLDL-apoB-100 secretion rate was the same in both groups, demonstrating that AA women secrete smaller VLDL particles containing less TG than do CC women.

Studies on the response of plasma lipids and lipoproteins to Kawasaki disease are scarce so far. The purpose of this study was to investigate the changes in plasma levels of lipids and apolipoproteins as well as the composition of different lipoproteins in patients during the acute and convalescence phases of Kawasaki disease. The results showed that during the acute phase, the concentrations of plasma high density lipoprotein (HDL)-cholesterol, apolipoprotein A-I (apoA-I) and A-II (apoA-II) were significantly reduced. While the reduction of HDL-cholesterol was mainly related to the lowering of esterified and unesterified cholesterols in HDL2 during the acute stage of Kawasaki disease, most of which recovered during the subsequent convalescence phase. The plasma concentration of triglycerides was 46% higher in patients during the acute phase of Kawasaki disease than in the control subjects, which may be ascribed to the increase of triglycerides in very low density lipoprotein (VLDL), low density lipoprotein (LDL) and HDL2. The variables studied above did not appear to be independent parameters. The level of plasma apoA-I showed a stronger negative association with triglyceride concentration (r = -0.22) than apoA-II (r = -0.11) and HDL-cholesterol (r = -0.07). Furthermore, the levels of cholesterol, apoA-I and apoA-II in HDL2, but not in HDL3, were inversely correlated with the levels of triglyceride. We conclude that the temporary changes of lipid levels associated with Kawasaki disease results predominantly from alterations of lipoprotein composition.

Lipoprotein cholesterol levels were determined without ultracentrifugation by using modified enzymatic methods for cholesterol, high-density-lipoprotein (HDL) cholesterol, and triglyceride and the formula, low-density-lipoprotein (LDL) cholesterol = total cholesterol-HDL cholesterol-triglycerides/5. The methods for cholesterol and triglyceride determinations were standardized for accuracy and precision by the Center for Disease Control's Lipid Standardization Laboratory, which monitored this laboratory for 16 months. The lipoprotein cholesterol values obtained correlated well with lipoprotein cholesterol values determined at the Minnesota Lipid Research Clinic Laboratory using ultracentrifugation. LDL cholesterol determined at the Minneapolis Veterans Administration Hospital Laboratories (Y axis) produced a curve with an intercept of 9.38 mg/dl, a slope of .977, standard error of the estimate (Sy.x) of 8.8 mg/dl, and a correlation coefficient (r) of .983 (n = 32). HDL cholesterol was Y = 0.998 X + .89 mg/dl, Sy.x = 1.6 mg/dl (r = .984, n = 53), and very-low-density-lipoprotein (VLDL) cholesterol was Y = 1.010 X -1.32 mg/dl, Sy.x = 1.3 mg/dl (r = .996, n = 54).

The effect of obesity on the relationship between very low density lipoprotein (VLDL)-triglyceride (TG) production rate and concentration was studied in 80 subjects whose TG concentrations ranged from 41-1315 mg/100 ml and whose relative weight varied from 0.74-1.46. There was a positive correlation between VLDL-TG production rate and plasma TG concentration in all 80 patients (r = 0.78), which was highly statistically significant (p less than 0.001). Both male and female subjects were subdivided into quartiles on the basis of relative weight; the relationship between VLDL-TG production rate and plasma TG concentration was found to be comparable in all subgroups. These observations suggest that moderate degrees of obesity do not affect VLDL-TG kinetics in patients whose plasma TG levels vary over an extremely wide range.

There exists much evidence suggesting a major role for the oxidized low density lipoprotein (LDL) and VLDL particles in the pathogenesis of atherosclerosis. Although obesity is characterized by dyslipidemia, less is known about the oxidation capacity of lipoproteins in obese subjects. We measured the oxidizability in vitro in 21 premenopausal women with a BMI of 36.7+/-5.4 and compared them to 18 age-matched controls (BMI 21.9+/-1.8). The oxidizability of the non-HDL fraction is evaluated by measuring the fluorescence and thiobarbituric acid reactive substances (TBARS; MDA nM/mg non-HDL) at different time intervals of incubation. TBARS formation increased linearly with the increase of lipids both in non-obese and obese subjects. TBARS, measured every 30 min, increased in non-obese controls up to a maximum of 59.6 at 180' in contrast to a maximum of 77.1 at 180' (P < 0.001) in obese, but healthy, normocholesterolemic subjects. At each measurement the TBARS were significantly higher (P < 0.01-0.001) in obese subjects. Also the lag-time (period from zero to the start of the particle oxidation process) was significantly lower (92.5 vs. 123.4; P < 0.001) in obese subjects, when compared to lean controls. BMI correlates significantly with TBARS formation and its log transformed values (maximum P < 0.001). The lag-time was negatively related (n=39 total group, r=- 0.57, P < 0.001) to body weight and BMI. A significant relationship exists between TBARS formation (up to r=0.59) and triglyceride levels and a negative relationship exists with HDL-cholesterol levels. In vitro oxidizability of non-HDL lipoproteins is significantly increased in obese, non-diabetic subjects and related to increased body weight and triglyceride levels. Further studies are necessary to explore the underlying mechanisms for this phenomenon.

This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL). Four weeks of treatment with ACOL reduced fasting and postprandial plasma triglycerides (TGs), an effect associated with lower VLDL-TG secretion rate (-25%), and decreased mRNA of microsomal triglyceride transfer protein (MTP; -29%). ACOL increased liver TG concentration (+100%) and amplified the feeding-induced increase in the master lipogenic regulators sterol-regulatory element binding protein-1a (SREBP-1a) and SREBP-1c. ACOL decreased total, HDL, and non-HDL cholesterol (CHOL) by 50%. SREBP-2 mRNA and HMG-CoA reductase activity were minimally affected by ACOL. However, in the fasted state, liver concentration of scavenger receptor class B type I (SR-BI) protein, but not mRNA, was 3-fold higher in ACOL-treated than in control animals and correlated with plasma HDL-CHOL levels (r = 0.80, P < 0.002). Liver LDL receptor (LDLR) protein, but not mRNA, was increased 2-fold by ACOL, independently of the nutritional status. This study demonstrates that ACOL possesses the unique ability among SERMs to reduce VLDL-TG secretion, likely by reducing MTP expression, and strongly suggests that the robust hypocholesterolemic action of ACOL is related to increased removal of CHOL from the circulation as a consequence of enhanced liver SR-BI and LDLR abundance.

Interferon-alpha 2 (IFN-alpha 2) produced by recombinant DNA technology and purified to homogeneity, was assessed for effects on plasma lipids and lipoprotein composition in 10 patients with metastatic malignant melanoma. Patients received 30 X 10(6) U/m2 IFN intravenously for 5 consecutive days every 3 weeks. Plasma cholesterol concentrations were significantly decreased after 3 days of IFN administration (171 +/- 37 mg/dl, mean +/- SD) when compared with pretreatment concentrations (211 +/- 28 mg/dl, p less than 0.05). Approximately 34% of the decrease in plasma cholesterol concentration was contributed by high-density lipoprotein (HDL). Significant decreases in plasma HDL cholesterol (44 +/- 8 to 34 +/- 7 mg/dl, p less than 0.05) and apolipoprotein A-1 concentrations (124 +/- 14 to 95 +/- 17 mg/dl, p less than 0.05) occurred. Although decreases in low-density lipoprotein (LDL) cholesterol concentrations contributed to the majority of the total decrease observed in plasma cholesterol, IFN did not alter the cholesterol-to-protein ratio of the LDL. When IFN-alpha 2 was discontinued, alterations in plasma lipoproteins returned to pretreatment levels. Plasma triglyceride concentrations were not influenced by IFN treatment nor did administration of IFN decrease very-low-density lipoprotein (VLDL). The overall effect of recombinant (r) IFN-alpha 2 on lipid composition was to reduce LDL and HDL without alteration of VLDL or triglycerides.

OBJECTIVE

To assess the association of hypovitaminosis D with clinical and biochemical characteristics of type 2 diabetic patients and to determine the effect of glycemic control optimization on 25-hydroxyvitamin D (25(OH)D) concentrations.

METHODS

Cross-sectional study of 63 patients with type 2 diabetes (mean age 60 ± 9.8 years, 69.8% men). Twenty of the 63 patients were also studied before and after glycemic control optimization.

RESULTS

Mean 25(OH)D concentrations were 63.64 ± 25.51 nmol/L and 74.6% of patients had hypovitaminosis D. Compared with patients with vitamin D sufficiency, patients with hypovitaminosis D had higher prevalence of overweight or obesity (72.3% versus 37.5%; p = 0.012) and higher VLDL cholesterol (VLDL-c) (0.71 (0.24-3.59) versus 0.45 (0.13-1.6) mmol/L; p = 0.011) and C-reactive protein (3.28 (0.36-17.69) versus 1.87 (0.18-17.47) mg/L; p = 0.033) concentrations. The composition of HDL particles also differed in both groups, with higher relative content of triglycerides and lower of cholesterol in patients with hypovitaminosis D. After adjustment for age, seasonality and BMI, differences remained significant for VLDL-c and triglyceride content of HDL. No differences were found regarding other diabetes characteristics. Improvement of glycemic control (HbA1c 9.4 (7.6-14.8) versus 7.3 (6.2-8.7)%; p = 0.000) was accompanied by a decrease in 25(OH)D concentrations (72.7 ± 33.3 to 59.0 ± 21.0 nmol/L; p = 0.035). Correlation analysis revealed that changes in 25(OH)D concentrations were negatively associated to changes in HbA1c (r - 0.482; p = 0.032).

CONCLUSIONS

Hypovitaminosis D is associated with features of the metabolic syndrome in type 2 diabetes and improvement of glycemic control decreases 25(OH)D concentrations.

We investigated the effects of dietary fat saturation on very low density lipoprotein (VLDL) production in guinea pigs fed semipurified diets containing 15% (w/w) fat, either corn oil (CO, 58% linoleic acid), lard (LA, 42% oleic and 24% palmitic acids) or palm kernel oil (PK, 52% lauric and 18% myristic acids) for 4 weeks. Animals were given an intravenous injection of Triton WR 1339 to block VLDL catabolism and rates of VLDL triacylglycerol (TAG) and apolipoprotein (apo) B secretion were measured over time. Plasma TAG concentrations increased linearly for 8 h (r = 0.99) and VLDL-TAG secretion rates were significantly higher (P < 0.01) in guinea pigs fed LA (72.7 +/- 14.7 mg/kg-h, n = 12) compared to animals fed PK (55.4 +/- 13.4 mg/kg-h, n = 12) or CO (48.6 +/- 17.5 mg/kg-h, n = 15). VLDL apoB secretion rates were highest in PK-fed animals (3.1 +/- 1.8 mg/kg-h) compared to guinea pigs fed LA (1.5 +/- 0.8 mg/kg-h) or CO (1.1 +/- 0.6 mg/kg-h) diets (P < 0.005). Concurrent with analysis of VLDL secretion, turnover of 125I-labeled LDL was measured. Low density lipoprotein (LDL) fractional catabolic rates were not altered by Triton treatment and LDL apoB specific radioactivity (cpm/microgram) did not change over time indicating that: a) the Triton blockage of VLDL catabolism was complete, and b) there was no direct secretion of LDL by the liver. These data demonstrate that intake of lard increases the rate of VLDL-triacylglycerol secretion and that nascent VLDL particles from the lard and corn oil diet groups have the same relative triacylglycerol content, whereas palm kernel oil intake increases secretion of VLDL particles which have a reduced triacylglycerol content. These results demonstrate that dietary fat chain length and saturation have specific effects on VLDL secretion rates affecting both particle number and composition.

The process of cholesterylester (CE) transfer is supposed to be a regulatory factor in the distribution of CE between lipoproteins. In addition to the activity of CE transfer protein, this process may be affected by acceptor lipoprotein characteristics. In this study the effect of the composition of different very low density lipoproteins (VLDL) and low density lipoproteins (LDL) on the ability to accept CE from HDL in vitro was investigated. [3H]-CE high density lipoprotein (HDL) (100 nmol CE) from one batch was incubated with VLDL (75 nmol CE), isolated from fifteen subjects for 4 h and separately with LDL (250 nmol CE), isolated from thirteen subjects for 16 h, both in the presence of lipoprotein-free plasma providing a source of cholesterylester transfer protein. The CE transfer rate of VLDL (range 1.34-2.84% [3H]-CE transferred h-1) was correlated to the triacylglycerol (TG):CE molar ratio (r: 0.63, P less than 0.05), to the phospholipid (PL):CE molar ratio (r: 0.75, P less than 0.01), to the protein (Pr):CE ratio (expressed in g nmol-1) (r: 0.72, P less than 0.01) and to the free cholesterol (FC):CE molar ratio (r: 0.69, P less than 0.01), but not to the FC:PL molar ratio (r: -0.08, NS). The CE transfer rate to LDL (range 1.18-3.59 nmol CE h-1) was correlated to the Pr:CE ratio (r: 0.72, P less than 0.01) and inversely to the FRC:PL molar ratio (r: -0.88, P less than 0.001), but not to the TG:CE molar ratio (r: 0.40, NS), nor to the FC:CE molar ratio (r: -0.37, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The plasma concentration of ionized magnesium (iMg++), the serum total magnesium concentration (tMg), and lipoprotein status were assessed in 29 elderly men with impaired insulin sensitivity but who were otherwise healthy and not receiving antidiabetic pharmacologic treatment. Plasma iMg++ was inversely correlated with serum concentrations of VLDL cholesterol (r = -0.39, P < 0.04), LDL cholesterol (r = -0.57, P < 0.002), total cholesterol (r = -0.55, P < 0.002), VLDL triacylglycerol (r = -0.36, P < 0.05), LDL triacylglycerol (r = -0.48, P < 0.01), and total triacylglycerol (r = -0.41, P < 0.03). The serum total magnesium concentration also tended to be inversely correlated with these lipid fractions, but not significantly so. Furthermore, iMg++ was inversely correlated with the apolipoprotein B concentration (r = -0.56, P < 0.002) and with the ratio of apolipoprotein B to A-I in serum (r = -0.58, P < 0.001). The corresponding values for tMg were r = -0.37 (P = 0.05) and r = -0.37 (P = 0.05), respectively. Insulin increment and the area under the insulin curve during an intravenous glucose tolerance test were inversely correlated with iMg++ [r = -0.56 (P < 0.01) and r = -0.64 (P < 0.0005), respectively], but were not significantly correlated with tMg. Insulin-mediated glucose uptake and the insulin sensitivity index during the hyperinsulinemic euglycemic clamp test were not significantly correlated with tMg (r = 0.05 and 0.12, respectively; NS) nor with iMg++ (r = 0.23 and 0.31, respectively; NS). Atherogenic lipid fractions and some glucometabolic variables were more closely correlated with iMg++ than with tMg.

The effect of dietary protein on lipid levels of serum and liver and mineral contents of bone tissue was studied in female rats by using 13 semi-purified diets differing with respect to protein source. The diets were characterized with regard to contents of protein, amino acids, fat, crude fiber, phytate, zinc, copper, iron, magnesium, calcium, sodium, potassium, tocopherol and metabolizable energy. Six of the proteins tested were of animal origin and six proteins used were plant proteins. Each diet was fed at a 20% protein, 10% fat level. There was a large variation between groups in the serum content of lower density lipoproteins (VLDL + LDL). Rats fed plant protein diets showed values in a lower range than rats consuming animal protein diets. Triglyceride values showed a similar tendency. A comparison of dietary amino acid composition and blood lipid parameters revealed a significant negative correlation between dietary arginine content and serum VLDL + LDL levels (r = 0.863; P < 0.01). Group differences in total serum cholesterol were also observed. However, this variation was within the same range in animal as well as plant protein diets. Serum tocopherol levels were correlated to the total dietary intakes of tocopherol. No significant trend was observed for the mineral content of bone tissue or for the total lipid content of liver with regard to class of dietary protein. However, all rats fed a blood protein diet developed fatty livers.

OBJECTIVE

To assess whether plasma IGFBP-2 is independently associated with components of the lipoprotein-lipid profile and to suggest a cutoff value that could identify subjects with the features of the metabolic syndrome.

METHODS

In this cross-sectional study, 379 Caucasian men from the general population and covering a wide range of BMI were recruited through the media. Subjects with type 2 diabetes, BMI values>> 40 kg/m(2), or taking medication targeting glucose or lipid metabolism or blood pressure were excluded. Anthropometric data were collected and plasma IGFBP-2 concentrations, glucose tolerance and an extensive plasma lipid profile were determined after an overnight fast.

RESULTS

Subjects with low IGFBP-2 levels were characterized by increased fat mass (p < 0.0001), impaired insulin sensitivity (p < 0.0001) and higher plasma triglyceride (TG) levels (p < 0.0001). When divided into 6 quantiles, only subjects with the highest IGFBP-2 levels (>221.5 ng/mL) did not meet the NCEP ATP III criteria for the clinical diagnosis of the metabolic syndrome. In addition, circulating IGFBP-2 levels were significantly associated with VLDL-TG (r = -0.51, p < 0.0001) and HDL-C (r = -0.27, p < 0.0001) levels. After adjustments, plasma IGFBP-2 was found to be independently associated with VLDL-TG levels but not with HDL-C concentrations.

CONCLUSIONS

In our cohort, IGFBP-2 levels <221.5 ng/mL are incrementally associated with a detrimental plasma lipoprotein-lipid profile. After adjustment for covariates, IGFBP-2 remained independently associated with VLDL-TG but not HDL-C levels. This study supports further investigations in other populations and validation of IGFBP-2 as a biomarker of early dyslipidemia.

OBJECTIVE

This study was undertaken to evaluate a possible association of adipocytokines with metabolic syndrome (MetS), inflammation and other cardiovascular risk factors in primary antiphospholipid syndrome (PAPS).

METHODS

Fifty-six PAPS patients and 72 controls were included. Adiponectin, leptin, visfatin, resistin, plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a), glucose, ESR, CRP, uric acid and lipid profiles were measured. The presence of MetS was determined as defined by the International Diabetes Federation (IDF), and insulin resistance was rated using the homeostasis model assessment (HOMA) index.

RESULTS

Concentrations of leptin were higher [21.5 (12.9-45.7) ng/mL] in PAPS patients than in the controls [12.1 (6.9-26.8) ng/mL), p=0.001]. In PAPS patients, leptin and PAI-1 levels were positively correlated with BMI (r=0.61 and 0.29), HOMA-IR (r=0.71 and 0.28) and CRP (r=0.32 and 0.36). Adiponectin levels were negatively correlated with BMI (r=-0.28), triglycerides (r=-0.43) and HOMA-IR (r=-0.36) and positively correlated with HDL-c (r=0.37) and anti-β2GPI IgG (r=0.31). The presence of MetS in PAPS patients was associated with higher levels of leptin (p=0.002) and PAI-1 (p=0.03) levels and lower levels of adiponectin (p=0.042). Variables that independently influenced the adiponectin concentration were the triglyceride levels (p<0.001), VLDL-c (P=0.002) and anti-β2GPI IgG (p=0.042); the leptin levels were BMI (p<0.001), glucose (p=0.046), HOMA-IR (p<0.001) and ESR (p=0.006); and the PAI-1 levels were CRP (p=0.013) and MetS (p=0.048).

CONCLUSIONS

This study provides evidence that adipocytokines may be involved in low-grade inflammation, insulin resistance and MetS in PAPS patients.

Pioglitazone is an insulin-sensitizing agent that has been reported to have anti-arteriosclerotic effects. The aim of this study was to obtain a better understanding of the mechanism involved in the insulin sensitizing effect of pioglitazone. A total of 50 newly diagnosed patients with type 2 diabetes were enrolled in this study and divided into two groups, 25 of who were treated with 15 mg/day pioglitazone and 25 with 500 mg/day metformin for 12 weeks. Changes in various parameters of insulin resistance including lipoprotein subclass according to particle size determined by high performance liquid chromatography, as well as glucose metabolism, were monitored to determine the relationship between lipoprotein subclass and other insulin resistance parameters. Both pioglitazone and metformin treatment were associated with significant reductions in hyperglycemia, HOMA-IR and HbA1c levels. Pioglitazone treatment, but not metformin treatment resulted in significant reductions in serum large very low-density lipoprotein (VLDL: 44.5-64.0 nm) and increases in serum adiponectin levels (both <0.001). In the pioglitazone group, the change in large VLDL levels correlated positively with changes in HbA1c (r=0.468, P=0.0174), HOMA-IR (r=0.593, P=0.0014), very small LDL (r=0.714, P<0.0001) and net electronegative charged modified-LDL (r=0.412, P=0.0399), and inversely with changes in adiponectin level (r=-0.526, P=0.0061). The results in this study suggest that the hypoglycemic effect of pioglitazone is achieved mainly through improvement of hepatic insulin resistance, and that pioglitazone may have an antiatherosclerotic effect by decreasing serum atherogenic modified-LDL and by increasing adiponectin.

Obesity is associated with unfavorable alterations in plasma lipid concentrations. Data obtained from studies in cultured cells and rodent models show that Protein Convertase Subtilisn/Kexin 9 (PCSK9), a secreted protein that leads to degradation of LDL receptors in the liver, is an important regulator of plasma LDL cholesterol concentrations. Recent evidence suggests that PCSK9 may also regulate the very low density lipoprotein (VLDL) receptor expression and VLDL-triglyceride (TG) metabolism. The purpose of this study was to determine whether circulating PCSK9 concentrations are correlated with VLDL-triglyceride kinetics in obese people. Plasma PCSK9 concentration and VLDL-TG kinetics were evaluated in 39 nondiabetic, obese subjects (body mass index 36.9 ± 4.3 kg/m(2)). Body composition was assessed by using dual-energy x-ray absorptiometry, and VLDL-TG kinetics were assessed by using stable isotopically labeled tracer infusion. We found that plasma PCSK9 concentrations correlated significantly with percent body fat (r = 0.322, P = 0.046) and serum LDL-cholesterol concentrations (r = 0.333, P = 0.036), but not with VLDL-TG secretion rate (r = 0.083, P = 0.614) or clearance rate (r = 0.032, P = 0.845). These data suggest that PCSK9 is likely involved in LDL-cholesterol metabolism, but it is not a clinically important regulator of VLDL kinetics in obese individuals.