Effect of the microsomal triglyceride transfer protein -493 G/T polymorphism and type 2 diabetes mellitus on LDL subfractions

Genetic variation in the microsomal triglyceride transfer protein (MTP) affects the secretion pattern and plasma concentration of apolipoprotein (aopB)-containing lipoproteins and a common functional -493 G/T polymorphism has been reported to influence plasma lipids levels. Recent data suggest that carriers of the T allele might be more sensitive to detrimental factors such as features of the insulin resistance syndrome. Since type 2 diabetes is associated with obesity and insulin resistance, the present study investigated the effect of this polymorphism on plasma lipids, apoB and LDL subfractions in 281 Chinese type 2 diabetic subjects and 364 non-diabetic controls. The frequency of the rare T allele was 0.162 and 0.126 in subjects with and without diabetes respectively. There were no differences in the effect of the polymorphism on plasma lipids and apoB in the two groups. However, the TT genotype was associated with a higher concentration of small dense LDL-III than the GT or GG variants in the diabetic subjects (P=0.01) whereas no such effect was observed in the controls. In the diabetic patients, age, plasma triglyceride and the MTP genotype were independent determinants of LDL-III concentrations in linear regression analysis (R(2)=10%, P=0.04) whereas in the controls, only plasma triglyceride and age were important determinants (R(2)=15%, P=0.01). In conclusion, the -493 G/T polymorphism only has a minor effect on LDL subfraction pattern in Chinese and the effect is only apparent in the presence of type 2 diabetes.     

Visceral obesity and hyperinsulinemia modulate the impact of the microsomal triglyceride transfer protein -493G/T polymorphism on plasma lipoprotein levels in men

The dyslipidemic state of visceral obesity is characterized by increased plasma triglyceride levels, low high-density lipoprotein-cholesterol concentration and alterations in low-density lipoprotein (LDL) composition and concentration. A functional, non-coding microsomal triglyceride transfer protein (MTP) −493G/T polymorphism of the microsomal triglyceride transfer protein gene has been related to variations in LDL-cholesterol levels. To study the effect of the MTP −493G/T polymorphism on lipoprotein levels in visceral obesity and hyperinsulinemia, a total of 227 men were assigned into two groups on the basis of their MTP −493G/T polymorphism, including 121 GG homozygotes and 105 carriers of the T allele (92 GT and 13 TT). The two genotypic groups did not differ for their physiological characteristics nor for lipoprotein–lipid profiles, before and after adjustment for age. However, GG homozygotes were characterized by higher fasting insulin levels than carriers of the T allele (P<0.05). When the two genotypic groups were further divided on the basis of their visceral adipose tissue (AT) accumulation, assessed by computed tomography, we observed that T allele carriers with low levels of visceral AT (<130 cm²) had decreased plasma total cholesterol and LDL-apolipoprotein B (LDL-apoB) levels compared to viscerally obese men (P=0.035 and P=0.0001, respectively). Among GG homozygotes, no significant difference were observed. Although not significant, T allele carriers characterized by visceral obesity tended to have smaller, denser LDL particles than T allele carriers characterized by a low accumulation of visceral AT. When subjects were divided on the basis of their fasting insulin levels, it appears that hyperinsulinemic men were characterized by a deteriorated lipoprotein–lipid profile when they were carriers of the T allele compared to normoinsulinemic men. In summary, visceral obesity and hyperinsulinemia modulate the impact of the MTP −493G/T polymorphism on plasma total cholesterol and LDL-apoB levels, as well as on LDL peak particle diameter.     

Genetic variants of ApoE account for variability of plasma low-density lipoprotein and apolipoprotein B levels in FHBL

We report two novel APOB mutations causing short apolipoprotein B (apoB) truncations undetectable in plasma and familial hypobetalipoproteinemia (FHBL). In Family 56, a 5 bp deletion in APOB exon 7 (870_874del5) causes a frame shift, converting tyrosine to a stop codon (Y220X) and producing an apoB-5 truncation. In Family 59, a point mutation (1941G>T) in APOB exon 13 converts glutamic acid to stop codon (E578X), specifying apoB-13. A recurrent mutation in exon 26 (4432delT) produces apoB-30.9 in Family 58. In some members of these families, we observed that plasma low-density lipoprotein (LDL) cholesterol and apoB levels were unusually low even for subjects heterozygous for FHBL. To ascertain whether genetic variations in apolipoprotein E (apoE) would explain some of the variations of apoB and LDL cholesterol levels, apoE genotypes were assessed in affected subjects from a total of eight FHBL families with short apoB truncations. Heterozygous FHBL with the epsilon3/epsilon4 genotype had 10-1 5mg/dL higher plasma LDL cholesterol and apoB levels compared to subjects with the epsilon2/epsilon3 and epsilon3/epsilon3 genotypes. The apoE genotype has been reported to account for approximately 10% of the variation of LDL cholesterol in the general population. It accounted for 15-60% of the variability of plasma LDL cholesterol or apoB levels in our FHBL subjects. The physiologic bases for the greater effects of apoE in FHBL remain to be determined.     

Low-density lipoprotein cholesterol/apolipoprotein B ratio may be a useful index that differs in statin-treated patients with and without coronary artery disease: a case control study

Low density lipoproteins (LDLs) are heterogeneous aggregations of molecules of different particle sizes, and small-size LDLs are more potent risk factors for atherosclerosis. We examined the qualitative characteristics of LDLs in patients with stable coronary artery disease (CAD) receiving statin therapy. LDL-particle size was estimated based on the LDL-cholesterol/apolipoprotein B ratio (LDL-C/apoB) in 214 age-adjusted men receiving statin therapy. The LDL-C/apoB ratio was significantly lower in the CAD (+) group (n = 107) than in the CAD (-) group (n = 107) (median, 1.17 versus 1.19, P = 0.0095). LDL-C/apoB was significantly lower in patients with serum TG ≥ 150 mg/dL than in those with serum TG < 150 mg/dL, and in patients with serum HDL-C < 40 mg/dL than in those with serum HDL-C ≥ 40 mg/dL (1.06 versus 1.18, P = 0.012; 1.08 versus 1.22, P = 0.0023). Stepwise logistic regression analysis revealed that elevated serum TG was an independent predictor for smaller sizes of LDLs, both in the overall subjects (β : -0.165, P = 0.02) as well as in the subset with serum LDL-C < 100 mg/dL (β : -0.252, P = 0.011). This study demonstrated that not only the absolute serum LDL-C level, but also the qualitative characteristics of LDL may be monitored for secondary prevention of CAD. Such monitoring is particularly important in patients with elevated serum TG levels, which is associated with smaller sizes of LDL-particles.     

Fish oil supplementation does not lower plasma cholesterol in men with hypercholesterolemia. Results of a randomized, placebo-controlled crossover study

STUDY OBJECTIVE: To determine the effects of fish oil supplementation on plasma cholesterol in middle-aged men with isolated hypercholesterolemia. DESIGN: Randomized double-blind placebo-controlled (safflower oil) two-period crossover trial with 12-week treatment periods. SETTING: Outpatient general medicine clinic at a university-affiliated Veterans Affairs hospital. PATIENTS: Thirty-eight men with plasma cholesterol between 5.68 and 7.76 mmol/L (220 to 300 mg/dL), triglyceride levels less than 3.39 mmol/L (300 mg/dL), and free of coexisting diseases. INTERVENTIONS: Fish oil and placebo (safflower oil) supplementation. After basal measurements and a 4-week lead-in period, twenty 1-g capsules of either fish oil or placebo oil were provided for 12 weeks (period 1). After a 4-week washout phase participants then received the other oil for an additional 12 weeks (period 2). MEASUREMENTS AND MAIN RESULTS: Blood was drawn at the beginning and end of each study period and analyzed for levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A1, and apolipoprotein B. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald equation. Total and LDL cholesterol increased from the before treatment values by 4.8% and 9.1%, respectively, after ingestion of fish oil. Compared with placebo, LDL cholesterol was significantly higher (4.5 compared with 4.1 mmol/L, P = 0.01) and triglycerides lower (1.3 compared with 1.8 mmol/L, P = 0.01) after fish oil. Total and HDL cholesterol and apolipoprotein A1 and B levels did not differ. CONCLUSIONS: Fish oil supplements do not lower plasma cholesterol levels in middle-aged men with hypercholesterolemia without elevated triglycerides. They should not be recommended as a method to lower plasma cholesterol in these patients.     

SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women

Insulin regulates apoB metabolism via activation of PI3K or regulation of MTP via MAPK/ERK signalling. SHP-2 enhances both pathways through increased IRS-1 phosphorylation. We hypothesized that variants in the SHP-2 gene PTPN11 and PI3K p85alpha subunit gene PIK3R1 may influence fasting levels of plasma apoB and/or LDL cholesterol. We tested association of tagging SNPs (tSNPs) in each gene with serum lipids in a large sample of unselected population-based Caucasian female twins (n=2771, mean age 47.4+/-12.5 years) and then tested interaction between tSNPs in determining apoB and LDL levels. PTPN11 tSNP rs11066322 was associated with apoB (P=0.007) and rs11066320 was associated with LDL cholesterol (P=0.016). PIK3R1 tSNP rs251406 was associated with apoB (P=0.0003) and rs706713 was associated with LDL cholesterol (P=0.009). PTPN11 tSNP rs11066322 interacted with PIK3R1 tSNP rs251406 in determining serum apoB levels (P=0.012) and with PIK3R1 tSNP rs40318 in determining LDL cholesterol levels (P=0.009). Association of single tSNPs with both apoB and LDL cholesterol as well as interactions between the two genes suggest that variants influencing SHP-2 activity may modulate the acute pathway by which insulin regulates these lipids.     

Myocardial infarction in young adults with low-density lipoprotein cholesterol levels < or = 100 mg/dL: clinical profile and 1-year outcomes.

STUDY OBJECTIVES: To define the clinical profile of young adults with optimal low-density lipoprotein (LDL) cholesterol levels who present with acute myocardial infarctions (MIs); to compare and contrast differences in the clinical profiles of young adults admitted to the hospital with MIs who have LDL cholesterol levels < or = 100 mg/dL and those with LDL cholesterol values > or = 160 mg/dL; and to evaluate the clinical outcomes for the two groups at 1 year. DESIGN: A retrospective chart review was conducted on all young men (55 years) and women (65 years) admitted to the hospital for MIs within a 2-year period (n = 232). A history of cardiovascular risk factors and 1-year outcomes were obtained. SETTING: Rural community medical center serving a tri-state area in the midwestern United States. PATIENTS: Patients were included in this analysis if (1) a lipid profile was drawn within 24 h of hospital admission and (2) the patient was not receiving a statin medication on hospital admission. MEASUREMENTS AND RESULTS: Of the 183 patients who met the inclusion criteria, as many as 68% (124 patients) had LDL cholesterol levels of < or = 130 mg/dL, 29% (53 patients) had LDL cholesterol level of < or = 100 mg/dL, and only 14% (26 patients) had LDL cholesterol levels of > or = 160 mg/dL. Patients were categorized into group 1 if their LDL cholesterol level was < or = 100 mg/dL and were categorized into group 2 if their LDL cholesterol level was > or = 160 mg/dL. In group 2, 92% of patients were placed on a statin medication. By 1 year, the mean LDL cholesterol level had decreased from 188 to 106 mg/dL. The rate of coronary artery bypass graft and percutaneous coronary intervention procedures was similar between groups. Hospital readmission rates (43.4% vs 50%, respectively) and 1-year mortality rates (9% vs 8%, respectively) were not different between groups group 1 and 2. CONCLUSIONS: Young adults experiencing acute MIs typically have acceptable cholesterol levels (ie, < or = 130 mg/dL) or optimal values (ie, < or = 100 mg/dL). In those patients with abnormal cholesterol levels, a combined strategy of aggressive intervention and adherence to secondary prevention protocols including lipid control is successful in improving outcomes.     

Gemfibrozil therapy in primary type II hyperlipoproteinemia: effects on lipids, lipoproteins and apolipoproteins

Gemfibrozil lowers triglycerides, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol. It also promotes a significant increase of high density lipoprotein (HDL) cholesterol. It has been established that normalization of apolipoproteins is an important protective factor against atherosclerosis. The present report examines the effectiveness of 12 months of gemfibrozil treatment on plasma lipids and apolipoproteins in types IIa (VLDL 18 +/- 2 mg cholesterol/dL) and IIb (VLDL 58 +/- 7 mg cholesterol/dL) hypercholesterolemic patients. Gemfibrozil lowered plasma triglycerides, VLDL cholesterol and apolipoprotein B (apoB), increased HDL cholesterol and apoAI levels in both groups, and induced a very substantial reduction in LDL cholesterol in type IIa patients only. Even though HDL particles were enriched in cholesterol, indicating improvement in the reverse cholesterol transport and lower risk of atherosclerosis in both groups, it is important to note that production of cholesterol-poor LDL particles and reduction in LDL cholesterol and the LDL/HDL cholesterol ratio were observed only in the normotriglyceride group (type IIa). Due to the initially elevated concentration of plasma triglycerides and VLDL in type IIb patients and the increased catabolism of VLDL to LDL during gemfibrozil therapy, this drug has a more efficient regulating effect on LDL particles in type IIa compared with type IIb hyperlipidemia.     

Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study

BACKGROUND: Patients with newly diagnosed rheumatoid arthritis have adverse serum lipid profiles. We sought to determine the effects of treating rheumatoid arthritis with antirheumatic drugs on these abnormal lipid levels. SUBJECTS AND METHODS: We studied 42 patients with newly diagnosed rheumatoid arthritis who had not been treated with corticosteroids or disease-modifying antirheumatic drugs. We measured serum lipid profiles at baseline and 1 year later, and determined whether there were differences in the changes in lipid levels between patients who met the American College of Rheumatology criteria for a 20% improvement in rheumatoid arthritis and those who did not. RESULTS: Of the 42 patients, 27 (64%) met the criteria for a 20% improvement in rheumatoid arthritis during the 12-month study. In these patients, mean high-density lipoprotein (HDL) cholesterol levels increased by 21% (P <0.001), apolipoprotein A-I levels increased by 23% (P <0.001), and the ratio of low-density lipoprotein (LDL) cholesterol to HDL cholesterol level decreased by 13% (P = 0.10). There were significant between-group differences (responders-nonresponders) in the mean 12-month changes in HDL cholesterol levels (8.0 mg/dL; 95% confidence interval [CI]: 3 to 13 mg/dL; P = 0.002), apolipoprotein A-I levels (21 mg/dL; 95% CI: 8 to 33 mg/dL; P = 0.003), and the LDL cholesterol to HDL cholesterol ratio (-0.6; 95% CI: -0.1 to -1.0; P = 0.03), but not in LDL cholesterol, apolipoprotein B-100, or lipoprotein(a) levels. CONCLUSION: Active rheumatoid arthritis is associated with an adverse lipid profile that improves substantially following effective treatment of rheumatoid arthritis. This improvement may reduce the risk of cardiovascular disease.     

Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age

PURPOSE: Because the effects of androgen replacement on lipoprotein levels are uncertain, we sought to determine the effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in elderly men. SUBJECTS AND METHODS: One hundred and eight healthy men more than 65 years of age who had serum testosterone concentrations >1 SD below the mean for young men were randomly assigned to receive either testosterone (54 men; 6 mg/day) or placebo (54 men) transdermally in a double-blind fashion for 36 months. Serum concentrations of lipids and apolipoproteins were measured, and cardiovascular events recorded. RESULTS: Serum total cholesterol concentrations decreased in both the testosterone-treated men and placebo-treated men, but the 3-year mean (+/- SD) decreases in the two groups (testosterone treated, -17 +/- 29 mg/dL; placebo treated, -12 +/- 38 mg/dL) were not significantly different from each other (P = 0.4). Similarly, serum low-density lipoprotein (LDL) cholesterol levels decreased in both treatment groups, but the decreases in the two groups (testosterone treated, -16 +/- 24 mg/dL; placebo treated, -16 +/- 33 mg/dL) were similar (P = 1.0). Levels of high-density lipoprotein (HDL) cholesterol, triglycerides, and apolipoproteins A-I and B did not change. Lipoprotein(a) levels increased in both groups by similar amounts (testosterone treated, 3 +/- 9 mg/dL; placebo treated, 4 +/- 6 mg/dL; P = 1.0). The number of cardiovascular events was small and did not differ significantly between the testosterone-treated men (9 events) and the placebo-treated men (5 events) during the 3-year study (relative risk = 1.8; 95% confidence interval: 0.7 to 5.0). CONCLUSIONS: As compared with placebo, transdermal testosterone treatment of healthy elderly men for 3 years did not affect any of the lipid or apolipoprotein parameters that we measured. The effect of testosterone treatment on cardiovascular events was unclear, because the number of events was small.     

Low density lipoprotein particle diameter in young,nonobese, normolipidemic Japanese men

Background: prospective studies have demonstrated that a predominance of small, dense LDL particles (pattern B) precedes the clinical onset of coronary heart disease. Prevalence and characteristics of subjects with this LDL size abnormality were studied in young, nonobese, Japanese normolipidemic men. Methods and results: LDL peak particle diameter (PPD) was measured by continuous disc polyacrylamide gel electrophoresis in 223 nonobese normolipidemic men aged 18–20 years (mean±S.D. body mass index: 21.9±3.7 kg/m², total cholesterol: 180±29 mg/dl, triglyceride: 62±34 mg/dl, HDL cholesterol: 58±12 mg/dl). Men with small LDL (PPD <25.8 nm) were found in only 5.4% (n=12) whereas 197 men (88.3%) had a preponderance of large LDL (PPD 26.3 nm). As compared with men in a top tertile (PPD 27.5 nm) those in a low tertile (PPD <26.9 nm) had higher serum levels of LDL cholesterol (120±31 vs 104±24 mg/dl), triglyceride (72±39 vs 49±16 mg/dl) and apolipoprotein (apo) B (84±21 vs 68±14 mg/dl), and lower HDL cholesterol (54±10 vs 60±12 mg/dl). They also had greater body mass index (23.2±4.6 vs 20.9 3.1 kg/m²) and percent body fat (21.5±7.7 vs 17.5±4.9%). LDL-PPD was positively correlated with HDL cholesterol (R=0.20, P=0.002) and was negatively correlated with apoB (R=0.34, P<0.001), triglyceride (R=0.32, P<0.001), percent body fat (R=0.26, P<0.001), body mass index (R=0.24, P<0.001), fat mass (R=0.23, P=0.001), total cholesterol (R=0.20, P=0.002). In multiple regression analysis, apoB, triglyceride, HDL cholesterol, apoAI and percent body fat explained 18% of LDLPPD variability. Conclusion: even in young, nonobese, normolipidemic men, LDL size appears to be associated with triglyceride-rich lipoprotein metabolism and body fat.     

The Pro12Ala polymorphism in PPARgamma2 gene affects lipid parameters in Greek primary school children: A case of gene-to-gender interaction

BACKGROUND: In the present study we sought to evaluate the impact of the PPAR-gamma2 Pro12Ala polymorphism on blood lipid levels of primary school children. METHODS: 81 male and 92 female schoolchildren were genotyped. Biochemical, anthropometric, and lifestyle variables were assessed. RESULTS: 14.1% females and 14.8% males were heterozygotes, while the rest of the subjects were homozygotes for the Pro allele. A significant interaction between the PPARgamma-2 gene and gender on blood lipid levels was detected. In particular, Pro/Pro females exhibited higher values of total cholesterol (194 +/- 32 vs 180 +/- 28 mg/dL, P = 0.06) and triglycerides (94 +/- 31 vs 77 +/- 11 mg/dL, P = 0.045) compared to Pro/Ala individuals. The gene-to-gender interaction term was highly significant (P < 0.001). On the other hand, Pro/Pro males showed higher values of HDL cholesterol (47 +/- 8 vs 43 +/- 9 mg/dL, P = 0.001), lower total cholesterol/HDL ratio (4.04 +/- 0.59 vs 4.45 +/- 0.61, P = 0.031), lower values of apoB (59.8 +/- 11.3 vs 66.8 +/- 6.6 mg/dL, P = 0.007) and lower values of apoB/apoA1 ratio (0.41 +/- 0.09 vs 0.48 +/- 0.08, P = 0.019) compared with Pro/Ala. Even after adjusting for body mass index (BMI), total energy intake, total fat intake and saturated fat intake, differences in total cholesterol/high-density lipoprotein (HDL) cholesterol and the apoB/apoA1 ratios remained significant. Regarding females, no differences were observed among genotypes concerning total cholesterol/HDL levels (P for gene-to-gender interaction = 0.001) and the apoB/apoA1 levels (P for gene-to-gender interaction = 0.029). CONCLUSION: We show for the first time a gene-to-gender interaction on total cholesterol/HDL and apoB/apoA1 ratios, in male schoolchildren genotyped for PPAR-gamma2 Pro12Ala.     

载脂蛋白A5 c553G/T基因多态性与急性冠状动脉综合征的相关性

目的:探讨载脂蛋白A5(APOA5)c553G/T基因多态性与急性冠状动脉综合征(ACS)的相关性。方法:以254例ACS患者(ACS组)和229名健康对照者(对照组)为研究对象,用聚合酶链反应限制性片段长度多态性分析G/T位点多态性的分布,并用酶法检测血脂水平。结果:APOA5c553T等位基因在ACS组中的分布频率明显高于对照组(P<0.05),对ACS具有独立的影响(OR=2.344,P<0.01)。2组APOA5c553TT纯合子及GT杂合子个体比GG纯合子个体具有高TG、TC、LDL水平和低HDL水平。结论:APOA5c553G/T基因多态性与血浆TG、TC、HDL和LDL具有相关性。APOA5c553T等位基因可能为ACS的危险因素。     

The effects of uncoupling protein-1 genotype on lipoprotein cholesterol level in Korean obese subjects

Uncoupling protein-1 (UCP-1) plays a major role in thermogenesis, and has been implicated in the pathogenesis of obesity and metabolic disorders. The purpose of this study was to estimate the effects of A-3826G polymorphism of the UCP-1 gene on the plasma lipid profiles in 190 Korean obese subjects with a body mass index (BMI) more than 30 kg/m2. Height, weight, BMI, wait-to-hip ratio (WHR), obesity index, and body composition were measured and genotype of UCP-1 was analyzed by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method. Serum concentrations of fasting glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride were measured. The frequencies of UCP-1 genotypes were AA type, 22.1%; AG type, 53.7%; and GG type, 24.2%; and the frequency of G allele was 0.51. Among many parameters, diastolic blood pressure (DBP) (P = .023) and low-density lipoprotein (LDL) cholesterol (P = .011) were significantly higher in AG and GG types compared with AA type, whereas HDL cholesterol was significantly lower in GG type compared with other types (P < .05). Atherogenic index was significantly higher in GG type compared with AA type (P = 0.027). LDL-to-HDL cholesterol ratio was significantly increased in the order of AA < AG < GG types (P = .001). When the subjects were divided into a normal group and a hyper-LDL cholesterolemia group by LDL cholesterol level of 3.626 mmol/L (140 mg/dL), the frequency of hyper-LDL cholesterolemia was significantly higher in GG type compared with other types by Fisher's exact (chi-square) test (P = .05). When logistic regression analysis was conducted to find the risk factors of hyper-LDL cholesterolemia, the odds ratio was 4.115 (P = .03) for GG type of UCP-1 gene. These results suggest that the GG type of the UCP-1 gene has a strong association with increased LDL cholesterol level and might be a significant risk factor for hyper-LDL cholesterolemia among Korean obese subjects.     

A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral-naive patients: effect of sex and ethnicity

OBJECTIVES: To compare the lipid and metabolic effects, efficacy, and safety of twice-daily regimens of Trizivir (abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg triple nucleoside tablet; TZV), Combivir (lamivudine 150 mg/zidovudine 300 mg combination tablet; COM)+nelfinavir (NFV), and stavudine (d4 T)+lamivudine (3TC)+NFV. STUDY DESIGN: An international, phase 4, open-label, parallel-group, 34-centre study was conducted in 254 non-diabetic, antiretroviral-naive, HIV-infected out-patients with an HIV-1 RNA level of >1000 HIV-1 RNA copies/mL and < or =200,000 copies/mL and a CD4 cell count of >50 cells/microL. METHODS: Patients were randomized 1 : 1 : 1 to TZV twice daily (n = 85), COM/NFV 1250 mg twice daily (n = 88), or d4T 40 mg+3TC 150 mg+NFV 1250 mg twice daily (n = 81) for 96 weeks. Treatments were compared using analysis of covariance (ANCOVA) with regard to changes from baseline in fasting lipids in the total population and in sex and ethnic subgroups. The proportions of patients achieving HIV-1 RNA <50 and <400 copies/mL were compared using a 95% confidence interval (CI) on the difference between proportions. RESULTS: The study population was diverse (50% female, 40% black and 37% Hispanic). Mean baseline low-density lipoprotein (LDL) cholesterol was 99 mg/dL, HIV-1 RNA was 4.43 log10 copies/mL and CD4 cell count was 355 cells/microL. At week 96, fasting LDL cholesterol changed minimally in the TZV group [least square mean (LSM) change from baseline, -8 mg/dL], but increased with d4T/3TC/NFV and COM/NFV (+29 and +19 mg/dL, respectively; P < 0.001 versus TZV). Week 96 LDL-cholesterol levels were significantly lower in the TZV group than in the other two treatment groups in women and men and lower than in the d4T/3TC/NFV group in Hispanic and black patients. In black patients, the week-96 LSM change from baseline in LDL cholesterol was significantly less with TZV than with d4T/3TC/NFV (+1 vs+39 mg/dL; P = 0.003). Total cholesterol >200 mg/dL occurred in a smaller proportion of patients receiving TZV (30%) compared with COM/NFV (50%) or d4T/3TC/NFV (60%; P = 0.005 vs TZV). High-density lipoprotein (HDL) cholesterol did not change markedly with any treatment. Although triglycerides increased, they changed least in women and Hispanic patients receiving TZV. Virological and CD4 responses to the treatments were similar in the total population and in the subgroups. Diarrhoea was reported more often in the NFV arms and nausea in the ZDV arms. CONCLUSIONS: Over 96 weeks, TZV twice daily has significantly less effect on LDL cholesterol than COM/NFV or d4T/3TC/NFV twice daily, especially in women and black patients, and is associated with similar virological and CD4 responses.     

Black-white differences in postprandial triglyceride response and postheparin lipoprotein lipase and hepatic triglyceride lipase among young men.

Black-white differences in serum triglycerides and high-density lipoprotein (HDL) cholesterol concentrations are known. However, the metabolic basis for these differences is not clear. This study determined the magnitude of postprandial triglyceride concentrations, lipoprotein lipase and hepatic triglyceride lipase activities in postheparin plasma, and serum lipid and lipoprotein cholesterol concentrations in healthy young adult black men (n = 22) and white men (n = 28). Postprandial triglyceride concentrations were measured at 2, 3, 4, 5, 6, and 8 hours after a standardized test meal. Serum lipid and lipoprotein cholesterol concentrations were similar between the races in this study sample. However, incremental (above basal) increases in triglycerides were significantly greater in white men versus black men at 2 hours (P = .01) and tended to be greater at 3 hours (P = .12) and 4 hours (P = .06) after the fat load. In a multivariate analysis that included age, race, apolipoprotein E (apoE) genotype, fasting triglycerides, obesity measures, alcohol intake, and cigarette use, fasting triglycerides (P = .04) and, to a lesser extent, race (P = .07) were associated independently with the 2-hour incremental increase in triglycerides. The incremental triglyceride response correlated inversely with HDL cholesterol in both whites (r = -.38, P = .04) and blacks (r = -.59, P = .004). Lipoprotein lipase activity was higher (P = .049) and hepatic triglyceride lipase activity lower (P = .0001) in black men compared with white men; racial differences persisted after adjusting for the covariates. While lipoprotein lipase activity tended to associate inversely with the postprandial triglyceride concentration in both races, hepatic triglyceride lipase activity tended to correlate positively in whites and inversely in blacks. These results suggest that compared with whites, blacks may have an efficient lipid-clearing mechanism that could explain the black-white differences in lipoproteins found in the population at large.     

A functional polymorphism in the promoter region of the microsomal triglyceride transfer protein (MTP -493G/T) influences lipoprotein phenotype in familial hypercholesterolemia

The microsomal triglyceride transfer protein (MTP) has a key function in intracellular apolipoprotein (apo) B lipidation and secretion of very low density lipoprotein (VLDL). A recently discovered functional polymorphism in the promoter of the MTP gene (-493G/T) affects the plasma concentration of low density lipoprotein (LDL) cholesterol and the VLDL distribution between large and small particle species in healthy men. This phenotype is likely to be explained by an effect on VLDL synthesis. Against this background, we studied the effect of the MTP-493G/T polymorphism in a large cohort (217 men and 211 women) with heterozygous familial hypercholesterolemia (FH). A 40% to 50% lower serum triglyceride level was observed in homozygous carriers of the MTP-493 T allele (T/T, 0.93+/-0.34; G/T, 1.54+/-1.40; and G/G, 1.56+/-1.24 mmol/L; T/T vs G/T P=0.04, T/T vs G/G P=0.02). In contrast to the situation in healthy subjects, the MTP promoter polymorphism did not have a significant effect on the LDL cholesterol levels in FH subjects, although the same trend was observed (T/T, 7.31+/-1.87; G/T, 7. 80+/-2.12; and G/G, 7.91+/-2.31 mmol/L, NS). Adjustment for the apo E gene polymorphism by inclusion of subjects homozygous for the apo E3 allele only revealed a reciprocal high density lipoprotein cholesterol-elevating effect (T/T, 1.41+/-0.73; G/T, 1.18+/-0.27; and G/G, 1.16+/-0.29 mmol/L; T/T vs G/T P=0.06, T/T vs G/G P=0.04). This effect seemed to be sex-specific because it was accounted for by the female patients. In conclusion, the LDL cholesterol-lowering effect of the rare MTP gene promoter variant (MTP-493T) present in healthy subjects is shifted to a triglyceride-lowering effect in FH. These data suggest that the MTP gene has a role in modulating the clinical phenotype of FH.     

Overexpression of apolipoprotein E3 in transgenic rabbits causes combined hyperlipidemia by stimulating hepatic VLDL production and impairing VLDL lipolysis

The differential effects of overexpression of human apolipoprotein (apo) E3 on plasma cholesterol and triglyceride metabolism were investigated in transgenic rabbits expressing low (<10 mg/dL), medium (10 to 20 mg/dL), or high (>20 mg/dL) levels of apoE3. Cholesterol levels increased progressively with increasing levels of apoE3, whereas triglyceride levels were not significantly affected at apoE3 levels up to 20 mg/dL but were markedly increased at levels of apoE3 >20 mg/dL. The medium expressers had marked hypercholesterolemia (up to 3- to 4-fold over nontransgenics), characterized by an increase in low density lipoprotein (LDL) cholesterol, while the low expressers had only slightly increased plasma cholesterol levels. The medium expressers displayed an 18-fold increase in LDL but also had a 2-fold increase in hepatic very low density lipoprotein (VLDL) triglyceride production, an 8-fold increase in VLDL apoB, and a moderate decrease in the ability of the VLDL to be lipolyzed. However, plasma clearance of VLDL was increased, likely because of the increased apoE3 content. The increase in LDL appears to be due to an enhanced competition of VLDL for LDL receptor binding and uptake, resulting in the accumulation of LDL. The combined hyperlipidemia of the apoE3 high expressers (>20 mg/dL) was characterized by a 19-fold increase in LDL cholesterol but also a 4-fold increase in hepatic VLDL triglyceride production associated with a marked elevation of plasma VLDL triglycerides, cholesterol, and apoB100 (4-, 9-, and 25-fold over nontransgenics, respectively). The VLDL from the high expressers was much more enriched in apoE3 and markedly depleted in apoC-II, which contributed to a >60% inhibition of VLDL lipolysis. The combined effects of stimulated VLDL production and impaired VLDL lipolysis accounted for the increases in plasma triglyceride and VLDL concentrations in the apoE3 high expressers. The hyperlipidemic apoE3 rabbits have phenotypes similar to those of familial combined hyperlipidemia, in which VLDL overproduction is a major biochemical feature. Overall, elevated expression of apoE3 appears to determine plasma lipid levels by stimulating hepatic VLDL production, enhancing VLDL clearance, and inhibiting VLDL lipolysis. Thus, the differential expression of apoE may, within a rather narrow range of concentrations, play a critical role in modulating plasma cholesterol and triglyceride levels and may represent an important determinant of specific types of hyperlipoproteinemia.     

Discordance between lipoprotein (a) and LDL-cholesterol levels in cardiovascular risk assessment in apparently healthy subjects

Background and aimsLipoprotein(a) is a recognized independent cardiovascular risk factor and apolipoprotein B (apoB) level better reflects the risk than LDL-cholesterol. Despite this cardiovascular prediction mostly relies on traditional risk factors. We evaluated the association between Lp(a) and lipid biomarkers of cardiovascular risk in relation to age and sex in apparently healthy individuals.Methods and results422 presumably healthy subjects aged 19–84 were included. Lipid profile, Lp(a), apoB and small dense low-density lipoprotein cholesterol (sdLDL-C) were assayed. Subjects were divided at desirable cut-points of apoB and LDL-C. A group with elevated apoB (≥100 mg/dL) at low LDL-C (≤115 mg/dL) was appointed as high-risk and a group with low apoB but elevated LDL-C as low-risk. Significantly elevated triglycerides, TG/HDL-C and sdLDL-C were found in high risk group, but Lp(a) levels were comparable. TG/HDL-C was the best predictor of high risk with a very good diagnostic accuracy (AUC = 0.85), whereas Lp(a) had no discriminatory power. Women aged ≤40 with low LDL-C ≤ 100 mg/dL and elevated Lp(a) ≥ 40 mg/dL had higher levels of apoB and sdLDL-C (p = 0.002; p = 0.07) than those with Lp(a) < 40 mg/dL, which was not observed in men. In young females increase of LDL-C and apoB significantly raised the risk of elevated Lp(a).ConclusionsWomen younger than 40 with low LDL-C may be at increased cardiovascular risk associated with elevated Lp(a) and apolipoprotein B levels. Inclusion of Lp(a) and apoB in the routine lipid testing providing information on an individual level may improve the prediction of cardiovascular risk in primary prevention.     

In vivo metabolism of ApoB, ApoA-I, and VLDL triglycerides in a form of hypobetalipoproteinemia not linked to the ApoB gene

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder that may result from different mutations in the apolipoprotein B (apoB) gene or chromosome 2. However, linkage of FHBL to the apoB gene was ruled out in 2 kindreds reported to date, and the genetic and metabolic bases for FHBL remain unknown. One of the reported kindreds is our 40-member F kindred, in which we found linkage of FHBL to a novel susceptibility region on chromosome 3p21. 1-2. In addition to having low apoB levels, some, but not all, of the affected subjects in the F kindred also had low levels of high density lipoprotein (HDL) cholesterol and apoA-I. Our aim was to define the metabolic bases of the disorder in the F kindred. Therefore, we studied the in vivo kinetics of apoB and apoA-I and very low density lipoprotein (VLDL) triglycerides in 4 affected subjects and 5 normolipidemic relatives. Deuterated leucine and deuterated glycerol were used to label the apolipoproteins and triglycerides, respectively. Compartmental modeling was used to obtain the kinetic parameters. Affected subjects had (1) normal fractional catabolic rates (FCRs) for VLDL apoB, (2) increased FCRs for low density lipoprotein (LDL) apoB (0.050+/-0.009 versus 0. 030+/-0.006 pools per hour for normal subjects, P=0.005), and (3) decreased production rates of VLDL apoB (11.4+/-1.7 versus 25.6+/-4. 9 mg. kg(-1). d(-1), P=0.003), LDL apoB (7.8+/-1.3 versus 12.7+/-3.7 mg. kg(-1). d(-1), P=0.04), and VLDL triglycerides (8.2+/-4.5 versus 19.6+/-10.8 58 micromol. kg(-1). h(-1), P=0.09). These data differ from those obtained in previously studied FHBL heterozygotes bearing apoB-2 and apoB-9, 2 very short truncations of apoB. Low HDL cholesterol and apoA-I levels were caused by higher apoA-I FCRs (0. 035+/-0.005 versus 0.018+/-0.005 pools per hour in controls, P<0.01) without significant decrease in apoA-I production rates (18.7+/-2.7 versus 22.8+/-5.6 mg. kg(-1). d(-1)). In conclusion, decreased secretion of apoB-containing lipoproteins and hypercatabolism of LDL account for low apoB and cholesterol levels in this novel form of FHBL.