Increase In High-density Lipoprotein Cholesterol Concentration Research Articles

Effect of low-ratio n-6/n-3 PUFA on blood lipid level: a meta-analysis.

The aim of this meta-analysis was to evaluate the effects of low-ratio n-6/n-3 PUFA on blood lipid levels. We searched the PubMed, Embase, and Cochrane Library databases for randomized controlled trials of n-6/n-3 PUFA interventions up to March 2019. The change values were calculated as weighted mean differences (WMDs) by using a random-effect model. Subgroup analysis and meta-regression were used to explore the source of heterogeneity. A total of 30 randomized controlled trials with 1368 participants were identified. Compared with control, low-ratio n-6/n-3 PUFA significantly reduced triglyceride (TG) concentration (WMD: - 0.079mmol/L, 95% confidence interval (CI): - 0.148mmol/L to - 0.009mmol/L, p = 0.026) and increased high-density lipoprotein cholesterol (HDL-C) concentration (WMD: 0.033mmol/L, 95% CI: 0.007 to 0.058mmol/L, p = 0.012). Subgroup analysis revealed that the effects of low-ratio n-6/n-3 PUFA on blood lipid levels were better for a longer time. The effects of α-linolenic acid on total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations were more obvious among participants. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) had more significant effects on TG and HDL-C concentrations. No significant publication bias was observed for TG and HDL-C, as suggested by the results of Begg's test and Egger's test. Low-ratio n-6/n-3 PUFA significantly reduced TG concentration and increased HDL-C concentration. The beneficial effects of low-ratio n-6/n-3 PUFA on TG, TC, HDL-C, and LDL-C concentrations were enhanced with time. However, n-3 PUFA derived from plants significantly reduced TC and LDL-C concentrations, and n-3 PUFA derived from EPA and DHA significantly reduced TG concentration and increased HDL-C concentration.

Protective effect of celastrol on type 2 diabetes mellitus with nonalcoholic fatty liver disease in mice.

To investigate the protective effects of celastrol on mice with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), and to explore its underlying mechanism. The levels of low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), total cholesterol (TC), and triglyceride (TG) in serum were tested. Malondialdehyde (MDA) and superoxide dismutase (SOD), GOT, and GPT in serum were also detected. The histopathological changes of liver tissues were observed by HE staining. The apoptosis cell number of liver tissues was measured by TUNEL staining. Nrf‐2 and HO‐1 protein and mRNA expression were evaluated by IHC, WB, and RT‐PCR assay. Celastrol had effects to depress TG, TC, LDL‐C, GPT, GOT, and MDA concentration and increase HDL‐C and SOD concentration (p < .05, respectively) with dose‐dependent. Compared with model group, apoptosis cell number was significantly depressed in Cel‐treated groups with dose‐dependent (p < .05, respectively). Nrf‐2 and HO‐1 mRNA and protein expressions were significantly improved in Cel‐treated groups with dose‐dependent (p < .05, respectively). Celastrol can inhibit the oxidative stress reaction and liver cell apoptosis via regulation Nrf2/HO‐1 pathway in T2DM mice with NAFLD.

Efficacy and safety of statin use in children and adolescents with familial hypercholesterolaemia: A systematic review and meta–analysis of randomized–controlled trials

Statins are the mainstay of treatment for patients with familial hypercholesterolaemia (FH). However, their efficacy and safety in children and adolescents with FH has not been well-documented. The purpose of this study was to systematically investigate and meta-analyze the best available evidence from randomized-controlled trials (RCTs) regarding the efficacy and safety of statins in this population. A comprehensive search was conducted in PubMed, Scopus and Cochrane, up to 10 January 2020. Data were expressed as mean differences with 95% confidence intervals (CI). The I2 index was employed for heterogeneity. Ten RCTs were included in the qualitative and quantitative analysis (1191 patients, aged 13.3 ± 2.5 years). Compared with placebo, statins led to a mean relative reduction in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride and apolipoprotein B (apo-B) concentrations by −25.5% (95% CI −30.4%, −20.5%; I2 91%), −33.8% (95% CI −40.1%, −27.4%; I2 90%), −8.4% (95% CI −14.8%, −2.03%; I2 26%) and −28.8% (95% CI −33.9%, −23.6%; I2 83%), respectively. High-density lipoprotein cholesterol (HDL-C) was increased by 3.1% (95% CI 1.1%−5.2%; I2 0%). Statins were well-tolerated, with no significant differences in transaminase and creatine kinase levels or other adverse effects compared with placebo. Statins exerted no effect on growth or sexual development. Statins are quite effective in reducing TC, LDL-C, TG and apo-B and increasing HDL-C concentrations in children and adolescents with FH. No safety issues were seen with statin use.

Efficacy and safety of statin use in children and adolescents with familial hypercholesterolaemia: a systematic review and meta-analysis of randomized-controlled trials.

Statins are the mainstay of treatment for patients with familial hypercholesterolaemia (FH). However, their efficacy and safety in children and adolescents with FH has not been well-documented. The purpose of this study was to systematically investigate and meta-analyze the best available evidence from randomized-controlled trials (RCTs) regarding the efficacy and safety of statins in this population. A comprehensive search was conducted in PubMed, Scopus and Cochrane, up to 10 January 2020. Data were expressed as mean differences with 95% confidence intervals (CI). The I2 index was employed for heterogeneity. Ten RCTs were included in the qualitative and quantitative analysis (1191 patients, aged 13.3 ± 2.5 years). Compared with placebo, statins led to a mean relative reduction in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride and apolipoprotein B (apo-B) concentrations by -25.5% (95% CI -30.4%, -20.5%; I2 91%), -33.8% (95% CI -40.1%, -27.4%; I2 90%), -8.4% (95% CI -14.8%, -2.03%; I2 26%) and -28.8% (95% CI -33.9%, -23.6%; I2 83%), respectively. High-density lipoprotein cholesterol (HDL-C) was increased by 3.1% (95% CI 1.1%-5.2%; I2 0%). Statins were well-tolerated, with no significant differences in transaminase and creatine kinase levels or other adverse effects compared with placebo. Statins exerted no effect on growth or sexual development. Statins are quite effective in reducing TC, LDL-C, TG and apo-B and increasing HDL-C concentrations in children and adolescents with FH. No safety issues were seen with statin use.

Effects of Bariatric Surgery on HDL Cholesterol.

Low levels of high-density lipoprotein cholesterol (HDLc) are independent predictive factors of coronary heart disease. Bariatric surgery increases HDLc concentration, but the chronology and predictors of this improvement in HDLc levels are not well-established. The aim of the present study was to analyse the changes over time in HDLc concentrations after bariatric surgery and to determine the predictors of their increase. This was a retrospective, observational study. The medical records of patients who had undergone bariatric surgery at a tertiary care hospital between January 2007 and March 2015 were reviewed. Patients who underwent revisional surgery or were treated with fibrates were excluded from the analysis. A total of 185 patients were included in the study. Follow-up rates were as follows: 87% (year 2) and 28% (year 5). At postoperative month 3, HDLc levels decreased significantly versus baseline (- 11.1%; p = 0.000), at which point they began to rise, reaching their maximum level 2years after bariatric surgery (26.2% increase from baseline; p = 0.000). The increase in HDLc concentration 2years after surgery correlated with the preoperative HDLc level (r = - 0.292, p = 0.001), and it was greater in patients who underwent sleeve gastrectomy versus gastric bypass (0.36 ± 0.4 vs. 0.18 ± 0.4mmol/L, respectively; p = 0.018). Bariatric surgery has a beneficial effect on HDLc levels. The maximum increase in postoperative HDLc concentrations is observed 2years after surgery. Preoperative HDLc and the type of surgery are both significant predictors of the maximum increase in HDLc levels.

The Effect of Ginger (Zingiber officinale) on Diet Induced Hyperlipidemia and Tissue Histology in Adult Female Wistar Rats: A Biochemical and Histopathological Study

The study is aimed at determining the atheroprotective property of ginger (Zingiber officinale) aqueous extract to rats fed with a high-fat diet. Each group consisted of 5 rats. Group 1 represent the control group and received normal rat pellets; groups 2-5 were maintained on high-fat diet for 6 weeks to establish hyperlipidemia. Groups 1, 2, 3, 4 and 5 received distilled water, distilled water, 400, 500 and 600 mg/kg (body weight) Zingiber officinale respectively for 4 weeks. Serum concentrations of triglycerides (TG), total cholesterol (TC) and high-density lipoprotein-cholesterol (HDL-C) were determined using standard biochemical methods. Histologic examination of tissues was by Hematoxylin-Eosin staining technique. Data were analyzed using Student’s t-test and P&lt;0.05 was considered significant. A decrease in the mean concentrations of TG, TC, low-density lipoprotein (LDL-C) and increase in HDL-C concentration of each of the treatment groups (3, 4, 5) were observed when compared with that of group 2. In rats fed high-fat diet, histologic abnormalities were observed for the heart, liver, and kidney which were not adequately corrected by ginger treatment. Results suggest that at dosage levels studied, aqueous ginger extract ameliorated biochemical but not histologic consequences of the high-fat diet.

Serum Paraoxonase-1-Related Variables and Lipoprotein Profile in Patients with Lung or Head and Neck Cancer: Effect of Radiotherapy.

We investigated alterations in the levels of the antioxidant paraoxonase-1 (PON1) and the lipoprotein profile (analyzed by nuclear magnetic resonance) in patients with lung cancer (LC) or head and neck cancer (HNC), and the effects produced thereon by radiotherapy (RT). We included 33 patients with LC and 28 patients with HNC. Before irradiation, and one month after completion of RT, blood samples were obtained. The control group was composed of 50 healthy subjects. Patients had significantly lower serum PON1 activity and concentration before RT than the control group. PON1-related variables were good predictors of the presence of LC or HNC, with analytical sensitivities and specificities greater than 80%. Patients showed a significant increase in the number of particles of all subclasses of very-low-density lipoproteins (large, medium and small). However, these changes were not maintained when adjusted for age, sex, and other clinical and demographic variables. Irradiation was associated with a significant increase in PON1 concentration and, only in patients with HNC, with an increase in high-density lipoprotein-cholesterol concentration. Our results suggest that determinations of the levels of PON1-related variables may constitute good biomarkers for the evaluation of these diseases. Studies with a larger number of patients are needed to fully confirm this hypothesis.

Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk

BackgroundCholesteryl ester transfer protein (CETP) inhibitors are a class of drugs that targets the CETP enzyme to significantly increase serum high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels. As HDL-C has potential antidiabetic properties, and the beneficial effects of CETP drugs on glucose homoeostasis have not been sufficiently studied, the aims of this study were: (1) to evaluate the effect of CETP inhibitors on the incidence of diabetes; and (2) to assess the association between CETP inhibitor-induced changes in HDL-C levels and incidence of diabetes. MethodsA meta-analysis was performed of randomized controlled clinical trials of CETP inhibitor therapy, either alone or combined with other lipid-lowering drugs, reporting data from new cases of diabetes with a minimum of 6 months of follow-up, after searching the PubMed/MEDLINE, Embase and Cochrane Controlled Trials databases. A fixed-effects meta-regression model was then applied. ResultsFour eligible trials of CETP inhibitors, involving a total of 73,479 patients, were considered for the analyses, including 960 newly diagnosed cases of diabetes in the CTEP inhibitor group vs 1086 in the placebo group. CETP inhibitor therapy was associated with a significant 12% reduction in incidence of diabetes (OR: 0.88, 95% CI: 0.81–0.96; P=0.005). Assessment of the relationship between on-treatment HDL-C and the effect of CETP inhibitors showed a statistically non-significant trend (Z=–1.13, P=0.26). ConclusionCETP inhibitors reduced the incidence of diabetes. The improvement in glucose metabolism may have been related, at least in part, to the increase in HDL-C concentration.

HDL-cholesterol and cardiovascular disease: rethinking our approach.

A low level of plasma high density lipoprotein cholesterol (HDL-C) is a strong and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). However, several large studies recently revealed that pharmacologic interventions that increase HDL-C concentration have not improved cardiovascular outcomes when added to standard therapy. In addition, specific genetic variants that raise HDL-C levels are not clearly associated with reduced risk of coronary heart disease. These observations have challenged the 'HDL hypothesis' that HDL-C is causally related to ASCVD and that intervention to raise HDL-C will reduce ASCVD events. This article will present the current data on the HDL hypothesis and provide a revised paradigm of considering HDL in the atherosclerotic pathway. Recent evidence has shed light on the complex nature of HDL-C metabolism and function. There are compelling data that the ability of HDL to promote cholesterol efflux from macrophages, the first step in the 'reverse cholesterol transport' (RCT) pathway, is inversely associated with risk for ASCVD even after controlling for HDL-C. This has led to the 'HDL flux hypothesis' that therapeutic intervention that targets macrophage cholesterol efflux and RCT may reduce risk. Preclinical studies of such interventions show promise and early phase clinical studies, though small, are encouraging. The role of HDL-C in modulating atherosclerotic disease is as yet uncertain. However, new findings and therapies targeting HDL-C show early promise and may provide an important intervention in attenuating the burden of ASCVD in the future.

Participation in a Social-Support Physical Activity Intervention Modestly Improves Lipoprotein Cholesterol Distribution Among Postpartum Sedentary Hispanic Women.

The effects of moderate intensity walking on lipoprotein remodeling in postpartum Hispanic women are unknown. Sedentary postpartum Hispanic women (28.2 ± 5.6 y; BMI = 29.3 ± 3.3 kg/m2) participating in a social support physical activity (PA) intervention, were randomly assigned to a 12-month walking program (walkers; n = 22; target 150 min/wk, moderate intensity) or a control group (nonwalkers; n = 22). Fasting lipids and cholesterol distribution within low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles were measured at baseline (BL), 6 months, and 12 months. Walkers had an 11% increase and nonwalkers a 7% decrease in HDL cholesterol from 6 to 12 months (P = .0367) without an effect on LDL cholesterol. Whereas nonwalkers had virtually no change in mean LDL particle size, walkers had a borderline reduction in LDL size from BL (268.7 ± 4.1 Å) to 6 months (266.9 ± 4.9 Å), followed by a significant increase in size by 12 months (269.7 ± 4.1 Å; P = .011). The proportion of cholesterol in large LDL particles decreased by 15% from BL to 6 months, but subsequently increased 25% by 12 months among walkers; changes among nonwalkers were smaller and in opposite direction (4% and -3%, respectively; P = .0004). Participation in the social-support PA intervention resulted in slightly increased HDL cholesterol concentrations and a modest and beneficial shift toward larger, less atherogenic LDL particles.

A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol concentrations after the consumption of a soy protein and soluble fiber dietary portfolio.

Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs5030952, rs2975762, rs3792267, and rs2975760) associated with type 2 diabetes. Subjects with the GG genotype of the rs2975762 variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs2975762-GG genotype are better responders to this dietary intervention.

No improvement of high-density lipoprotein (HDL) vasorelaxant effect despite increase in HDL cholesterol concentration in type 2 diabetic patients treated with glitazones.

High-density lipoproteins (HDLs) from type 2 diabetic patients are unable to counteract the inhibitory effect of oxidized low-density lipoproteins (ox-LDLs) on vasorelaxation. We hypothesized that glitazones, which improve glycemic control and dyslipidemia, could correct this abnormality. We compared the ability of HDL from controls (n = 12) and from type 2 diabetic patients before and after 6 months of treatment with either rosiglitazone (n = 11) or pioglitazone (n = 8) to counteract the inhibitory effect of ox-LDL on vasodilatation of rabbit aorta rings. Rosiglitazone induced a decrease in hemoglobin A1c (7.7% ± 1.1% vs 9.8% ± 1.0%, P = .003) and an increase in HDL cholesterol (1.14 ± 0.32 vs 0.98 ± 0.24 mmol/L, P = .033). Pioglitazone induced a decrease in hemoglobin A1c (8.3% ± 2.5% vs 9.5% ± 3.2%, P = .068) and serum triglycerides (1.58 ± 0.89 vs 2.03 ± 0.70 mmol/L, P = .069) and an increase in HDL cholesterol (1.39 ± 0.22 vs 1.14 ± 0.22 mmol/L, P = .018). The triglyceride content of HDL was unchanged by rosiglitazone and was decreased by 25% (P = .068) by pioglitazone. HDL from controls counteracted the inhibitory effect of ox-LDL on vasodilatation (maximal relaxation [Emax] = 74.4% ± 3.5% vs 51.9% ± 3.3%, P = .0029), whereas HDL from type 2 diabetic patients did not (Emax = 51.7% ± 5.8% vs 52.3% ± 4.6% [P = .66] and 52.7% ± 5.5% vs 51.9% ± 4.5% [P = .78] for the rosiglitazone and pioglitazone group, respectively). Rosiglitazone or pioglitazone did not improve Emax (58.6% ± 5.9% vs 52.3% ± 4.6% [P = .15] and 49.3% ± 6.5% vs 51.9% ± 4.5% [P = .48], respectively). Glitazones increased the concentration of HDL cholesterol without restoring the ability of HDL particles to protect the endothelium from oxidative stress-induced dysfunction, meaning that HDL remained dysfunctional with impaired antiatherogenic properties.

Impact of a 12-week, pharmacist-directed walking program in an established employee preventive care clinic.

The impact on physical activity and health of a 12-week, pharmacist-directed walking program incorporated into an employee health and wellness clinic was evaluated. Clinic participants were eligible for study inclusion if they or their spouse was a current or retired employee of Ohio Northern University. Participants received a pedometer, a calendar with specific daily walking goals for the 12-week period, and maps with walking routes. Participants also met with a pharmacist and a student pharmacist for point-of-care tests measuring lipid and fasting glucose concentrations and blood pressure. Participants reported to weekly pedometer checks where steps were recorded and medications were reassessed by the pharmacist or student pharmacist. As an incentive to meet the walking goals, the participants received a raffle ticket each week their goal had been achieved. After 12 weeks, participants reported for a final appointment when all baseline variables were reassessed by a team of health care professionals. A total of 144 participants were screened at baseline and included in the study, 65 of whom completed the program. At baseline, there were 240 abnormal laboratory test values found in participants with no prior history of dyslipidemia, hyperglycemia, or hypertension. After 12 weeks, significant changes in high-density-lipoprotein (HDL) cholesterol concentrations (p = 0.0012), fasting blood glucose concentrations (p = 0.0017), and blood pressure (p = 0.021) were noted. A pharmacist-directed walking program that included clinical assessments, walking goals, and weekly pedometer checks was an effective approach to increase employee activity levels, identify previously unknown health conditions, lower blood glucose concentrations and blood pressure values, and increase HDL cholesterol concentrations.

Effect of Gastric Bypass Versus Diet on Cardiovascular Risk Factors

To assess the effect of Roux-en-Y gastric bypass (RYGB) on high-density lipoprotein cholesterol (HDL-C) concentration and its apolipoprotein A4 (ApoA4) content at 1 year after bariatric surgery in comparison with a hypocaloric diet. Secondary aim was to measure total cholesterol and triglycerides levels and insulin sensitivity after interventions. Very few prospective uncontrolled studies have investigated the effects of RYGB on cardiovascular risk factors. No controlled studies had as primary goal the changes in HDL-C after gastric bypass. Forty subjects with a body mass index more than 40 or 35 kg/m or more in the presence of diabetes were enrolled. Twenty of them underwent RYGB, whereas 20 received lifestyle modification suggestions and medical therapy for obesity complications (diabetes, hypertension, and hyperlipidemia). A significant (P < 0.0001) increase in HDL-C concentrations was observed only in the surgical arm (from 41.95 ± 7.24 to 56.55 ± 9.01 mg/dL). Mean systolic and diastolic blood pressures were significantly reduced (P < 0.0001) in both groups with no between-group differences, probably in relation to the optimization of the antihypertensive treatment. Plasma concentration of ApoA4, a major HDL-C protein fraction, significantly increased 1 year after RYGB (from 496.61 ± 400.41 to 987.88 ± 637.41μg/L, P < 0.01). Circulating triglycerides concentration significantly decreased after surgery, whereas both peripheral and hepatic insulin resistance increased significantly. Our study shows that HDL-C and ApoA4 significantly increase after gastric bypass and that this increase is associated with a net improvement in hepatic insulin sensitivity. Furthermore, we speculate that ApoA4, which induces satiety in animals, can eventually play a role on the appetite reduction after RYGB because there is a strict and inverse relationship between weight and ApoA4 changes. (NCT01707771).

Green Tea, Cocoa, and Red Wine Polyphenols Moderately Modulate Intestinal Inflammation and Do Not Increase High-Density Lipoprotein (HDL) Production

Although polyphenols are often merely perceived as antioxidants, their biological activities are manifold and include anti-inflammatory actions. A new area of research on polyphenols and health concerns their putative role in cholesterol metabolism, in particular, their high-density lipoprotein-cholesterol (HDL-c)-raising potential. Indeed, some human studies showed that administration of polyphenol-rich foods such as cocoa, green tea, and extra virgin olive oil modulate and increase HDL-c concentrations. This study assessed the effects of polyphenols on intestinal inflammation, using the physiologically relevant Caco-2 Transwell model and using lipopolysaccharide (LPS) to trigger inflammation. This study also investigated the mechanisms of actions behind the proposed HDL-c-increasing effects of polyphenols. The data suggest that polyphenols (at least those from red wine, cocoa, and green tea) administered at a dietary dose moderately modulate intestinal inflammation but do not increase cholesterol secretion by intestinal cells or enhance HDL functionality. Nutraceuticals and supplements provide pharmanutritional doses that might, conversely, produce beneficial effects.

Association of lipoprotein lipase polymorphism rs2197089 with serum lipid concentrations and LPL gene expression

Many single-nucleotide polymorphisms (SNPs) have been reported to be associated with lipid concentrations in recent genome-wide association studies. The aim of this study was to validate the associations of rs2197089 in the lipoprotein lipase (LPL) gene with serum lipid concentrations and gene expression levels in the Chinese Han population and examine the potential interactions. A total of 9339 participants were recruited and genotyped for rs2197089. Gene expression levels of LPL in blood cells of 309 participants were evaluated by real-time PCR. We observed significant associations between rs2197089 and decreased triglycerides (TG) (P=0.0006), but not high-density lipoprotein cholesterol (HDL-C) concentration (P=0.0881). However, weak evidence of interaction between cigarette smoking and rs2197089 was detected (P=0.0362). In smokers, significant association between rs2197089 and increased HDL-C concentration was found (P=0.0068). Participants with the minor allele A had higher expression levels of LPL (P=0.0243). The results of our study indicated that rs2197089 was significantly associated with TG but it was associated with HDL-C only in smokers. This SNP seemed to have influence on the expression level of LPL.

Does Combination Therapy with Statins and Fibrates Prevent Cardiovascular Disease in Diabetic Patients with Atherogenic Mixed Dyslipidemia?

Type 2 diabetes mellitus (T2DM) is associated with the development and progression of cardiovascular disease (CVD). Statins have an established efficacy in the management of dyslipidemia primarily by decreasing the levels of low-density lipoprotein cholesterol and thus decreasing CVD risk. They also have a favorable safety profile. Despite the statin-mediated benefit of CVD risk reduction a residual CVD risk remains, especially in T2DM patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) values. Fibrates decrease TG levels, increase HDL-C concentrations, and improve many other atherosclerosis-related variables. Fibrate/statin co-administration improves the overall lipoprotein profile in patients with mixed dyslipidemia and may reduce the residual CVD risk during statin therapy. However, limited data exists regarding the effects of statin/fibrate combination on CVD outcomes in patients with T2DM. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study the statin/fibrate combination did not significantly reduce the rate of CVD events compared with simvastatin/placebo in patients with T2DM. However, it did show a possible benefit in a pre-specified analysis in the subgroup of patients with high TG and low HDL-C levels. Furthermore, in the ACCORD study the simvastatin/fenofibrate combination significantly reduced the rate of progression of retinopathy compared with statin/placebo administration in patients with T2DM. The present review presents the available data regarding the effects of statin/fibrate combination in patients with T2DM and atherogenic mixed dyslipidemia.

The effect of equol injection in ovo on lipid metabolism and hepatic lipogenic gene expression in broilers

This study investigated the effects of in ovo administration of equol (Eq) on post-hatch growth and hepatic lipid metabolism in broiler chickens. Fertilized eggs (146 eggs/group) were injected with 0 μg (control, Con), 20 μg (low dose, L) and 100 μg (high dose, H) Eq in the albumen on the 7th day of incubation. Except a trend increase in the weight of total fat (P = 0.09), Eq had no effect on growth or liver weight in broilers at 49 days of age. Males presented higher liver and BWs and lower total fat and relative liver weights than females (P < 0.01). However, there were no significant effects of Eq or Eq–gender interactions on growth performance or tissues weight (P > 0.05). With respect to lipid parameters in the serum, the results showed that female broilers presented higher triacyglycerol (TG) and low-density lipoprotein cholesterol concentrations than males, whereas there was no gender difference in serum total cholesterol (TC) or high-density lipoprotein cholesterol (HDLC) concentration (P > 0.05). Eq administration significantly decreased serum TG and TC but increased HDLC concentrations in serum of broilers at 49 days of age (P < 0.05), whereas there were no interactions between gender and Eq (P > 0.05). To elucidate the mechanism behind the significant changes of serum TG and TC levels, the expression of genes involved in lipid metabolism in the liver was investigated in female chickens using reverse transcription-PCR. Carnitine palmitoyl transferase I (CPTI) messenger RNA (mRNA) was significantly upregulated by 20 and 100 μg Eq (P < 0.05). High-dose Eq significantly decreased fatty acid synthase (FAS) and enhanced cholesterol-7alpha-hydroxylase (CYP7A1) mRNA levels in the liver (P < 0.05). Eq had no significant effects on acetyl-CoA carboxylase, sterol regulatory element binding protein-1c, malic enzyme, low-density lipoprotein receptor or 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA in the liver (P > 0.05). These results in female broilers suggest that Eq decreased blood TG by upregulating CPTI and downregulating FAS mRNA expression in the liver, and that high serum cholesterol levels stimulated CYP7A1 gene transcription in the liver.

Design, synthesis, and biological evaluation of sulfonic acid ester and benzenesulfonamide derivatives as potential CETP inhibitors

Epidemiological studies have established an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol concentration, and incidence of coronary artery disease (CAD); thus, the development of novel therapies that attempt to exploit the atheroprotective functions of HDL is a major goal. Inhibition of cholesteryl ester transfer protein (CETP) is one of the approaches targeted to increase HDL cholesterol concentration. CETP is a glycoprotein involved in transporting lipoprotein particles and neutral lipids between HDL and low-density lipoproteins (LDL), and therefore CETP inhibitors could be useful agents in the future for treating dyslipidemia and related disorders. Guided by our previously reported pharmacophore and QSAR models for CETP inhibition, we synthesized and bioassayed a series of sulfonic acid ester and benzenesulfonamide derivatives that can serve as a promising lead compounds for the development of potential and selective CETP inhibitors. The most potent compound 6k illustrated an IC50 of 3.4 μM.

HDL-C: Role as a risk modifier

Evidence that low-density lipoprotein-cholesterol (LDL-C) causes cardiovascular disease (CVD) is overwhelming. It has also been proven beyond all doubt that lowering the level of LDL-C using statins reduces CV risk. However, many people remain at high risk even when their level of LDL-C has been reduced by aggressive treatment with statins. One reason for this residual risk can be a low level of high-density lipoprotein-cholesterol (HDL-C). The concentration of HDL-C is an independent, inverse predictor for CVD. This relationship is apparent even when treatment with statins has reduced the level of LDL-C to below 1.8 mmol/L (70 mg/dL). It has therefore been suggested that raising the level of HDL-C should be considered as a therapeutic strategy for reducing the residual CV risk that persists in some people, despite aggressive LDL-C lowering with statins. HDL particles have several functions with the potential to protect against arterial disease, the best known of which relates to their ability to promote cholesterol efflux from macrophages in the artery wall. However, HDLs have several additional protective properties that are independent of their involvement in cholesterol metabolism. For example, they have properties that reduce oxidation, vascular inflammation and thrombosis, improve endothelial function, promote endothelial repair, enhance insulin sensitivity and promote insulin secretion by pancreatic beta islet cells. There is also a large and compelling body of evidence in animal models showing that interventions that increase HDL levels are profoundly anti-atherogenic. Major causes of low HDL are abdominal obesity and type 2 diabetes, the worldwide incidences of which are increasing at alarming rates. Strategies to increase the concentration of HDL should begin with lifestyle changes such as weight reduction, increased physical activity and smoking cessation. However, compliance with such measures is frequently poor and pharmacological intervention may be required. Currently available HDL-raising medications include fibrates, niacin and statins. There is indisputable evidence that lowering LDL-C levels using statins translates into a large reduction in CV risk. There is also mounting evidence that increasing the level of HDL-C using statins contributes to an additional reduction in CV risk. For example, the increase in HDL-C levels that was associated with simvastatin treatment in the 4S study was a significant predictor for the reduction in CV events. Moreover, a meta-analysis of 1,455 patients in 4 coronary intravascular ultrasound imaging trials showed that both the achieved level of LDL-C and the increase in HDL-C concentration during statin treatment were significant independent predictors for coronary atheroma progression as assessed by coronary intravascular ultrasound. In conclusion, evidence suggests that low levels of HDL-C are associated with an increased CV risk even when LDL-C is reduced to below 1.7 mmol/L (70 mg/dL) with a statin. Moreover, there is mounting evidence that increasing the level of HDL-C has the capacity to reduce CV risk. Thus, there is a compelling case for targeting both the LDL and HDL fractions to reduce CV risk in people with dyslipidemia, high CV risk and low levels of HDL-C.