Micronized fenofibrate, decreased triglyceride levels, total cholesterol and LDL fractions in serum

Elevated serum level of triglycerides is a classic indication for fibrates. Micronized fenofibrate is hypolipemic drug with proven safety and efficacy in a view of triglycerides reduction, but according to few papers published so far on the subject is also effective in decreasing elevated total and LDL cholesterol. The aim of study was to confirm results obtained from these few previous studies. Forty seven persons with lipid disturbances (25 males and 22 females, age range 34-71 yrs. mean 48.0) entered the study. Thirty two patients had a history myocardial infarction and fifteen persons without clinical symptoms of heart diseases. All of them were treated with micronized fenofibrate 200 mg daily. Micronized fenofibrate decreased serum concentration of total cholesterol by 13.4% (p < 0.01), LDL cholesterol by 21.2% (p < 0.001) and triglycerides by 39.5% (p < 0.001) in whole group of patients. Most beneficial effects were obtained in persons with mixed hyperlipidemia: reduction of total cholesterol, triglycerides and LDL cholesterol serum levels was 22.4% (p < 0.01), 52.5% (p < 0.0001), 25.4% (p < 0.01), respectively. In individuals with hypercholesterolemia a reduction of total cholesterol by 11% (p < 0.05) and LDL cholesterol by 15.4% (p < 0.05) was observed. In the group with hypertriglyceridemia or mixed hyperlipidemia reduction of serum triglycerides concentration by 33.5% (p < 0.05) was achieved. No significant change in serum HDL cholesterol level in any group was observed. The treatment with micronized fenofibrate was well tolerated. Our study shows that this drug is safe and seems to be effective in some cases with increased serum total and LDL cholesterol level as well.     

Melatonin treatment in peri- and postmenopausal women elevates serum high-density lipoprotein cholesterol levels without influencing total cholesterol levels

Abstract:  The purpose of this study was to investigate the effects of melatonin on lipid metabolism in peri- and postmenopausal women. Forty-six women were enrolled in these studies. The relationship between night-time serum melatonin levels and serum total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol was investigated in 36 women. Night-time serum melatonin levels had a negative correlation with serum total cholesterol and LDL-cholesterol, and a loose positive correlation with HDL-cholesterol. To examine the effects of exogenous melatonin on lipid metabolism, serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were determined in 10 women before the onset of therapy and after 1 month of oral melatonin administration (1 mg melatonin daily). Melatonin administration significantly increased the serum levels of HDL-cholesterol. These results show that melatonin may influence cholesterol metabolism and suggest that the melatonin administration may become a new medical application for improvement of lipid metabolism and prevention of cardiovascular disease in peri- and postmenopausal women.     

Evaluation of the gene-age interactions in HDL cholesterol, LDL cholesterol, and triglyceride levels: the impact of the SORT1 polymorphism on LDL cholesterol levels is age dependent

Several genes that influence HDL-C, LDL-C, and triglyceride levels have been identified. The effects of genetic polymorphisms on lipid levels may be age dependent. We replicated 17 of these previously identified associations and then used cross-sectional and longitudinal analysis to investigate age-SNP interaction effects. The rs646776 SNP at the SORT1 locus showed an age interaction that was significant in cross-sectional analyses of 1350 individuals from Utah (p = 0.0003) and in 2977 individuals from the NHLBI Family Heart Study (p = 0.007) as well as in longitudinal analysis of a subsample of 1099 individuals from the Utah cohort that had been followed for over 20 years (p = 0.0001). The rs646776 genotype-specific difference in LDL-C levels was significantly greater for younger individuals than for older individuals. These findings may help elucidate the mode of action of the SORT1 gene and impact potential therapeutic interventions targeting this pathway.     

Reduced serum calcium and inorganic phosphate levels in normal elderly women

Because published data on the effect of normal aging on serum calcium and phosphate levels are scanty and contradictory, we measured these parameters in 36 normal women over the age of 65 and compared these values with those obtained previously and concurrently in younger women. We found a significant decline in both serum calcium and phosphate levels after the age of 65. We also measured corrected total serum calcium, serum ultrafiltrable calcium, and serum ionized calcium levels in all of the elderly women and in 29 of the younger women and concluded that the decline in total serum calcium levels seen with aging was attributable in part to decreased levels of protein bound calcium but that there was also a slight reduction of ionic calcium levels. Data obtained in elderly women with proven parathyroid adenomas are included to illustrate how the recognition of these age related changes in total serum calcium levels may aid in the identification of slight but clinically important hypercalcemia in elderly adults.     

Smoking and atherosclerotic cardiovascular disease in women with lower levels of serum cholesterol

This cohort study of Koreans examines the relationship between smoking on atherosclerotic cardiovascular disease (ASCVD) and whether serum levels of total cholesterol modify the impact of smoking on ASCVD.

A 10-year prospective cohort study was carried out on 234,399 Korean women, ranging 40–69 years of age who received health insurance from the National Health Insurance Corporation and had a medical evaluation in 1993. The main outcome measures were hospital admissions and deaths from ischemic heart disease (IHD), cerebrovascular disease (CVD), and total ASCVD.

At baseline, 13,696 (5.8%) were current smokers and 105,755 (45.1%) had a total cholesterol <200 mg/dl. Between 1994 and 2003, 4534 IHD (176/100,000 person year), 7961 CVD (310/100,000 person year), and 2418 other ASCVD events (94/100,000 person year) occurred. In multivariate Cox proportional hazard models controlling for age, hypertension, hypercholesterolemia, diabetes and alcohol drinking, current smoking increased the risk of IHD [hazard ratio (HR) = 1.7 (95% CI: 1.5–1.9)], CVD [HR = 1.6 (95% CI: 1.5–1.6)], and total ASCVD events [HR = 1.6 (95% CI: 1.5–1.7)]. Throughout the range of serum cholesterol levels, current smoking significantly increased the risk of myocardial infarction and CVD, but not angina pectoris. There was no evidence of an interaction between smoking and serum cholesterol (p for interaction = 0.469, 0.612, and 0.905 for IHD, CVD, and total ASCVD, respectively).

This study demonstrated that smoking was a major independent risk factor for IHD, CVD and ASCVD in Korean women. A low cholesterol level confers no protective benefit against smoking-related ASCVD.     

Urokinase plasminogen activator (uPA) stimulates cholesterol biosynthesis in macrophages through activation of SREBP-1 in a PI3-kinase and MEK-dependent manner

Urokinase plasminogen activator (uPA) is expressed in human atherosclerotic lesions, predominantly in macrophages, and contributes to atherosclerosis progression. Since atherogenesis is characterized by the formation of cholesterol-loaded macrophage foam cells, we questioned whether uPA atherogenicity may involve macrophage cholesterol accumulation, and by what mechanisms. uPA increased cellular cholesterol content by 44% (mainly unesterified cholesterol) in THP-1 macrophages, and this effect was inhibited by statins. This effect was associated with 172% elevated cholesterol biosynthesis, which required the binding of uPA to its receptor. An upregulation of HMGCoA reductase (HMGCR) expression (protein and mRNA) was noted. Since HMGCR expression is controlled by sterol regulatory element-binding proteins (SREBPs), we next analyzed this issue. Indeed, treatment of macrophages with uPA increased SREBP-1 processing, and mature SEREBP-1 content (by 5.7-fold) in the nucleus. These latter effects were mediated by uPA-induced activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK). Finally, uPA was found to activate MAP-kinase through PI3 kinase (PI3K), as PI3K inhibition abrogated both uPA-induced ERK phosphorylation and cholesterol biosynthesis. In conclusion, uPA-induced macrophage cholesterol accumulation is a novel pathway by which uPA may contribute to accelerated atherosclerosis development. These findings provide new insight into the atherogenicity of uPA and may suggest new novel therapeutic means.     

Essential role for the (hepatic) LDL receptor in macrophage apolipoprotein E-induced reduction in serum cholesterol levels and atherosclerosis

Apolipoprotein E (apoE) is a high affinity ligand for several receptor systems in the liver, including the low-density lipoprotein (LDL) receptor, and non-LDL receptor sites, like the LDL receptor-related protein (LRP), the putative remnant receptor and/or proteoglycans. Although the liver is the major source of apoE synthesis, apoE is also produced by a wide variety of other cell types, including macrophages. In the present study, the role of the LDL receptor in the removal of lipoprotein remnants, enriched with macrophage-derived apoE from the circulation, was determined using the technique of bone marrow transplantation (BMT). Reconstitution of macrophage apoE production in apoE-deficient mice resulted in a serum apoE concentration of only 2% of the concentration in wild-type C57Bl/6 mice. This low level of apoE nevertheless reduced VLDL and LDL cholesterol 12-fold (P<0.001) and fourfold (P<0.001), respectively, thereby reducing serum cholesterol levels and the susceptibility to atherosclerosis. In contrast, reconstitution of macrophage apoE synthesis in mice lacking both apoE and the LDL receptor induced only a twofold (P<0.001) reduction in VLDL cholesterol and had no significant effect on atherosclerotic lesion development, although serum apoE levels were 93% of the concentration in normal C57Bl/6 mice. In conclusion, a functional (hepatic) LDL receptor is essential for the efficient removal of macrophage apoE-enriched lipoprotein remnants from the circulation and thus for normalization of serum cholesterol levels and protection against atherosclerotic lesion development in apoE-deficient mice.     

Circulating osteoprotegerin levels are associated with age, waist-to-hip ratio, serum total cholesterol, and low-density lipoprotein cholesterol levels in healthy Korean women

Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the receptor activator of nuclear factor I masculine B ligand. Osteoprotegerin has been shown to be an important inhibitor of osteoclastogenesis and arterial calcification in animal models. Recently, OPG has been proposed as a link molecule between osteoporosis and arterial calcification, but the relationship between circulating OPG levels and cardiovascular disease in human populations is unclear. Thus, the aim of this study was to investigate the relationship between circulating OPG levels and cardiovascular risk factors in healthy Korean women. The subjects were 286 women aged 37 to 73 (mean +/- SD, 51.5 +/- 6.9 years). We examined blood pressure, body mass index, and waist-to-hip ratio. Serum concentrations of OPG were determined by enzyme-linked immunosorbent assay. Fasting plasma glucose levels, serum lipid profiles, insulin levels, and serum follicle-stimulating hormone (FSH) levels were determined by standard methods and homeostasis model assessment of insulin resistance was calculated. We observed a significant association between serum OPG levels and age, waist-to-hip ratio, total cholesterol, low-density lipoprotein cholesterol, and FSH levels (P < .05). Among the metabolic components, the older, obese, and hypercholsterolemic subjects had higher serum OPG levels (P < .05). However, no significant relationship was found between serum OPG levels and blood pressure and fasting plasma glucose levels. We found that mean serum OPG levels were about 11% greater in postmenopausal women (mean +/- SD, 1358.5 +/- 380.0 pg/mL) than in premenopausal women (mean +/- SD, 1228.8 +/- 407.7 pg/mL, P < .001). In multiple regression analysis with OPG as the dependent variable, serum FSH and low-density lipoprotein cholesterol levels were the significant predictor for serum OPG level (R(2) = 0.051, P < .05). In conclusion, our results show that circulating OPG levels are partly associated with cardiovascular risk factors and menopausal status in healthy Korean women. Out findings suggest that OPG may be an important paracrine factor of cardiovascular disease in the female population.     

Relation of the -514C/T polymorphism in the hepatic lipase gene to serum HDL and LDL cholesterol levels in postmenopausal women under hormone replacement therapy

Hepatic lipase (HL) is a lipolytic enzyme that catalyzes hydrolysis of triglycerides and phospholipids in all major classes of lipoproteins. Recently, a -514C/T polymorphism in the promoter region of the HL gene was found to be associated with variations in hepatic lipase activity and serum high density lipoprotein cholesterol (HDL-C) levels. Postmenopausal hormone replacement therapy (HRT) has known favorable effects on serum lipid and lipoprotein levels. In this study, we examined the relation between the -514C/T polymorphism and serum lipid and lipoprotein levels in postmenopausal women prior to and after 3 months of HRT. Significant associations between the -514 C/T polymorphism and HDL-C, low density lipoprotein cholesterol (LDL-C) and apolipoprotein A-I (apo A-I) levels were observed before and/or after 3 months of HRT. With HRT, serum total cholesterol (TC), LDL-C and apolipoprotein B (apo B) levels were reduced significantly (P=0.0001), and HDL-C and apo A-I levels were increased significantly (P=0.0001). However, the degrees of change in lipid and lipoprotein levels due to HRT did not differ significantly between the HL genotypes.     

正常妊娠和不孕不育妇女血清TORCH抗体比较

目的比较正常妊娠和不孕不育妇女血清TORCH感染情况。方法对380例正常孕妇和417例不孕不育妇女,采用ELISA法检测血清中特异性TORCH系列IgM抗体。结果380例正常妊娠孕妇弓形虫（TOX）、巨细胞病毒（CMV）、风疹病毒（RUV）、单纯疱疹病毒（HSV）IgM抗体阳性率分别为0.26%、2.37%、0.52%、0,总阳性率为3.16%;417例不孕不育妇女中IgM抗体阳性率分别为2.40%、5.28%、0.24%、1.92%,总阳性率为9.83%。结论不孕不育妇女TOX-IgM、CMV-IgM、HSV-IgM明显高于正常孕妇,TORCH感染与不孕不育密切相关。     

Polymorphisms in oestrogen and progesterone receptor genes: possible influence on prolactin levels in women

OBJECTIVE: Oestrogen and progesterone are known to influence the release of human prolactin. The present study was undertaken in order to investigate the possible influence of polymorphisms of the genes encoding the oestrogen receptor (ER)alpha, ERbeta and the progesterone receptor (PGR), on prolactin levels in premenopausal women. DESIGN AND MEASUREMENTS: Serum levels of prolactin were measured in the follicular phase of the menstrual cycle. Subjects were genotyped with respect to a TA repeat polymorphism of the ERalpha gene, a CA repeat polymorphism of the ERbeta gene, and two polymorphisms of the PGR gene: one insertion polymorphism (PROGINS) and one single nucleotide polymorphism (G331A). SUBJECTS: A population-based cohort of 270 42-year-old women. RESULTS: The CA repeat polymorphism of the ERbeta gene and the G331A polymorphism of the PGR gene appeared to be associated with prolactin levels. In contrast, we found no evidence for an influence of the PROGINS polymorphism of the PGR gene or the TA repeat polymorphism of the ERalpha gene on the levels of this hormone. CONCLUSIONS: These data suggest that genetic variants of both the ERbeta and the PGR may influence prolactin release.     

Association of UCP2 and UCP3 gene polymorphisms with serum high-density lipoprotein cholesterol among Korean women

Decreased serum high-density lipoprotein (HDL-C) cholesterol is a major risk factor for atherosclerosis and vascular disease. In this study, we assessed the association of 10 uncoupling protein (UCP) 2 and UCP3 polymorphisms with serum HDL cholesterol levels and atherogenic indexes among 658 Korean women. Among the 10 single nucleotide polymorphisms (SNPs) in the UCP2 and UCP3 genes, 2 SNPs in UCP2, -866G>A and +4787C>T (A55V) that were tightly linked (r(2) = 0.97), were significantly associated with decreased HDL cholesterol levels after Bonferroni correction (P = .003 in the recessive model). +4589C>T (Y210Y) in UCP3, a silent variation of Tyr210Tyr in exon 5, was also significantly associated with HDL cholesterol after multiple comparison correction. These 3 SNPs also exhibited some association with increases in the atherogenic index. Source-of-variation analysis revealed that -866G>A SNP accounted for 8.09% of the variation in serum HDL cholesterol levels independent of body mass index. We believe that our results may provide clues to the association of UCP genes with the risk of atherosclerosis through their effects on HDL cholesterol.     

Murine GPVI stimulates weak integrin activation in PLCgamma2-/- platelets: involvement of PLCgamma1 and PI3-kinase

Collagen stimulates platelet activation through a tyrosine kinase-based pathway downstream of the glycoprotein VI (GPVI)-Fc receptor (FcR) gamma-chain complex. Genetic ablation of FcR gamma-chain results in a complete inhibition of aggregation to collagen. In contrast, a steady increase in light transmission is induced by collagen in phospholipase Cgamma2-deficient (PLCgamma2-/-) platelets in a Born aggregometer, indicating a weak level of activation. This increase is inhibited partially in the presence of an alpha2beta1-blocking antibody or an alphaIIbbeta3 antagonist and completely by a combination of the 2 inhibitors. It is also abolished by the Src kinase inhibitor PP1 and reduced in the presence of the phosphatidylinositol (PI) 3-kinase inhibitor wortmannin. The GPVI-specific agonists convulxin and collagen-related peptide (CRP) also stimulate weak aggregation in PLCgamma2-/- platelets, which is inhibited by wortmannin and PP1. Collagen and CRP stimulate tyrosine phosphorylation of PLCgamma1 at its regulatory site, Tyr 783, in murine but not in human platelets through a Src kinase-dependent pathway. Adhesion of PLCgamma2-/- platelets to a collagen monolayer is severely reduced at a shear rate of 800 s-1, relative to controls, whereas it is abolished in FcR gamma-chain-/- platelets. These results provide strong evidence that engagement of GPVI stimulates limited integrin activation in PLCgamma2-/- platelets via PLCgamma1 and PI3-kinase.     

Relationship between serum cholesterol and thromboxane B2 levels and atherosclerotic lesions in rabbits fed a high cholesterol diet

The aim of our study was to evaluate the effects of diet induced hypercholesterolemia and associated atherosclerosis in rabbits on serum thromboxane B2 levels. We have determined thromboxane B2 in serum of hypercholesterolemic rabbits with atherosclerosis and in normocholesterolemic rabbits without atherosclerosis. Our data show only a mildly higher serum thromboxane levels in hypercholesterolemic rabbits and extensive atherosclerosis than in controls without atherosclerosis. In conclusion, these results show that diet induced hypercholesterolemia was not associated with thromboxane B2 generation, in spite of a diffuse experimental atheromatosis.     

Genome-wide scan identifies novel QTLs for cholesterol and LDL levels in F2[Dahl RxS]-intercross rats

Hypercholesterolemia is a significant risk factor for coronary artery disease development. Genes influencing nonmonogenic hypercholesterolemia susceptibility in humans remain to be identified. Animal models are key investigative systems because major confounding variables such as diet, activity, and genetic background can be controlled. We performed a 121-marker, total genome-analysis of an F2[Dahl RxS]-intercross selected for contrasting parental strain susceptibilities for hyperlipidemia on regular rat diets at 6 months of age. Quantitative traits studied were plasma total cholesterol, triglyceride, HDL, and LDL levels adjusted for obesity. Genome-wide analysis of 200 F2-intercross male rats detects two QTLs with highly significant linkage for total cholesterol (TC) on chromosome (chr) 5-133.3 Mbp (LOD 5.8), and chr5-54.2 Mbp (LOD 4.8), and two QTLs with significant linkage for TC: on chromosome 8, chr8-60.4 Mbp (LOD 3.8), and chromosome 2, chr2-243.5 Mbp (LOD 3.4). A QTL for LDL with significant linkage is detected on chromosome 5, chr5-104 Mbp (LOD 3.7). These QTLs contribute from 7% to 12% of total trait variance, respectively, with Dahl-S allele effects resulting in increased TC and LDL levels consistent with hyperlipidemia susceptibility in the parental Dahl-S rat strain. Predicted QTL-peaks do not coincide with previous genome scans. Human homologues of two TC-QTLs span genes listed in a LocusLink profile for cholesterol. Only suggestive loci were detected for HDL and total triglyceride levels. Altogether, the data demonstrates the contribution of multiple QTLs to hypercholesterolemia making a multipathway pathogenic framework imperative. QTL-peak candidate genes delineated are syntenic between rat and human genomes, increasing clinical relevance and mandating further study.     

Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes

Patients with hepatitis C virus (HCV) infection have a greater risk of developing type 2 diabetes mellitus. However, the mechanism of this association is unclear. In this study, we examined the potential defects in upstream insulin signaling pathways in liver specimens obtained from nonobese/nondiabetic subjects with HCV infection. Fasting liver biopsy specimens were obtained from 42 HCV-infected subjects and 10 non-HCV-infected subjects matched for age and body mass index. Liver tissues were exposed to insulin and examined for the contents and phosphorylation/activation status of the upstream insulin signaling molecules by immunoprecipitation and Western blot analysis. HCV infection resulted in a trend toward a 2-fold to 3-fold increase in insulin receptor (IR) and insulin receptor substrate (IRS)-1 contents when compared with non-HCV. In contrast, insulin-stimulated IRS-1 tyrosine phosphorylation was decreased by 2-fold in HCV-infected subjects compared with non-HCV-infected subjects (P <.05). The observed reductions in IRS-1 tyrosine phosphorylation were accompanied by a 3.4-fold decrease in IRS-1/p85 phosphatidylinositol 3-kinase (PI3-kinase) association and a 2.5-fold decrease in IRS-1-associated PI3-kinase enzymatic activity (P <.05 vs. non-HCV). This was accompanied by a marked reduction in insulin-stimulated Akt phosphorylation without any alterations in mitogen-activated protein kinase (MAPK) phosphorylation. Cellular contents of the hepatic p85 subunit of PI3-kinase were comparable between HCV-infected and non-HCV-infected subjects. In conclusion, we found that (1). HCV infection leads to a postreceptor defect in IRS-1 association with the IR and (2). insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to insulin resistance, which leads to the development of type 2 diabetes mellitus in patients with HCV infection.