A number of researches have evaluated the association between the ABCB1 polymorphism and the lipid-lowering response of statins, but the results have been inconclusive. To examine the lipid-lowering efficacy and safety associated with the ABCB1 C3435T polymorphism in hypercholesterolemic patients receiving statin, all available studies were included in this meta-analysis.
A systematic search for eligible studies in the Cochrane library database, Scopus and PubMed was performed. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated by the meta-analysis.
The results indicated that the comparisons of CC+CT vs. TT were associated with a significant elevation of the serum HDL-C levels after statin treatment (CC+CT vs. TT: MD, 2.46; 95 % CI, 0.36 to 4.55; P = 0.02), and the ABCB1 C3435T variant in homozygotes was correlated with decreases in LDL-C (CC vs. TT: MD, 2.29; 95 % CI, 0.37 to 4.20; P = 0.02) as well as TC (CC vs. TT: MD, 3.05; 95 % CI, 0.58 to 5.53; P = 0.02) in patients treated with statin. However, we did not observe a significant association in the TG group or an association between other genetic models serum lipid parameters. In addition, statin treatment more than 5 months led to a higher risk of muscle toxicity.
The evidence from the meta-analysis demonstrated that the ABCB1 C3435T polymorphism may represent a pharmacogenomic biomarker for predicting treatment outcomes in patients on statins and that statin treatment for more than 5 months can increase the risk of myopathy.
ABCB1; Polymorphism; Statin; Serum lipid level; Myopathy; Meta-analysis
Hypercholesterolemia is a major risk factor for coronary artery disease (CAD). As Numb is an important regulating factor for intestinal cholesterol absorption and plasma cholesterol level, the aim of the present study is to assess the association between human Numb gene polymorphism and CAD among Han and Uighur Chinese.
We have conducted two independent case–control studies in Han Chinese (384 CAD patients and 433 controls) and Uighur Chinese (506 CAD patients and 351 controls) subjects. All subjects were genotyped for four kinds of SNPs (rs12435797, rs2108552, rs1019075 and rs17781919) and SNP is used as a genetic marker for human Numb gene. Genotyping was undertaken using TaqMan SNP genotyping assay, and the subjects’ ethnicity and gender were considered in the analysis.
We found that rs2108552 was associated with CAD in the dominant model (CC vs CG + GG) for the total Han Chinese population (n = 200) and Han Chinese males (n = 115) (P = 0.004 and P = 0.001, respectively). The difference remained statistically significant after multivariate adjustment (total: OR = 1.687, P = 0.004; male: OR = 1.498, P = 0.006). Further, for the total (n = 817) and male (n = 490) Han Chinese, the frequency of the haplotype (T-C-T-C) was significantly higher in the CAD patients than in the controls (P = 0.004 and P = 0.002), and the frequency of the haplotype (G-G-T-C) was significantly lower in the CAD patients than in the control subjects (P = 0.013, P = 0.007). In addition, for the total (n = 857) and male (n = 582) Uighur Chinese, we observed that rs12435797 was associated with CAD in an additive and recessive model (P = 0.021 and P = 0.009; P = 0.048 and P = 0.034). However, the difference did not remain statistically significant after multivariate adjustment. The overall distribution of rs2108552, rs1019075 and rs17781919 genotypes, alleles and the frequency of the haplotype established by four SNPs showed no significant difference between CAD patients and control subjects in the total, male and female Uighur Chinese.
The results of this study indicate that CC genotype of rs2108552 and T-C-T-C haplotypes in Numb gene is a possible risk genetic marker and G allele and G-G-T-C haplotypes is a possible protective genetic marker for CAD in male Han Chinese.
Coronary artery disease; Case–control study; Genetic polymorphism; Numb
We recently demonstrated that feeding a natural CLAt10,c12-enriched butter to lean female rats resulted in small, but significant increases in fasting glucose and insulin concentrations, and impaired insulin tolerance. Our goal was to extend these findings by utilizing the diabetes-prone female fatty Zucker rat. Rats were fed custom diets containing 45 % kcal of fat derived from control and CLAt10,c12-enriched butter for 8 weeks.
CLA t10,c12-enriched butter was prepared from milk collected from cows fed a high fermentable carbohydrate diet to create subacute rumen acidosis (SARA); control (non-SARA) butter was collected from cows fed a low grain diet. Female fatty Zucker rats (10 weeks old) were randomly assigned to one of four diet treatments: i) low fat (10 % kcal), ii) 45 % kcal lard, iii) 45 % kcal SARA butter, or iv) 45 % kcal non-SARA butter. A low fat fed lean Zucker group was used as a control group. After 8 weeks, i) glucose and insulin tolerance tests, ii) insulin signaling in muscle, adipose and liver, and iii) metabolic caging measurements were performed.
Glucose and insulin tolerance were significantly impaired in all fatty Zucker groups, but to the greatest extent in the LARD and SARA conditions. Insulin signaling (AKT phosphorylation) was impaired in muscle, visceral (perigonadal) adipose tissue and liver in fatty Zucker rats, but was generally similar across dietary groups. Physical activity, oxygen consumption, food intake and weight gain were also similar amongst the various fatty Zucker groups.
Increasing the consumption of a food naturally enriched with CLAt10,c12 significantly worsens glucose and insulin tolerance in a diabetes-prone rodent model. This outcome is not explained by changes in tissue insulin signaling, physical activity, energy expenditure, food intake or body mass.
Conjugated linoleic acid; CLA (t10,c12); Glucose tolerance; Insulin tolerance; Insulin-stimulated glucose uptake; Female Zucker rats
Molecular genetic mechanisms underlying the anti-inflammatory effects of ethanol extract (GB) from G. bimaculatus, a type of cricket, are not fully elucidated. G. bimaculatus was reported to be rich in unsaturated fatty acid and to decrease the omega-6/omega-3 fatty acid ratio when fed to chickens. GB may reduce the amount of fat or increase the unsaturated fatty acid ratio.
Male Wistar rats fed a high-fat diet (HFD) were orally administered with 5 groups: phosphate buffered saline (PBS, control), GB (100 mg/kg or 200 mg/kg), Pravastatin or Isaria sinclairii (IS) extract, which is reported to have fat-reducing effects, for either 1 or 2 months. GB’s sero-biochemial, hematological and anti-oxidizing hepato-cellular biomarker levels were evaluated to dertermine their antilipidemic, anti-inflammatory, and anti-coagulant effect in rats after 1 or 2 month GB treatments on HFD (fat 60 %) Wistar rat. The abdominal and epididymidal fat weight were measured and the composition of fatty acid was analyzed by GC/MS. Microarray analyses were performed with a rat 28 K cDNA clone set array to identify the gene-expression profiles for the GB exposed high fat dieted Wistar rat.
The weight and fatty acid composition of abdominal fat and epididymidal fat, total cholesterol, LDL-cholesterol, and triglyceride in GB treated rats were at lower levels than those of the control group. The anti-oxidant hepato-cellular biomarker levels, protein carbonyl content and malondialdehyde concentration in GB treated rats were significantly decreased. Compared to the control, the GB treated rat group (treated at a dose of 100 and 200 mg/kg), had 190 up-regulated genes including Gpm6a (glycoprotein m6a), Tmem14a (transmembrane protein 14A) and Fasin (fatty acid synthase), with down-regulated 235 genes including Cc121b (chemokine ligand 21b), Glycan1 (glycosylation dependent cell adhesion moleule, Serpinb1a (serine proteinase inhibitor) and Tcrb (T-cell receptor beta chain).
The data suggest Fasin-related fatty acid synthesis and adipose differentiation related protein (Adfp), which is related to obesity, were upregulated by GB treatment, indicating their potential therapeutic markers for anti-atheriosclerosis or inflammation.
Anti- atherosclerosis effect; G. Bimaculatus extract; Wistar rats; 1-month treatments
To study the effect of Interferon (INF) alpha-2b therapy on the serum lipids and fatty acid (FA) level in pre and post treated hepatitis C (HCV) patients.
Fifty samples were collected from pre and post treated patients along with age and gender matched controls. After separating serum, lipid contents were analyzed by microlab and gas chromatography.
The hepatitis C infection results in hypolipidemia with reduced level of triglyceride (113 mg/dl), high density lipoprotein (37.1 mg/dl), low density lipoprotein (74.3 mg/dl), cholesterol (149.9 mg/dl) that increase the infection resolution and after the IFN treatment, the lipid profile of the patients were increased. The myristic (2.8 g/100 g) and palmitic acids (26.6 g/100 g) were significantly higher while linoleic acid (20.94 g/100 g) was significantly lower in HCV patients. The higher oleic: stearic (1.4) and palmitoleic: palmitic acid (0.2) ratios were detected in HCV patients, showing enhanced stearoyl-CoA desaturase activity. The levels of serum saturated (44.9 g/100 g) and monounsaturated FA’s (26.98 g/100 g) were higher while polyunsaturated FA’s (25.9 g/100 g) were found lower in HCV patients in comparison of controls (40.1; 25.01; 33.44 g/100 g respectively). An inverse correlation was found HCV RNA viral load and PUFA (R2 = 0.4555). Elevated levels of serum saturated free FA (45.7 g/100 g) in HCV patients indicates stimulated lipoapoptosis.
The present study conclude that serum PUFA level was lower in HCV patients, hence PUFA may provide synergistic antiviral effects when given as a food supplement during the INF based anti- HCV therapy.
Hepatitis C virus; Alpha-2b interferon; Fatty acids; Cholesterol; GC-FID; Triacylglycerol; High density lipoprotein; Low density lipoprotein; Saturated fatty acid; Polyunsaturated fatty acid
Up-regulation of angiotensin II (AngII) occurs in cardiac diseases, such as congestive heart failure, cardiac hypertrophy, myocardial ischemia and atrial fibrillation, which represent major health problems. Evidence from in vivo studies suggests that the level of Apolipoprotein-J (ApoJ) is also elevated but plays a protective role in cardiovascular disease. This study aimed to evaluate the protective effects of ApoJ against cytotoxicity of AngII in neonatal rat ventricular cells (NRVCs).
Methods and results
In culture, NRVCs were damaged by exposure to AngII, and ApoJ overexpression using an adenovirus vector significantly reduced the AngII-induced cell injury. ApoJ also prevented AngII from augmenting Nox2/gp91phox expression. The reactive oxygen species (ROS) scavenger, Mn(III)TBAP, showed similar results of attenuating AngII-induced cell damage. Furthermore, ApoJ overexpression increased phosphorylation of Akt, and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 diminished the antioxidant effects of ApoJ, and prevented the protective effect of ApoJ against the cytotoxicity of AngII. Moreover, upregulation of nuclear factor κB (NF-κB) p65 expression and phosphorylation of p38 mitogen-activated protein kinase (MAPK) mediated by AngII in cultured NRVCs were significantly inhibited by overexpression of ApoJ. The p38 MAPK inhibitor SB203580 and the NF-κB inhibitor PDTC protected NRVCs from injury caused by AngII.
ApoJ serves as a cytoprotective protein in NRVCs against cytotoxicity of AngII through the PI3K-Akt-ROS and MAPK/ NF-κB pathways.
AngII; ApoJ; Apoptosis; Neonatal rat ventricular cells
Triglycerides (TGs) are proatherogenic lipoproteins involving the risk of coronary heart disease (CHD), while apolipoprotein A5 (APOA5) and apolipoprotein C3 (APOC3) are main lipoproteins composing TG-rich lipoproteins. In this study, we aim to explore the correlation of CHD with APOA5 -1131 T > C and APOC3 -455 T > C single nucleotide polymorphisms (SNPs).
A sum of 210 CHD patients, hospitalized between Jan. 2013 and Mar. 2015 at China-Japan Union Hospital, Jilin University, were selected as our case group and 223 healthy individuals who had physical examination at same hospital at the same period were selected as control group. The frequency distribution of genotypes of APOA5 -1131 T > C and APOC3 -455 T > C SNPs were measured by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Stata 12.0 software was utilized for statistical analyses.
There was no significant difference on age and sex between case and control group (P > 0.05). History of smoking, drinking, hypertension and diabetes mellitus, body mass index and levels of TG and fasting blood sugar in case group were shown to be higher than control group (P < 0.05), while levels of total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in case group were lower than control group (P < 0.05). Both CC and TC′ + CC frequencies of APOA5 -1131 T > C and APOC3 -455 T > C in case group were higher compared to control group (both P < 0.05). Additionally, T allele frequencies of the two SNPs in case group were lower than control group, while C allele in case group has higher frequencies compared to control group (both P < 0.05). The results of meta-analysis under allele and dominant models showed that APOA5 -1131 T > C and APOC3 -455 T > C SNPs are likely to increase the risk of CHD (both P < 0.05).
APOA5 -1131 T > C and APOC3 -455 T > C SNPs may play potent roles in the development and progression of CHD.
Apolipoprotein A5; Apolipoprotein C3; Single nucleotide polymorphism; Coronary heart disease; Triglyceride
While obesity and fat intake have been associated with an increased risk of prostate cancer (PCa) aggressiveness and mortality, the association between lipid levels and PCa phenotype remains unclear. Previous reports evaluating this association are inconsistent and highly variable when considering different racial/ethnic groups. There are scarce data regarding this association among Hispanics, and specifically Puerto Rico’s Hispanic men, a population with a higher burden of PCa, metabolic syndrome and overweight. This population has a different ancestry profile than other Hispanics from Central and South America. Due to the above the researchers inquired if there is a relationship between serum lipid levels and PCa phenotype in this understudied population using a cohort of patients treated with radical prostatectomy as their first treatment.
We performed an exploratory retrospective medical record review study of 199 PCa patients who underwent radical prostatectomy between 2005 and 2012. Variables analyzed included age at PCa diagnosis, Body Mass Index (BMI), preoperative serum prostate-specific antigen (PSA), lipid levels, and clinical parameters such as prostatectomy pathologic stage and Gleason Score (GS). PCa severity was defined using pathologic stage and GS. Unadjusted and adjusted logistic regression models were fitted to estimate the odds ratios (ORs) with 95 % confidence intervals (CI) to define the relationship among clinical characteristics and PCa severity.
Mean age for the cohort was 58.8 years (range: 40–75), 78.9 % were overweight or obese, 36.7 % had hypertriglyceridemia, and 35.2 % had low HDL levels. In the unadjusted logistic regression model, hypertriglyceridemia (OR: 2.11, 95 % CI = 1.13–3.93), low HDL (OR: 1.90, 95 % CI = 1.02–3.56-), and age (OR: 2.34, 95 % CI 1.25–4.40) were significantly associated with a diagnosis of high severity of PCa.
In Puerto Rican men with PCa, elevated hypertriglyceridemia, low HDL levels, and age were statistically associated with high grade PCa on bivariate analysis. Total cholesterol level was not associated with severity of disease. Associations lost significance upon multivariate adjustment. These data generate important hypotheses regarding the potential relationship between lipid pathways and PCa development and underscore the need to perform larger scale and longitudinal studies to sort out whether, hypertriglyceridemia is associated with PCa phenotype and development.
Triglycerides; Prostate cancer, Cholesterol, Obesity, Hispanics
Regular exercise prevents and regresses atherosclerosis by improving lipid metabolism and antioxidant defenses. Exercise ameliorates the reverse cholesterol transport (RCT), an antiatherogenic system that drives cholesterol from arterial macrophages to the liver for excretion into bile and feces. In this study we analyzed the role of aerobic exercise on the in vivo RCT and expression of genes and proteins involved in lipid flux and inflammation in peritoneal macrophages, aortic arch and liver from wild type mice.
Twelve-week-old male mice were divided into sedentary and trained groups. Exercise training was performed in a treadmill (15 m/min, 30 min/day, 5 days/week). Plasma lipids were determined by enzymatic methods and lipoprotein profile by fast protein liquid chromatography. After intraperitoneal injection of J774-macrophages the RCT was assessed by measuring the recovery of 3H-cholesterol in plasma, feces and liver. The expression of liver receptors was determined by immunoblot, macrophages and aortic mRNAs by qRT-PCR. 14C-cholesterol efflux mediated by apo A-I and HDL2 and the uptake of 3H-cholesteryl oleoyl ether (3H-COE)-acetylated-LDL were determined in macrophages isolated from sedentary and trained animals 48 h after the last exercise session.
Body weight, plasma lipids, lipoprotein profile, glucose and blood pressure were not modified by exercise training. A greater amount of 3H-cholesterol was recovered in plasma (24 h and 48 h) and liver (48 h) from trained animals in comparison to sedentary. No difference was found in 3H-cholesterol excreted in feces between trained and sedentary mice. The hepatic expression of scavenger receptor class B type I (SR-BI) and LDL receptor (B-E) was enhanced by exercise. We observed 2.8 and 1.7 fold rise, respectively, in LXR and Cyp7a mRNA in the liver of trained as compared to sedentary mice. Macrophage and aortic expression of genes involved in lipid efflux was not systematically changed by physical exercise. In agreement, 14C-cholestrol efflux and uptake of 3H-COE-acetylated-LDL by macrophages was similar between sedentary and trained animals.
Aerobic exercise in vivo accelerates the traffic of cholesterol from macrophages to the liver contributing to prevention and regression of atherosclerosis, independently of changes in macrophage and aorta gene expression.
Atherosclerosis; HDL; Physical exercise; Reverse cholesterol transport; Macrophages
We previously demonstrated that hyperglycemia could suppress apolipoprotein M (apoM) synthesis both in vivo and in vitro; however, the mechanism of hyperglycemia-induced downregulation of apoM expression is unknown yet.
In the present study we further examined if hexosamine pathway, one of the most important pathways of glucose turnover, being involved in modulating apoM expression in the hyperglycemia condition. We examined the effect of glucosamine, a prominent component of hexosamine pathway and intracellular mediator of insulin resistance, on apoM expression in HepG2 cells and in rat’s models. In the present study we also determined apolipoprotein A1 (apoA1) as a control gene.
Our results demonstrated that glucosamine could even up-regulate both apoM and apoA1 expressions in HepG2 cell cultures. The glucosamine induced upregulation of apoM expression could be blocked by addition of azaserine, an inhibitor of hexosamine pathway. Moreover, intravenous infusion of glucosamine could enhance hepatic apoM expression in rats, although serum apoM levels were not significantly influences.
It is concluded that both exogenous and endogenous glucosamine were essential for the over-expression of apoM, which may suggest that the increased intracellular content of glucosamine does not be responsible for the depressed apoM expression at hyperglycemia condition.
Apolipoprotein M; Glucosamine; Hyperglycemia; Hexosamine pathway
The traditional view on the relationship between lipid biomarkers and CVD risk has changed during the last decade. However, it is not clear whether novel lipid biomarkers are able to confer a better predictability of CVD risk, compared to traditional ones.Under this perspective, the aim of the present work was to evaluate the predictive ability of blood lipids’ profile on all cause mortality as well as 10-year incidence of CVD, in a sample of apparently healthy adults of the ATTICA epidemiological study.
From May 2001 to December 2002, 1514 men and 1528 women (>18 y) without any clinical evidence of any other chronic disease, at baseline, were enrolled. In 2011–12, the 10-year follow-up was performed in 2583 participants (85 % follow-up participation rate). Incidence of fatal or non-fatal CVD was defined according to WHO-ICD-10 criteria. Baseline serum blood lipids’ profile (Total-C, HDL-, non HDL-, LDL-cholesterol, triglycerides (TG), apolipoprotein (Apo)A1 and B, and lipoprotein–(a) levels were also measured.
The 10-year all-cause mortality rate was 5.7 % for men and 2.0 % for women (p = 0.55). The, 10-year CVD incidence was 19.7 % in men and 11.7 % in women (p < 0.001). Multi-adjusted analysis revealed that TC, non-HDL-C, TG and TG/HDL-C ratio, were independent predictors of all cause mortality (RR per 1 mg/dL or unit (95 % CI): 1.006 (1.000–1.013), 1.006 (1.000–1.013), 1.002 (1.000–1.004), 1.038 (1.001–1.077), respectively). Moreover, TC, HDL-, LDL-, non-HDL-cholesterol, TG, apoA1, TC/HDL-C and TG/HDL-C were independently associated with CVD risk. Among all lipid indices the ratio of apoB/apoA1 demonstrated the best correct reclassification ability, followed by non-HDL-C and TC/HDL-C ratio (continuous Net Reclassification Index 26.1 and 21.2 %, respectively).
Elevated levels of lipid biomarkers are independently associated with all-cause mortality, as well as CVD risk. The ratio of apoB/apoA1, followed by non-HDL-C, demonstrated the best correct classification ability of the developed CVD risk models.
Cardiovascular disease; All cause mortality; Lipids; Lipoproteins; Apolipoproteins; Epidemiology
Diet is an important environmental factor that interacts with genes to modulate the likelihood of developing disorders in lipid metabolism and the relationship between diet and genes in the presence of other chronic diseases such as obesity. The objective of this study was to analyze the interaction of a high fat diet with the APOA2 (rs3813627 and rs5082), APOA5 (rs662799 and rs3135506) and LEPR (rs8179183 and rs1137101) polymorphisms and its relationship with obesity and dyslipidemia in young subjects.
The study included 200 young subjects aged 18 to 25 years (100 normal-weight and 100 obese subjects). Dietary fat intake was measured using the frequency food consumption questionnaire. Genotyping of polymorphisms was performed by PCR-RFLP.
Individuals carrying the APOA5 56 G/G genotype with a high saturated fatty acid consumption (OR = 2.7, p = 0.006) and/or total fat (OR = 2.4, p = 0.018), associated with an increased risk of obesity. We also found that A/G + G/G genotypes of the 668 A/G polymorphism in the LEPR gene with an intake ≥12 g/d of saturated fatty acids, have 2.9 times higher risk of obesity (p = 0.002), 3.8 times higher risk of hypercholesterolemia (p = 0.002) and 2.4 times higher risk of hypertriglyceridemia (p = 0.02), than those with an intake <12 g/d of saturated fatty acids. Similarly, LEPR 668 A/G + G/G carriers with a high fat total intake had 3.0 times higher risk of obesity (p = 0.002) and 4.1 times higher risk of hypercholesterolemia (p = 0.001).
Our results suggest that dietary fat intake modifies the effect of APOA5 and LEPR polymorphisms on serum triglycerides, cholesterol levels and obesity in young subjects.
Dyslipidemia; Obesity; LEPR; APOA2; APOA5; Gene-diet interaction
Statins reduce plasma low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) levels. Rosuvastatin 10 mg daily appears to be more potent in reducing LDL-C than simvastatin 40 mg, but the relative effect of these two statin doses on hsCRP is unknown.
Chinese hyperlipidaemic patients with high cardiovascular risk or familial hypercholesterolaemia (FH) were treated with rosuvastatin 10 mg and simvastatin 40 mg daily in an open-label crossover study. Lipid profiles were measured off treatment and after at least 4 weeks treatment with each of the two statins and hsCRP levels were measured on treatment with both statins.
Both treatments were well tolerated in 247 patients (age 55.7 ± 11.1 years; 100 male; 140 with FH) with good treatment compliance. There were statistically significant differences (P < 0.001) for rosuvastatin versus simvastatin for LDL-C reduction (−52.4 ± 11.9 % vs. -47.7 ± 10.8 %) and on-treatment LDL-C (2.62 ± 0.99 mmol/L vs. 2.86 ± 0.97 mmol/L), respectively, but the on-treatment hsCRP levels (1.33 ± 1.37 mg/L vs. 1.41 ± 1.57 mg/L, P > 0.05) were not significantly different. The lipid target (LDL-C <2.6 mmol/L) was achieved by 52.9 % with rosuvastatin compared with 42.6 % with simvastatin (P < 0.05). The proportions of patients attaining hsCRP targets of <2 and <1 mg/L were similar with the two statins (57.1 % and 74.6 % for rosuvastatin vs. 57.1 % and 80.1 % for simvastatin, P > 0.05).
A significantly greater proportion of patients achieved LDL-C targets with rosuvastatin 10 mg compared to simvastatin 40 mg in Chinese patients with hypercholesterolaemia, but there was no significant difference in achieving hsCRP target levels with the two statins.
High-sensitivity C-reactive protein; Statins; Low-density lipoprotein cholesterol; Chinese
Genome-wide association studies have been used extensively to identify genetic variants linked to metabolic syndrome (MetS), but most of them have been conducted in non-Asian populations. This study aimed to evaluate the association between MetS and previously studied single nucleotide polymorphisms (SNPs), and their interaction with health-related behavior in Korean men.
Seventeen SNPs were genotyped and their association with MetS and its components was tested in 1193 men who enrolled in the study at Seoul National University Hospital.
We found that rs662799 near APOA5 and rs769450 in APOE had significant association with MetS and its components. The SNP rs662799 was associated with increased risk of MetS, elevated triglyceride (TG) and low levels of high-density lipoprotein, while rs769450 was associated with a decreased risk of TG. The SNPs showed interactions between alcohol drinking and physical activity, and TG levels in Korean men.
We have identified the genetic association and environmental interaction for MetS in Korean men. These results suggest that a strategy of prevention and treatment should be tailored to personal genotype and the population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-015-0111-5) contains supplementary material, which is available to authorized users.
APOA5; APOE; Health behavior; Metabolic syndrome; Triglyceride
Circulating lipid metabolites are associated with many physiological and biological processes in the body, and therefore could be used as biomarkers for evaluating drug efficacy and safety in preclinical studies. However, differences in circulating lipid profiles among humans and animals often used in preclinical studies have not been fully investigated.
We performed lipidomic analysis to obtain circulating lipid profiles of fasted humans (Caucasian, n = 15) and three animal species used in preclinical studies (mice [BALB/c, n = 5], rats [Sprague–Dawley, n = 5], and rabbits [New Zealand White, n = 5]) by using liquid chromatography-mass spectrometry.
Our data showed marked differences in lipid profiles among humans and these animal species. Furthermore, we observed that the levels of many lipid metabolites, such as poly-unsaturated fatty acid-containing cholesteryl esters, ether-type phosphoglycerolipids, and sulfatides, were significantly different (p < 0.05) by more than 10-fold in these animals (depending on the animal species) from humans.
Our data could be useful while extrapolating the data on the biomarker candidates identified in preclinical studies into clinical studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-015-0104-4) contains supplementary material, which is available to authorized users.
Preclinical studies; LC-MS; Circulating lipid metabolites; Lipidomic analysis
Dyslipidemia is a well-established risk factor for cardiovascular disease. Serum lipids were affected by several gene polymorphisms, folate, homocysteine and other metabolite levels. We aim to investigate the effects of homocysteine metabolism enzyme polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) and their interactions with folate, homocysteine on serum lipid levels in Chinese patients with hypertension.
Participants were 480 hypertensive adults that enrolled in September to December 2005 from six different Chinese hospitals (Harbin, Shanghai, Shenyang, Beijing, Xi’an, and Nanjing). Known MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G genotypes were determined by PCR-RFLP methods. Serum folate was measured by chemiluminescent immunoassay, homocysteine was measured by high-performance liquid chromatography, serum lipids parameters were determined by an automatic biochemistry analyzer, low-density lipoprotein was calculated by Friedewald’s equation. Unitary linear regression model was used to assess the associations of gene polymorphisms, folate and homocysteine on serum lipid profiles. Unconditional logistic regression model was applied to test the interactions of folate, homocysteine and gene polymorphisms on dyslipidemia.
No correlations between gene polymorphisms and homocysteine on serum lipid profiles. Compared with normal folate patients, patients with low folate showed higher odds of hypertriglyceridemia (OR = 2.02, 95 % CI: 1.25-3.25, P = 0.004) and low levels of high-density lipoprotein cholesterol (OR = 1.88, 95 % CI: 1.07-3.28, P = 0.027). Each of four gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) combined with low folate showed higher odds of hypertriglyceridemia (P for trend: 0.049, 0.004, 0.007 and 0.005, respectively). MTHFR C677T and A1298C with low folate showed higher odds of low levels of high-density lipoprotein cholesterol (P for trend: 0.008 and 0.031).
Low folate status and homocysteine metabolism gene polymorphisms (MTHTR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) may have a synergistic effect increased the incidence of dyslipidemia in Chinese hypertensive population.
MTHFR C677T; MTHFR A1298C; MTR A2756G; MTRR A66G; Folate; Homocysteine; Serum lipids
Lipoprotein Lipase (LPL) deficiency is a rare autosomal recessive disorder with a heterogeneous clinical presentation. Several mutations in the LPL gene have been identified to cause decreased activity of the enzyme.
An 11-week-old, exclusively breastfed male presented with coffee-ground emesis, melena, xanthomas, lipemia retinalis and chylomicronemia. Genomic DNA analysis identified lipoprotein lipase deficiency due to compound heterozygosity including a novel p.Q240H mutation in exon 5 of the lipoprotein lipase (LPL) gene. His severe hypertriglyceridemia, including xanthomas, resolved with dietary long-chain fat restriction.
We describe a novel mutation of the LPL gene causing severe hypertriglyceridemia and report the response to treatment. A review of the current literature regarding LPL deficiency syndrome reveals a few potential new therapies under investigation.
Chylomicronemia; Triglyceride; Lipoprotein lipase deficiency
Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS.
This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg).
Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups.
The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773)
A disruption of cholesterol homeostasis characterized by the physical-chemical imbalance of cholesterol solubility in bile often results in formation of cholesterol gallstones. Our earlier studies revealed that curcumin (1000 mg/kg) could prevent formation of gallstones. It has been proved that curcumin is poorly absorbed while piperine is a bioavailability-enhancer. Nevertheless, whether curcumin combined with piperine could enhance the effect of curcumin in preventing gallstones is still awaited.
C57BL6 mice were fed on a lithogenic diet concomitant with curcumin at 500 or 1000 mg/kg and/or piperine at 20 mg/kg for 4 weeks. The ratio of gallbladder stone formation was recorded and samples of blood, bile, gallbladder, liver and small intestine were also collected. The volume of gallbladder and weight of liver were calculated, and blood and bile samples were analyzed through biochemical methods. Intestinal NPC1L1 and SREBP2 mRNA and protein expression were detected by real-time PCR and Western blot.
Combining with piperine can significantly enhance the effect of curcumin, thus preventing the development of gallbladder stones, lowering the saturation of blood lipids and cholesterol in bile, as well as decreasing the expression of NPC1L1 and SREBP2 in both mRNA and protein levels.
Curcumin can prevent the formation of cholesterol gallstones induced by high fat diet in mice and SREBP2 and NPC1L1 may participate in this process. Piperine can increase curcumin’s bioavailability, thereby enhancing the effect of curcumin.
NPC1L1; SREBP2; Cholesterol absorption; Curcumin; Piperine; Gallbladder stone
Long-chain n-3 polyunsaturated fatty acids (LC n-3-PUFA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) provide multiple health benefits for heart, brain and eyes. However, consumption of fatty fish, the main source of LC n-3-PUFAs is low in Western countries. Intakes of LC n-3-PUFA can be increased by taking dietary supplements, such as fish oil, algal oil, or krill oil. Recently, conflicting information was published on the relative bioavailability of these omega-3 supplements. A few studies suggested that the phospholipid form (krill) is better absorbed than the fish oil ethyl ester (EE) or triglyceride (TG) forms. Yet studies did not match the doses administered nor the concentrations of DHA and EPA per supplement across such comparisons, leading to questionable conclusions. This study was designed to compare the oral bioavailability of the same dose of both EPA and DHA in fish oil-EE vs. fish oil-TG vs. krill oil in plasma at the end of a four-week supplementation.
Sixty-six healthy adults (n = 22/arm) were enrolled in a double blind, randomized, three-treatment, multi-dose, parallel study. Subjects were supplemented with a 1.3 g/d dose of EPA + DHA (approximately 816 mg/d EPA + 522 mg/d DHA, regardless of formulation) for 28 consecutive days, as either fish oil-EE, fish oil-TG or krill oil capsules (6 caps/day). Plasma and red blood cell (RBC) samples were collected at baseline (pre-dose on Day 1) and at 4, 8, 12, 48, 72, 336, and 672 h. Total plasma EPA + DHA levels at Week 4 (Hour 672) were measured as the primary endpoint.
No significant differences in total plasma EPA + DHA at 672 h were observed between fish oil-EE (mean = 90.9 ± 41 ug/mL), fish oil-TG (mean = 108 ± 40 ug/mL), and krill oil (mean = 118.5 ± 48 ug/mL), p = 0.052 and bioavailability differed by <24 % between the groups. Additionally, DHA + EPA levels were not significantly different in RBCs among the 3 formulations, p = 0.19, providing comparable omega-3 indexes.
Similar plasma and RBC levels of EPA + DHA were achieved across fish oil and krill oil products when matched for dose, EPA, and DHA concentrations in this four week study, indicating comparable oral bioavailability irrespective of formulation.
Clinicaltrials.gov identifier NCT02427373.
Docosahexaenoic acid; Eicosapentaenoic acid; Krill; Plasma; Red blood cell; Fish oil; Omega-3; Bioavailability; Bioequivalence
This study examined the effects of a mixture of highly bioavailable omega-3 carboxylic acids (OM3-CA) on nuclear magnetic resonance spectroscopy–assessed lipoprotein particle concentrations and sizes and other cardiovascular risk markers in statin-treated patients with fasting triglycerides (TG) ≥2.3 mmol/L (200 mg/dL) and <5.6 mmol/L (500 mg/dL) and at high cardiovascular risk.
After a diet lead-in and statin-stabilization period, 647 patients were randomly assigned to receive capsules of control (olive oil, OO) 4 g/d, OM3-CA 2 g/d (plus OO 2 g/d), or OM3-CA 4 g/d for 6 weeks.
Compared with OO, low-density lipoprotein (LDL) particle size was increased with OM3-CA 2 g/d (p < 0.01) and 4 g/d (p < 0.001), and very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) particle sizes were decreased with both OM3-CA dosages vs. OO (p < 0.001 and p < 0.05 for VLDL and HDL, respectively). Total VLDL/chylomicron remnant particle concentration was reduced by 8.5 and 16.0 % with OM3-CA 2 and 4 g/d, respectively, vs. a 6.9 % reduction with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Total HDL particle concentration was also reduced by 1.5 and 3.2 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.6 % increase with OO (at least p < 0.05 for both comparisons). Changes in total LDL particle concentration were not significantly different for OO vs. OM3-CA at either dosage. Apolipoprotein (Apo) CIII levels decreased by 7.6 and 13.1 % with OM3-CA 2 and 4 g/d, respectively, vs. 3.2 % with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass was reduced by 6.2 and 10.7 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.1 % increase with OO (p < 0.001 for both vs. OO). There were no significant differences between treatments in high-sensitivity C-reactive protein responses.
OM3-CA were associated with shifts in lipoprotein particle sizes and concentrations, and reductions in Apo CIII and Lp-PLA2, in patients with hypertriglyceridemia while taking a statin.
ClinicalTrials.gov Identifier NCT01408303.
Hypertriglyceridemia; Omega-3 fatty acids; Triglycerides; Statin; Low-density lipoprotein cholesterol; Apolipoprotein CIII; Lipoprotein-associated phospholipase A2; Lipoprotein subclasses; Eicosapentaenoic acid; Docosahexaenoic acid
Numerous studies have evidenced that statins can reduce the incidence of cardiovascular disease. However, the effects of high-dose rosuvastatin (RSV) preloading in patients undergoing percutaneous coronary intervention (PCI) are controversial.
We attempted to identify and quantify the potential cardioprotective benefits of high-dose RSV preloading on final thrombolysis in myocardial infarction (TIMI) flow grade, major adverse cardiac events (MACE), and peri-procedural myocardial injury (PMI) in patients undergoing PCI.
Pubmed, EMBASE, Cochrane Central Register of Controlled Trials and ISI Web of Science databases were systematically searched for randomized controlled trials (RCTs) up to June 2015. We assessed the incidence of MACE and PMI in all enrolled patients for subgroups stratified by clinical presentation and previous statin therapy during the follow-up period.
Fourteen trials with 3368 individuals were included in our meta-analysis. High-dose RSV preloading before PCI lead to a 58 % reduction in MACE (odds ratio [OR] = 0.42, 95 % confidence intervals [CI]: 0.29-0.61, P < 0.00001) and a 60 % reduction in PMI (OR = 0.40, 95 % CI: 0.25–0.63, P < 0.0001). This procedure also improved the final TIMI flow grade in patients undergoing PCI (OR = 1.61, 95 % CI: 1.09–2.38, P = 0.02). The benefits on MACE were significant for both stable angina patients (OR = 0.42, 95 % CI: 0.21-0.87, P = 0.02) and acute coronary syndrome (ACS) patients (OR = 0.42, 95 % CI: 0.27-0.65, P < 0.0001); and for both statin naïve patients (OR = 0.42, 95 % CI: 0.28-0.64, P < 0.0001) and previous statin therapy patients (OR = 0.28, 95 % CI: 0.10-0.73, P = 0.01).
High-dose RSV preloading can significantly improve myocardial perfusion and reduce both MACE and PMI in patients undergoing PCI. The cardioprotective benefits of RSV preloading were significant in not only stable angina and ACS patients but also statin naïve and previous statin therapy patients. The cardioprotective benefits of RSV preloading in the follow-up period mainly resulted from a reduction in spontaneous MI and TVR, especially for ACS and statin naïve patients.
Rosuvastatin; Clinical events; Peri-procedural myocardial infarction; Meta-analysis
Increasing evidence suggests that overnutrition during the early postnatal period, a critical window of development, increases the risk of adult-onset obesity and insulin resistance. In this study, we investigated the impact of overnutrition during the suckling period on body weight, serum biochemistry and serum fatty acid metabolomics in male rats.
Rats raised in small litters (SL, 3 pups/dam) and normal litters (NL, 10 pups/dam) were used to model early postnatal overnutrition and control, respectively. Serum glucose, triglyceride, high-density lipoprotein-cholesterol, free fatty acid, insulin and leptin concentrations were assayed using standard biochemical techniques. Serum fatty acids were identified and quantified using a gas chromatography–mass spectrometry-based metabolomic approach. mRNA and protein levels of key components of the insulin receptor signaling pathway were measured in epididymal fat and gastrocnemius muscle by quantitative PCR and western blotting.
SL rats were 37.3 % and 15.1 % heavier than NL rats at weaning and 16-weeks-old, respectively. They had increased visceral fat mass, adult-onset insulin resistance and glucose intolerance as well as elevated serum levels of free fatty acids and triglycerides. All detectable fatty acids were elevated in the serum of SL pups at weaning compared to NL controls, and significant increases in the levels of four fatty acids (palmitic acid, palmitoleic acid, oleic acid and arachidonic acid) persisted into adulthood. Moreover, a significantly positive correlation was identified between an insulin resistance index (HOMA-IR) and concentrations of myristic, palmitic, palmitoleic and oleic acid in serum at postnatal 16 weeks. Early postnatal overnutrition also resulted in a significant downregulation of insulin receptor substrate-1 (Irs-1), protein kinase B (Akt2) and glucose transporter 4 (Glut4) at the protein level in epididymal fat of SL rats at 16 weeks, accompanied by decreased mRNA levels for Irs-1 and Glut4. In gastrocnemius muscle, Akt2 and Glut4 mRNA and Glut4 protein levels were significantly decreased in SL rats.
This study demonstrates that early postnatal overnutrition can have long-lasting effects on body weight and serum fatty acid profiles and can lead to impaired insulin signaling pathway in visceral white adipose tissue and skeletal muscle, which may play a major role in IR.
Early overnutrition; Insulin resistance; Insulin receptor substrate 1; Glucose transporter 4; Fatty acid