Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder characterized by low levels of apolipoprotein (apo) B and low-density lipoprotein (LDL) cholesterol. Decreased production rates of apoB have been demonstrated in vivo in FHBL heterozygotes. In the present study, we wished to investigate whether the transport of triglycerides was similarly affected in these subjects. Therefore, we studied the in vivo kinetics of very-low-density lipoprotein (VLDL) triglycerides and VLDL apoB-100 simultaneously in 7 FHBL heterozygotes from 2 well-characterized kindreds and 7 healthy normolipidemic subjects. In both kindreds, hypobetalipoproteinemia is caused by mutations in the 5' portion of the apoB gene specifying short truncations of apoB undetectable in plasma. A bolus injection of deuterated palmitate and a primed constant infusion of deuterated leucine were given simultaneously, and their incorporation into VLDL triglycerides and VLDL apoB, respectively, were determined by gas chromatography-mass spectrometry. Kinetic parameters were calculated by using compartmental modeling. VLDL apoB fractional catabolic rates (FCRs) in FHBL heterozygotes and controls were similar (11. 6+/-3.9 and 10.9+/-2.4 pools per day, respectively, P=0.72). On the other hand, FHBL heterozygotes had a 75% decrease in VLDL apoB production rates compared with normal subjects (5.8+/-1.8 versus 23.4+/-7.1 mg/kg per day, P<0.001). The decreased production rates of VLDL apoB accounts for the very low concentrations of plasma apoB found in heterozygotes from these kindreds (24% of normal). Mean VLDL triglyceride FCRs in FHBL subjects and controls were not significantly different (1.06+/-0.74 versus 0.89+/-0.50 pools per hour, respectively, P=0.61). There was a good correlation between VLDL apoB FCR and VLDL triglyceride FCR in the 2 groups (r=0.84, P<0. 001). VLDL triglyceride production rates were decreased by 60% in FHBL heterozygotes compared with controls (9.3+/-6.0 versus 23.0+/-9. 6 micromol/kg per hour, P=0.008). Thus, the hepatic secretion of VLDL triglycerides is reduced in FHBL heterozygotes but to a lesser extent than the decrease in apoB-100 secretion. This is probably achieved by the secretion of VLDL particles enriched with triglycerides.

OBJECTIVE

Small, dense low density lipoprotein (sLDL) is known as an atherogenic lipoprotein and is often associated with metabolic syndrome (MS). A high frequency of sLDL is found in hypertriglyceridemic subjects. Also, fatty liver (FL) is often associated with MS; therefore, we studied whether the association of FL increases sLDL- cholesterol (C) in subjects with MS.

METHODS

In total, 207 patients were enrolled in this study and FL was estimated by echogram. The presence of MS was diagnosed according to the Japanese Guidelines for the Definition of Metabolic Syndrome.

RESULTS

sLDL-C and sLDL-C/LDL-C in the MS group were higher than in the non-MS group. Also, sLDL-C and sLDL-C/LDL-C in the FL group were higher than in the non-FL group. The simple correlation coefficient (r) between plasma triglyceride and sLDL-C or sLDL-C/LDL-C in all subjects was 0.36 and 0.51. In the MS group, r values were 0.32 and 0.52 while, in the non-FL group, r was 0.32 and 0.38, respectively. Two-way ANOVA revealed that FL was a powerful determinant of plasma sLDL-C and sLDL-C/LDL-C, but MS was not. When we divided all subjects into four groups, i.e., MS(-)FL(-), MS(-)FL(+), MS(+)FL(-) and MS(+)FL(+), sLDL-C/LDL-C of MS(+)FL(+) was significantly higher than all other groups.

CONCLUSIONS

Association of MS and FL significantly increased sLDL-C and sLDL-C/LDL-C. The significant relationship between sLDL-C/LDL-C and plasma triglyceride in the FL group indicates that FL may produce triglyceriderich VLDL, a precurser of sLDL, thereby contributing to the appearance of sLDL particles in the plasma of MS patients with FL.

We have previously shown that in Caucasian men and women fat in the trunk, and especially visceral fat, was related to cardiovascular disease (CVD) risk even after adjusting for fat in other depots. We also found that leg fat was negatively related to CVD. In order to determine if these relationships also exist in African-American women, blood lipids, insulin, and blood pressure in 26 pre-menopausal African-American women were evaluated. In addition, magnetic resonance imaging measured fat distribution was evaluated from the lateral malleolus to top of the shoulder. Percent fat was related to VLDL cholesterol, VLDLrol, triglycerides, insulin, and diastolic blood pressure. Inclusion of visceral and trunk fat together in multiple regression did little to improve the relationship with CVD risk. Leg fat, however, tended to be negatively related to CVD risk after adjusting for trunk fat and visceral fat. Partial correlations indicated that leg fat was negatively related to VLDL cholesterol (r = -0.36), triglycerides (r = -0.36), insulin (r = -0.46), and diastolic blood pressure (r = -0.43). These results indicate that in African-American women, visceral fat may be less atherogenic than in Caucasian men and women since it was poorly related to CVD risk after adjusting for fat in the trunk. In addition, consistent with results from Caucasians, leg fat is inversely related to CVD risk after adjusting for fat in other parts of the body. Caution must be made in the interpretation of correlational data. Further research is warranted to explore these intriguing relationships.

Hydroxypropyl methylcellulose (HPMC), a semisynthetic, nonfermentable soluble dietary fiber, is not absorbed by the body, but its presence in the intestinal lumen increases fecal fat, sterol, and bile acid excretions and decreases intestinal cholesterol absorption, all of which may indirectly affect hepatic lipid metabolism. We measured the expression of hepatic genes involved in cholesterol, bile acid, and fatty acid metabolism in hamsters fed diets containing 39% of energy as fat and 5% of weight as HPMC or microcrystalline cellulose (control) for 4 wk. HPMC-fed hamsters gained significantly less body weight than the control group but did not differ in food intake. They had significantly lower plasma triglyceride and total-, VLDL-, HDL-, and LDL-cholesterol concentrations and hepatic total lipid, total and free cholesterol and triglyceride concentrations than controls. Compared with controls, HPMC-fed hamsters had greater levels of mRNA for CYP7A1 (cytochrome P450 7A1; 8-fold of control; P < 0.05), CYP51 (lanosterol 14alpha-demethylase; 5.3-fold of control; P < 0.05), and HMG-CoAR (3-hydroxy-3-methylglutaryl CoA reductase; 1.8-fold of control; P < 0.05). The plasma total cholesterol concentrations from both the control and HPMC groups were inversely correlated with expression of hepatic CYP7A1 (r = -0.54; P < 0.05), CYP51 (r = -0.79; P < 0.005), and HMG-CoAR (r = -0.75; P < 0.005) genes. This suggests that HPMC supplementation affected both cholesterol and bile acid synthesis. Our data confirm that altered hepatic expression of lipid metabolism-related genes, possibly due to modulation of fecal bile acid excretion and intestinal cholesterol absorption, contributes to the lipid-lowering effects of HPMC.

OBJECTIVE

To investigate whether the specific lipoprotein (LP) abnormalities of peritoneal dialysis (PD) are associated with functional variables of this mode of dialysis.

METHODS

A survey of the LP profile in relation to peritoneal dialysis capacity (PDC) variables. The LP profile was compared to that of a group of age- and sex-matched controls.

METHODS

The Peritoneal Dialysis Unit at Sahlgrenska University Hospital in Gothenburg, Sweden.

METHODS

Twenty-two nondiabetic PD patients (5 women, 17 men) who had been on PD for at least 6 months.

METHODS

The LP profile included plasma lipids, apolipoproteins (Apo), and individual ApoA- and ApoB-containing LP. The PDC measurement determined peritoneal glucose uptake, protein losses, effective peritoneal surface area, and total weekly creatinine clearance.

RESULTS

The patients had been on PD for 6 to 48 months (mean 15.3 months) and had a total weekly creatinine clearance of 69.7+/-13.3 L/1.73 m2 body surface area, an average peritoneal glucose uptake corresponding to 446+/-162 kcal/24 hour, and a protein loss of 8.1+/-2.5 g/24 hr. The patients had significantly higher total cholesterol (7.1 mmol/L),VLDL-cholesterol (1.0 mmol/L), LDL-cholesterol (4.7 mmol/L), and triglyceride levels (2.5 mmol/L); whereas the HDL-cholesterol level (1.2 mmol/L) was significantly lower than in controls. The PD patients had increased levels of ApoB-containing LPs, both of the cholesterol-rich LP-B and of the triglyceride-rich LP-B complex, reflected in higher plasma concentrations of ApoB, ApoC-III, and ApoE. Furthermore, they had significantly lower levels of LP-A-I:A-II, as well as of ApoA-I and ApoA-II. The LP-A-I:A-II and ApoA-II levels correlated inversely with the duration of PD treatment (r = 0.54, p < 0.01 and r = 0.52, p < 0.05, respectively). The ApoA-II level was inversely correlated with the peritoneal surface area (r = 0.53, p < 0.05). There were no other correlations between LP variables and PDC variables, nor did any of the LP variables correlate with peritoneal glucose uptake or protein losses.

CONCLUSIONS

The proatherogenic lipoprotein profile of patients on PD is characterized by increased concentrations of cholesterol-rich and triglyceride-rich ApoB-containing LPs. While the duration of treatment appears to have some influence on the development of this type of dyslipidemia, the pathophysiological links to the dialysis mode must be further explored.

In order to assess the short-term effects of hyperinsulinaemia and hyperglycaemia on adipose tissue lipoprotein lipase activity and on serum lipoproteins, we measured these variables in ten normal subjects during euglycaemic and hyperglycaemic hyperinsulinaemic clamps. The mean steady-state plasma glucose and insulin concentrations, respectively, were 4.7 mmol/l and 101 mU/l during euglycaemic moderate-insulin clamp, 4.9 mmol/l and 565 mU/l during euglycaemic high-insulin clamp, and 8.8 mmol/l and 148 mU/l during hyperglycaemic clamp. Saline infusion was used as control. The adipose tissue lipoprotein lipase activity rose significantly over 5 h during high-insulin clamp (p less than 0.01) and during hyperglycaemic clamp (p less than 0.05), but did not change during the moderate-insulin clamp. The magnitude of change of lipoprotein lipase activity from baseline (either rise or fall) was inversely related to the preclamp activity during euglycaemic moderate-insulin clamp (r = -0.67), during hyperglycaemic clamp (r = -0.68) and during infusion of saline (r = -0.75, p less than 0.05). Total serum triglyceride concentration decreased significantly during all clamp studies compared with the control experiment. This change was mainly accounted for by a decrease of VLDL triglyceride. The LDL cholesterol level fell by an average of 5% (p less than 0.05) during the high-insulin clamp and by 10% (p less than 0.05) during the hyperglycaemic clamp. The HDL cholesterol level did not change significantly. It is concluded that adipose tissue lipoprotein lipase activity in man is increased by physiological insulin levels during hyperglycaemia and also by supraphysiological insulin levels during euglycaemia, but is not influenced by physiological hyperinsulinaemia without hyperglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Peroxidation of LDL and other lipoproteins is thought to play a central role in atherogenesis. Dietary thermally oxidised oils may increase atherogenic risk in consumers by increasing their oxidative status. The present paper compares the effects of two diets containing unused sunflower-seed oil (US) or sunflower-seed oil repeatedly used in frying (FS) (both 15 g/100 g diet) on weight gain, food efficiency ratio, serum lipid levels and lipoprotein composition, and the content of thiobarbituric acid-reactive substances (TBARS) in the liver, serum, and lipoproteins in growing Wistar rats. After sixty potato fryings the FS contained 27.7 g polar material/100 g oil and 16.6 g oligomers/100 g oil. The FS-fed rats had a significantly lower weight gain and food efficiency ratio. Liver-TBARS increased due to the consumption of the highly altered oil and showed a significant linear relationship (all r>> 0.68; P < 0.002) with the ingestion of thermally oxidised compounds. Serum-, VLDL-, LDL- and HDL-TBARS were significantly higher in the FS-fed rats (all P < 0.001). Concentrations of serum total and non-esterified cholesterol and phospholipids were significantly higher in the FS-fed rats (P < 0.05, P < 0.05, and P < 0.001, respectively). Serum triacylglycerol concentrations did not vary between the two dietary groups. Total and esterified cholesterol and phospholipid levels increased significantly in the HDL fraction (P < 0.05, P < 0.05, and P < 0.001, respectively) of the FS-fed rats. HDL-cholesterol and HDL-phospholipids were significantly correlated with liver-TBARS (r>> 0.747; P < 0.0001), VLDL-TBARS (r>> 0.642; P < 0.003), LDL-TBARS (r>> 0.475; P < 0.04), and HDL-TBARS (r>> 0.787; P < 0.0001). The data suggest that the rat increases HDL as a protecting mechanism against the peroxidative stress induced by the consumption of a diet containing the thermally oxidised oil.

BACKGROUND

The main purpose of this study was to evaluate the between-instrument variation of the HPLC method for the measurement of total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), VLDL-cholesterol (VLDL-C), chylomicron cholesterol (CM-C), LDL size, and HDL size. Furthermore, the accuracy of the HPLC was assessed for the determination of TC and HDL-C, compared with CDC reference methods.

METHODS

We used four HPLC instruments with different column-load numbers from 250 to 5000. For accuracy assessment of TC and HDL-C, we used the reference methods recommended by the CDC.

RESULTS

The values measured by the four instruments were highly correlated with each other (mean r = 0.965), and the absolute mean differences were 4-43 mg/L for TC, 4-30 mg/L for HDL-C, 0-48 mg/L for LDL-C, 7-66 mg/L for VLDL-C, 0-7 mg/L for CM-C, 0.1-0.3 nm for LDL size, and 0-0.1 nm for HDL size. For TC, the HPLC instruments showed high correlation and good agreement with the reference method: r = 0.997; total error <6.6%; absolute mean bias <1.2%. For HDL-C, the results from the HPLC method were significantly higher (10.8% absolute mean bias) than those of the CDC reference method, in spite of good correlation between the two methods (r = 0.998).

CONCLUSIONS

The between-instrument variation in serum lipoprotein analysis by HPLC was confirmed to be very small. This method met the US National Cholesterol Education Program's performance criteria for TC but not for HDL-C.

OBJECTIVE

To examine changes in plasma lipids and lipoproteins after 51 months of reduced energy intake and sustained weight loss.

METHODS

One-hundred patients were randomized to one of two dietary interventions for 3 months (weight loss period). Groups A and B received an energy-restricted diet plan of 5.2-6.3 MJ/day but group B was further instructed to replace two of three meals with a nutrient-fortified liquid meal replacement (MR). Upon completion of the weight loss period, all patients were given the same instructions regarding energy intake and were advised to use one MR daily. Body weight and 7 day food diaries were measured monthly or bimonthly and blood lipids at baseline, 3, 9 and 51 months.

RESULTS

Of the original 100 patients 75 had completed 4 y. Of those 75, 73 had complete lipid records. Baseline body weights of Groups A and B were 90.7+/-14.0 and 91.6+/-9.8 kg, respectively. The percentage change in total cholesterol (%DeltaTC) decreased in a linear fashion with increasing weight loss, when all data was combined, but did not approach statistical significance (P< or =0.26, r=0.02). Further regression analysis found a significant negative linear relationship (P< or =0.0001, r=0.69) between initial total cholesterol (TC) concentrations and %DeltaTC. Hence, data from 27 of the 73 completers who exhibited an elevated serum total cholesterol >> or =6.2 mmol/l) were isolated and analyzed further. Baseline TC was 6.75+/-0.64, 5.85+/-0.63 at 9 months (P<0.05) and 5.76+/-0.52 mmol/l at 51 months (P<0.05). Similar values for VLDL-cholesterol were 1.33+/-0.80, 0.74+/-0.24 and 0.66+/-0.21 mmol/l by 51 months (P<0.05). Weight decreased by 5.2+/-5.1, 7.6+/-4.9 and 6.7+/-4.6% at 3, 9 and 51 months, respectively.

CONCLUSIONS

Continuous energy restriction associated with a clinically meaningful weight loss significantly improved the lipid profile of high-risk patients. Similar weight and diet changes occurring in patients with normal plasma cholesterol were either increased or without affect.

Yorkshire (lean) and Ossabaw (obese) swine ca. one year of age were used to characterize the quantity and composition of plasma lipoproteins in animals with markedly different adiposity. While lean swine weighted more (175 vs 88 kg for obese), they had less backfat than obese swine (2.64 vs 5.97 cm; P < 0.05). Fasting plasma triacylglycerol (Tg) and cholesterol (CH) levels were elevated in obese swine. Swine plasma lipoproteins were fractionated into very low density lipoprotein (VLDL; d < 1.006), low density lipoprotein (LDL; d = 1.019-1.063), low density lipoprotein (LDL; d = 1.063-1.09), and high density lipoprotein (HDL; d = 1.09-1.21) by density ultracentrifugation. Obese VLDL-Tg, CH and protein (Pr) were elevated more than 2-fold. VLDL from obese swine were 2-fold larger than VLDL from lean swine. No alterations in LDL or LDL composition were observed. HDL-Tg, CH. Pr and phospholipid levels were significantly higher in obese swine. Plasma and VLDL-Tg levels were highly correlated with backfat thickness (r = 0.67 and r = 0.73, respectively). There was a positive correlation between adiposity and HDL-CH as well as VLDL-Tg and HDL-CH. These data indicate that (a) there are marked alterations in swine plasma lipoprotein composition between lean and obese swine; (b) that swine plasma lipoprotein levels may be useful parameters in estimating body composition; and (c) that HDL-CH is positively correlated with adiposity in swine.

OBJECTIVE

Reduced growth hormone (GH) secretion is observed in obesity and may contribute to increases in cardiovascular disease (CVD) risk. Lipoprotein characteristics including increased small dense low-density lipoprotein (LDL) particles are known independent risk factors for CVD. We hypothesized that reduced GH secretion in obesity would be associated with a more atherogenic lipid profile including increased small dense LDL particles.

METHODS

To evaluate this hypothesis, we studied 102 normal weight and obese men and women using standard GH stimulation testing to assess GH secretory capacity and performed comprehensive lipoprotein analyses including determination of lipoprotein particle size and subclass concentrations using proton NMR spectroscopy.

RESULTS

Obese subjects were stratified into reduced or sufficient GH secretion based on the median peak-stimulated GH (≤6·25 μg/l). Obese subjects with reduced GH secretion (n = 35) demonstrated a smaller mean LDL and HDL particle size in comparison to normal weight subjects (n = 33) or obese subjects with sufficient GH (n = 34) by ANOVA (P < 0·0001). Univariate analyses demonstrated peak-stimulated GH was positively associated with LDL (r = 0·50; P < 0·0001) and HDL (r = 0·57; P < 0·0001), but not VLDL (P = 0·06) particle size. Multivariate regression analysis controlling for age, gender, race, ethnicity, tobacco, use of lipid-lowering medication, BMI and HOMA demonstrated peak-stimulated GH remained significantly associated with LDL particle size (β = 0·01; P = 0·01; R(2) = 0·42; P < 0·0001 for overall model) and HDL particle size (β = 0·008; P = 0·001; R(2) = 0·44; P < 0·0001 for overall model).

CONCLUSIONS

These results suggest reduced peak-stimulated GH in obesity is independently associated with a more atherogenic lipoprotein profile defined in terms of particle size.

OBJECTIVE

The aim of this study was to investigate serum leptin, oxidized low density lipoprotein (ox-LDL) and asymmetric dimethylarginine (ADMA) levels and their interaction with dyslipidaemia in adolescents with polycystic ovary syndrome (PCOS).

METHODS

The study group consisted of 23 obese (obPCOS) and 21 nonobese girls with PCOS (nPCOS), and 31 lean healthy controls. PCOS was defined by the National Institutes of Health (NIH) criteria as the presence of chronic oligoanovulation and hyperandrogenism. Fasting leptin, ox-LDL, ADMA and detailed lipid-lipoprotein profile were determined. Atherogenic index (AI) was calculated as [Total cholesterol - HDL cholesterol/HDL cholesterol]. Logarithmic transformations were made for ox-LDL.

RESULTS

Total cholesterol, triglycerides, LDL cholesterol, very low density lipoprotein (VLDL) cholesterol, apolipoprotein B, lipoprotein A levels and AI were higher and apolipoprotein AI was lower in obPCOS compared to those in controls (P < 0.05). LDL cholesterol, apolipoprotein B and lipoprotein A levels were higher in nPCOS compared to controls (P < 0.05). ADMA and ox-LDL levels did not differ in the three groups. Leptin was significantly higher in obPCOS compared with that in the other two groups (P < 0.001) and it was correlated with triglycerides (r = 0.62), VLDL cholesterol (r = 0.45), lipoprotein A (r = 0.38) and AI (r = 0.43) in the PCOS group (P < 0.05).

CONCLUSIONS

Our data demonstrate that ADMA and ox-LDL levels in adolescent PCOS subjects were not different than those in controls. Abnormal lipid profile was shown in obese and nonobese girls with PCOS and leptin was related with these lipid abnormalities in the PCOS subjects.

The prevalence of metabolic disorders varies among ethnic populations and these disorders represent a critical health care issue for elderly women. This study investigated the correlation between genetic ancestry and body composition, metabolic traits and clinical status in a sample of elderly women. Clinical, nutritional and anthropometric data were collected from 176 volunteers. Genetic ancestry was estimated using 23 ancestry-informative markers. Pearsons correlation test was used to examine the relationship between continuous variables and an independent samples t-test was used to compare the means of continuous traits within categorical variables. Overall ancestry was a combination of European (57.49%), Native American (25.78%) and African (16.73%). Significant correlations were found for European ancestry with body mass index (r = 0.165; p = 0.037) and obesity (mean difference (MD) = 5.3%; p = 0.042). African ancestry showed a significant correlation with LDL (r = 0.159, p = 0.035), VLDL (r = -0.185; p = 0.014), hypertriglyceridemia (MD = 6.4%; p = 0.003) and hyperlipidemia (MD = 4.8%; p = 0.026). Amerindian ancestry showed a significant correlation with triglyceride levels (r = 0.150; p = 0.047) and hypertriglyceridemia (MD = 4.5%; p = 0.039). These findings suggest that genetic admixture may influence the etiology of lipid metabolism-related diseases and obesity in elderly women.

Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis remains undefined. To analyze the impact of gut microbiota on atherothrombosis, we rederived low-density lipoprotein receptor-deficient (Ldlr^-/- ) mice as germfree (GF) and kept these mice for 16 weeks on an atherogenic high-fat Western diet (HFD) under GF isolator conditions and under conventionally raised specific-pathogen-free conditions (CONV-R). In spite of reduced diversity of the cecal gut microbiome, caused by atherogenic HFD, GF Ldlr^-/- mice and CONV-R Ldlr^-/- mice exhibited atherosclerotic lesions of comparable sizes in the common carotid artery. In contrast to HFD-fed mice, showing no difference in total cholesterol levels, CONV-R Ldlr^-/- mice fed control diet (CD) had significantly reduced total plasma cholesterol, very-low-density lipoprotein (VLDL), and LDL levels compared with GF Ldlr^-/- mice. Myeloid cell counts in blood as well as leukocyte adhesion to the vessel wall at the common carotid artery of GF Ldlr^-/- mice on HFD were diminished compared to CONV-R Ldlr^-/- controls. Plasma cytokine profiling revealed reduced levels of the proinflammatory chemokines CCL7 and CXCL1 in GF Ldlr^-/- mice, whereas the T-cell-related interleukin 9 (IL-9) and IL-27 were elevated. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF Ldlr^-/- mice relative to CONV-R Ldlr^-/- mice. Ex vivo, this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF Ldlr^-/- mice on type III collagen.IMPORTANCE Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF Ldlr^-/- mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished ex vivo thrombus formation under arterial flow conditions.

BACKGROUND

Hepatic steatosis (HS) is closely associated to metabolic syndrome (MS). Both, VLDL-triglyceride oversecretion and intrahepatic deposits, can take place. We evaluated VLDL characteristics, CETP, hepatic lipase (HL), IDL and small dense LDL (sdLDL), in patients with HS associated to MS.

METHODS

We studied 3 groups matched by age and sex: 25 MS patients with HS (diagnosed by ultrasonography), 25 MS patients without HS and 25 healthy controls. Main measurements were: lipid profile, free fatty acids, VLDL composition, VLDL size by HPLC, CETP and HL activities, IDL-cholesterol and sdLDL-cholesterol.

RESULTS

Patients with HS presented higher triglyceride levels, HOMA-IR and free fatty acids, VLDL mass and VLDL-apoB (p<0.05). No differences in VLDL composition were observed. MS groups presented higher proportion of large VLDL than controls (p<0.05). HS group showed higher CETP than controls (p=0.01) and almost higher than MS without HS (p=0.06). CETP correlated with VLDL-cholesterol content, r=0.48, p<0.005. The increase in sdLDL-cholesterol correlated with CETP (r=0.47) and HL (r=0.56), independent of insulin resistance (p<0.003).

CONCLUSIONS

Despite intrahepatic fat, patients with HS secreted higher number of VLDL particles. CETP would have a remodeling action on VLDL in circulation, enriching it in cholesterol and also favoring, together with HL, the formation of sdLDL.

BACKGROUND

The relationship between CETP and postprandial hyperlipemia is still unclear. We verified the effects of varying activities of plasma CETP on postprandial lipemia and precocious atherosclerosis in asymptomatic adult women.

METHODS

Twenty-eight women, selected from a healthy population sample (n = 148) were classified according to three CETP levels, all statistically different: CETP deficiency (CETPd ≤ 4.5%, n = 8), high activity (CETPi ≥ 23.8, n = 6) and controls (CTL, CETP ≥ 4.6% and ≤ 23.7%, n = 14). After a 12 h fast they underwent an oral fat tolerance test (40 g of fat/m² of body surface area) for 8 hours. TG, TG-rich-lipoproteins (TRL), cholesterol and TRL-TG measurements (AUC, AUIC, AR, RR and late peaks) and comparisons were performed on all time points. Lipases and phospholipids transfer protein (PLTP) were determined. Correlation between carotid atherosclerosis (c-IMT) and postprandial parameters was determined. CETP TaqIB and I405V and ApoE-ε3/ε2/ε4 polymorphisms were examined. To elucidate the regulation of increased lipemia in CETPd a multiple linear regression analysis was performed.

RESULTS

In the CETPi and CTL groups, CETP activity was respectively 9 and 5.3 higher compared to the CETPd group. Concentrations of all HDL fractions and ApoA-I were higher in the CETPd group and clearance was delayed, as demonstrated by modified lipemia parameters (AUC, AUIC, RR, AR and late peaks and meal response patterns). LPL or HL deficiencies were not observed. No genetic determinants of CETP deficiency or of postprandial lipemia were found. Correlations with c-IMT in the CETPd group indicated postprandial pro-atherogenic associations. In CETPd the regression multivariate analysis (model A) showed that CETP was largely and negatively predicted by VLDL-C lipemia (R² = 92%) and much less by TG, LDL-C, ApoAI, phospholipids and non-HDL-C. CETP (model B) influenced mainly the increment in ApoB-100 containing lipoproteins (R² = 85% negatively) and phospholipids (R² = 13%), at the 6(th)h point.

CONCLUSIONS

The moderate CETP deficiency phenotype included a paradoxically high HDL-C and its sub fractions (as earlier described), positive associations with c-IMT, a postprandial VLDL-C increment predicting negatively CETP activity and CETP activity regulating inversely the increment in ApoB100-containing lipoproteins. We hypothesize that the enrichment of TG content in triglyceride-rich ApoB-containing lipoproteins and in TG rich remnants increases lipoproteins' competition to active lipolysis sites,reducing their catabolism and resulting on postprandial lipemia with atherogenic consequences.

BACKGROUND

In recent years, there has been a growing interest in understanding the pathogenic pathways of premature accelerated atherosclerosis (AS) in systemic lupus erythematosus (SLE). However, the role of both traditional and non-traditional, SLE-specific risk factors is still under debate.

OBJECTIVE

To assess surrogate biomarkers of subclinical AS in SLE and to evaluate potential relations with cardiovascular risk factors.

METHODS

Prospective observational study on 35 consecutive SLE women (ACR 1987 diagnostic criteria) evaluated according to a standard protocol including traditional cardiovascular risk factors (hypertension, obesity, diabetes mellitus, cigarette smoking, abnormal lipid metabolism), SLE-specific risk factors (renal disease, SLE activity and duration, corticosteroid therapy) and surrogate biomarkers of subclinical AS (carotid intima-media thickness, plaque) (B-mode color Doppler ultrasound, 7-10 MHz probe). Data were analyzed in SPSS 16 software, p<0.05.

RESULTS

Significant differences (p<0.05) among subgroups (with and without plaque, thickened and normal intima) have been registered; moreover, statistical significant correlations between cIMT and age (r=0.476), age at onset (r=0.451), VLDL (r=0.382), hsCRP (r=0.436), Framingham score (r=0.421) have been reported. In addition, significant association between homocysteine and SLE-duration (r=0.460), SLEDAI (r=0.466), SLICC÷ACR (r=0.846) has been demonstrated, while hsCRP was associated with ESR (r=0.472), C3 (r=0.396), SLEDAI (r=0.569) and age (r=-0.681). Several predictors for increased cIMT have also been identified (ANOVA): hsCRP (p=0.016), VLDL (p=0.037), Framingham (p=0.012).

CONCLUSIONS

Our data advocate for increased cardiovascular burden in SLE and support the value of cIMT and carotid plaque as surrogate AS biomarkers in women with SLE.

Several studies have demonstrated suppression of aortic atherosclerosis by dipeptidyl peptidase-4 (DPP-4) inhibitors in hypercholesterolemic mice. However, it remains unknown whether DPP-4 inhibitors also exert anti-atherogenic effects in coronary arteries. We examined the effect of anagliptin, a DPP-4 inhibitor, on atherosclerosis development in the aorta and coronary arteries in a high-cholesterol diet-fed rabbits.

Japanese white rabbits were fed either normal chow (n=8) or a diet containing 0.5% cholesterol (n=34) for 14weeks. Cholesterol-fed rabbits were given 0.3% anagliptin or not in drinking water (each n=16 and 18) for 12weeks.

Dietary cholesterol intake markedly increased serum total cholesterol (TC) levels (1464±150mg/dL, mean±SE), and the most striking increase was observed among the major lipoproteins in very low-density lipoprotein (VLDL) as determined by high-performance liquid chromatography. No significant changes were observed in body weight, water intake, hemoglobin A1c, or glucose response to intravenous glucose loading following anagliptin administration. Anagliptin decreased TC and VLDL-cholesterol as well as cholesterol absorption markers sitosterol and campesterol slightly, although not significantly. Serum DPP-4 activity was suppressed by 82%, and active glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide levels were increased 2- to 3-fold by anagliptin treatment. Severe hypercholesterolemia resulted in the development of atherosclerosis in the aorta, and the ratio of atherosclerotic lesions to the total aortic surface area was 22±2%. Anagliptin suppressed the lesion ratio to 9±2% (p<0.001). Atherosclerotic lesions were clearly observed in the coronary arteries, where the mean intima-media area was enlarged, and intimal formation was developed. Anagliptin treatment attenuated the intima-media area and the intimal area by 43%. Alpha-smooth muscle actin-positive and macrophage-positive areas in the coronary arteries were suppressed by 66 and 75%, respectively, after anagliptin treatment. The aortic lesion ratio and the coronary intima area were correlated with each other (r=0.506, p<0.01), and each lesion correlated with TC in the whole cholesterol-fed rabbits. Gene expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in the carotid arteries was markedly reduced by approximately 90%, and vascular DPP-4 activity was reduced by 66% after anagliptin treatment.

We demonstrated for the first time that a DPP-4 inhibitor can substantially suppress plaque formation in coronary arteries with a marked reduction in macrophage accumulation likely via its anti-inflammatory properties.

BACKGROUND

It is uncertain whether pharmacological reductions in very-low-density lipoproteins (VLDLs), and their component triglyceride and cholesterol could reduce residual risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals in whom low-density lipoprotein cholesterol (LDL-C) has been adequately lowered. We examined whether individuals with greater on-statin reductions in VLDL-related measures-beyond reductions in LDL-C-were at further reduced risk of ASCVD.

RESULTS

In 9423 participants in the JUPITER (Justification for the Use of Statins in Prevention) trial (NCT00239681), at baseline and on statin we measured standard lipids, 400-MHz proton nuclear magnetic resonance spectroscopy-measured <em>VLDL</em> particle subclasses (small, medium, and large <em>VLDL</em> lipoprotein particle concentration), and total <em>VLDL</em> cholesterol mass. Compared with individuals allocated to placebo, we examined risk of incident ASCVD (N=211) among statin-allocated participants who achieved minimal (<median) or greater (≥median) marker reductions using adjusted Cox models. On-statin changes in <em>VLDL</em>-related markers were only modestly correlated (Spearman r≤0.29) with change in LDL-C. On-statin median LDL-C was 54 mg/dL and triglyceride was 101 mg/dL. Dose-response reductions in ASCVD risk were observed for greater reductions in LDL-C, <em>VLDL</em> cholesterol mass, and small <em>VLDL</em> lipoprotein particle concentration; the latter 2 remained significant after incremental adjustment for change in LDL-C (P≤0.006). Conversely, there was no further risk reduction with greater reductions in triglycerides or large/medium <em>VLDL</em> lipoprotein particle concentration.

CONCLUSIONS

Pharmacological reduction in small, cholesterol-enriched, triglyceride-depleted VLDL was associated with reduction in ASCVD risk. Chemically measured triglycerides may not sufficiently capture risk related to VLDL pathways. These findings also support broader profiling of lipid and lipoprotein changes in response to statins as prognostic markers of individual benefit, supporting more precision-medicine, individualized approaches to cardiovascular risk reduction.

BACKGROUND

URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Blood transfusion can be a life-saving therapy for β-thalassemia major and β-thalassemia/HbE (β-TM) patients with chronic anemia, major caused severe iron overload particularly in β-TM patients received only blood transfusion therapy. We aim to evaluate the association of iron overload with oxidative stress, liver damage, and elevated very low density lipoprotein cholesterol (VLDL-C) in transfusion-dependent β-TM patients. Serum ferritin, malondialdehyde (MDA), liver profiles, triglycerides levels, and VLDL-C were significantly higher while total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein cholesterol and total antioxidant capacity were lower in β-TM than controls. Serum ferritin was significantly correlated with MDA, liver enzymes and lipid profiles (p < 0.05). Multiple forward stepwise linear regression analyses of the significant variables showed that in these β-TM patients, independent predictors of iron overload were MDA (β = 0.410, r (2) = 0.671, p < 0.001), ALT (β = 0.493, r (2) = 0.578, p < 0.001), and VLDL-C (β = 0.253, r (2) = 0.711, p < 0.001). In conclusion, iron overload associated with increased oxidative stress, lipid peroxidation, liver damage, decreased TC, LDL-C, HDL-C and over production of VLDL-C, is significantly problem in transfusion-dependent β-TM patients. These appeared the major cause of future morbidity and mortality in β-TM patients.

LDL receptor-deficient (LDLR(-/-)) mice fed a Western diet exhibit severe hyperlipidemia and develop significant atherosclerosis. Apolipoprotein E (apoE) is a multifunctional protein synthesized by hepatocytes and macrophages. We sought to determine effect of macrophage apoE deficiency on severe hyperlipidemia and atherosclerosis. Female LDLR(-/-) mice were lethally irradiated and reconstituted with bone marrow from either apoE(-/-) or apoE(+/+) mice. Four weeks after transplantation, recipient mice were fed a Western diet for 8 weeks. Reconstitution of LDLR(-/-) mice with apoE(-/-) bone marrow resulted in a slight reduction in plasma apoE levels and a dramatic reduction in accumulation of apoE and apoB in the aortic wall. Plasma lipid levels were unaffected when mice had mild hyperlipidemia on a chow diet, whereas IDL/LDL cholesterol levels were significantly reduced when mice developed severe hyperlipidemia on the Western diet. The hepatic VLDL production rate of mice on the Western diet was decreased by 46% as determined by injection of Triton WR1339 to block VLDL clearance. Atherosclerotic lesions in the proximal aorta were significantly reduced, partially due to reduction in plasma total cholesterol levels (r=0.56; P<0.0001). Thus, macrophage apoE-deficiency alleviates severe hyperlipidemia by slowing hepatic VLDL production and consequently reduces atherosclerosis in LDLR(-/-) mice.

Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis, but the underlying mechanisms are unclear. The size and number of lipoprotein particles may be better predictors of atherosclerosis than conventional cholesterol measurements. We measured lipoprotein subclasses by nuclear magnetic resonance spectroscopy (NMR), coronary artery calcification by electron beam computed tomography, and insulin resistance by homeostasis model assessment in 105 patients with SLE and 77 control subjects. VLDL particles were larger (50.0+/-8.5 versus 47.7+/-8.5 nm, P=0.01) and concentrations of large high-density lipoprotein (HDL) particles lower (10.1+/-5.3 versus 11.3+/-5.1 nmol/L, P=0.03) in patients with SLE than controls. In patients with SLE, small LDL concentration was associated with body mass index (rho=0.27), insulin resistance (rho=0.34), C-reactive protein (CRP; rho=0.30), and erythrocyte sedimentation rate (ESR; rho=0.20); all P<0.05. Large HDL concentration was inversely associated with insulin resistance (rho=-0.29), disease activity (rho=-0.23), and ESR (rho=-0.39); all P<0.05. VLDL concentrations correlated with CRP (rho=0.22), ESR (rho=0.24), disease damage (rho=0.20), and corticosteroid exposure (rho=0.29); all P<0.05. Neither the concentration of lipoprotein subclasses nor particle size was associated with coronary artery atherosclerosis. There were only minor differences in the NMR lipid profiles of patients with SLE and controls. Lipoprotein subclasses were associated with metabolic variables, inflammatory markers, and corticosteroid use but not with coronary artery atherosclerosis in SLE.

The efflux of cholesterol from cells and its incorporation into HDL is believed to be the initial step in reverse cholesterol transport. This report addresses the question of whether there is a relationship between the ability of serum to promote efflux of cholesterol from cells in culture and the severity of coronary artery atherosclerosis (CAA). Surgically postmenopausal cynomolgus monkeys (n=142) were treated for 2-years with conjugated equine estrogens (CEE), CEE plus medroxyprogesterone acetate, or two different doses of tibolone, a synthetic steroid. CAA was determined at necropsy, and the cholesterol efflux potential of serum from each animal was determined using 3H-cholesterol-labeled Fu5AH cells and human skin fibroblasts in culture. A significant negative correlation was seen between CAA and cholesterol efflux from Fu5AH cells (r=-0.44, P< or =0.0001), but not skin fibroblasts. Although there was a wide range of plasma HDL cholesterol concentrations in these animals (10-81 mg/dl), using multiple regression analysis, LDL+VLDL cholesterol and the serum cholesterol efflux potential were the only significant independent predictors of CAA, explaining 41.6 and 10.7% of the variability (P<0.0001), respectively. Thus, the potential of serum to promote cholesterol efflux from Fu5AH cells may represent a useful independent measure for improving the assessment of CAA risk.

The ability to discriminate between stereoisomers of alpha-tocopherol was studied in five patients with abetalipoproteinemia (ABL) because an impairment in secretion of apolipoprotein B-containing lipoproteins might impede the normally enhanced plasma transport of RRR-alpha-tocopherol. An oral dose containing 3.7 g of each 2R, 4'R,8'R-alpha-[5-C2H3]tocopheryl acetate (d3RRR-alpha-tocopheryl acetate) and 2RS,4'RS,8'RS-alpha-[5,7-(C2H3)2]tocopheryl acetate (d6 all rac-alpha-tocopheryl acetate) was administered, then the labeled and unlabeled alpha-tocopherol contents of plasma and red blood cells from multiple blood samples obtained at selected times up to 72 h following the dose were quantitated. ABL plasma contained about 1%-10% of the d3-RRR-alpha-tocopherol concentrations of normal subjects given only 150 mg of each isotope. Three of the patients discriminated between forms of alpha-tocopherol with ratios of RRR-/allrac-alpha-tocopherol>> or = 1.8, similar to normals. These data suggest that the hepatic tocopherol binding protein is present and functional in ABL patients. Although two of the patients did not discriminate between stereoisomers of alpha-tocopherol, it is likely that this resulted from nearly a complete block in very low density lipoprotein (VLDL) secretion. Thus, the ability of ABL patients to absorb and transport orally administered vitamin E is markedly impaired and variable among patients.