Raising High-density Lipoprotein Levels Research Articles

The Effect of Technology-Based Home Cardiac Rehabilitation on Risk Factor Modifications in Coronary Heart Disease Patients. A Systematic Review and Meta-Analysis.

The delivery channels and approaches related to cardiac rehabilitation (CR), such as eHealth, mHealth, and telehealth, are evolving. Several studies have identified their effects on patients with coronary heart disease, although no studies have focused on all the approaches collectively. Randomized controlled trials have investigated lipid profiles, through systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI). Stata software was used for analysis, while Egger's linear regression test and Begg's funnel plot were also applied. Technology-based home CR revealed significantly lower total cholesterol (TC) levels (standardized mean difference (SMD) = -0.19; 95% confidence interval [CI]: [-0.27, -0.11]); triglyceride (TG) levels (SMD = -0.26; 95% CI: [-0.35, 0.17]); low-density lipoprotein (LDL) levels (SMD = -0.18; 95% CI: [ -0.25, -0.11]); SBP (SMD = -0.26; 95% CI: [-0.33, -0.19]); DBP (SMD = -0.24; 95% CI: [-0.32, -0.16]); BMI (SMD = -0.12; 95% CI: [-0.18, -0.05]), and improved high-density lipoprotein (HDL) levels (SMD = 0.22; 95% CI: [0.14, 0.31]). Technology-based home CR can be used to lower TC, TG, and LDL levels, alongside the BMI, SBP, and DBP indexes, while also raising HDL levels; thus, its use should be widely promoted.

The Role of High-Density Lipoprotein in Cardiovascular Disease: Benefits, Functions, and Treatments

There is evidence that high-density lipoprotein (HDL) can prevent the development of cardiovascular disease, particularly atherosclerotic. The beneficial effects of HDL on the arterial wall are largely due to its rich function. For example, one of the essential components of HDL's atherosclerotic protective characteristics is reverse cholesterol transport (RCT). The low-density lipoprotein (LDL) oxidation risk may be decreased attributable to the anti-oxidation function of HDL, which would also decrease the possibility of atherosclerosis. In recent years, the anti-inflammatory function of HDL has been demonstrated to modulate and participate in several inflammatory phenomena of atherosclerotic plaque formation. Since various functional features of HDL have gradually shown to have positive effects on the treatment and prevention of atherosclerotic plaque development, a growing number of researchers are working to develop effective strategies to boost HDL. Fortunately, several treatment options have developed to increase HDL levels, including drugs and dietary patterns. This article will focus on the functional properties of HDL levels and several therapeutic approaches to raise HDL levels.

High-density lipoprotein: a double-edged sword in cardiovascular physiology and pathophysiology

: High-density lipoprotein (HDL) plays a central role in vascular biology. HDL participates in multiple pathways that may be involved in the development of atherosclerosis and coronary artery disease (CAD), including cholesterol removal from the tissues (including vascular arterial wall), endothelial function protection through anti-inflammatory, antioxidant and anti-apoptotic effects, endothelial repair, angiogenesis and improved endothelial cell survival. Initial epidemiological evidence supported an inverse relationship between HDL level and the risk for atherosclerosis and CAD. Although HDL showed an inverse relationship with cardiovascular risk, pharmacologically-based HDL-raising therapies and Mendelian randomization studies refuted a causal relationship between HDL and the risk for atherosclerosis and CAD. So far, no HDL-raising therapy that increased HDL level without a concomitant decrease in the low-density lipoprotein (LDL) level reduced the cardiovascular risk. HDL structure and function alterations in various morbid conditions including inflammatory states, metabolic diseases, chronic kidney disease, cardiovascular risk factors and CAD transform HDL from a vasoprotective and anti-atherosclerotic particle into a pro-inflammatory and pro-atherosclerotic dysfunctional equivalent. Genetic studies, failure of HDL-raising therapies to improve clinical outcome despite markedly raising HDL levels and a better understanding of HDL functions led to a paradigm shift in HDL studies from investigation of HDL concentration to investigation of HDL functions (such as, cholesterol efflux capacity and anti-inflammatory indices) as a response to various therapeutic interventions. Several therapies aiming to improve HDL functions are in clinical use or under development. Future studies are needed to assess the role of HDL in vascular biology and cardiovascular epidemiology, pathophysiology and pharmacology.

HDL Improves Cholesterol and Glucose Homeostasis and Reduces Atherosclerosis in Diabetes-Associated Atherosclerosis.

Background and Aims Apolipoprotein A-I (ApoA-I), the main component of high-density lipoprotein (HDL), not only promotes reverse cholesterol transport (RCT) in atherosclerosis but also increases insulin secretion in pancreatic β-cells, suggesting that interventions which raise HDL levels may be beneficial in diabetes-associated cardiovascular disease (CVD). Previously, we showed that TNF-related apoptosis-inducing ligand (TRAIL) deletion in Apolipoprotein Eknockout (Apoe−/−) mice results in diabetes-accelerated atherosclerosis in response to a “Western” diet. Here, we sought to identify whether reconstituted HDL (rHDL) could improve features of diabetes-associated CVD in Trail−/−Apoe−/− mice. Methods and Results Trail−/−Apoe−/− and Apoe−/− mice on a “Western” diet for 12 weeks received 3 weekly infusions of either PBS (vehicle) or rHDL (containing ApoA-I (20 mg/kg) and 1-palmitoyl-2-linoleoyl phosphatidylcholine). Administration of rHDL reduced total plasma cholesterol, triglyceride, and glucose levels in Trail−/−Apoe−/− but not in Apoe−/− mice, with no change in weight gain observed. rHDL treatment also improved glucose clearance in response to insulin and glucose tolerance tests. Immunohistological analysis of pancreata revealed increased insulin expression/production and a reduction in macrophage infiltration in mice with TRAIL deletion. Furthermore, atherosclerotic plaque size in Trail−/−Apoe−/− mice was significantly reduced associating with increased expression of the M2 macrophage marker CD206, suggesting HDL's involvement in the polarization of macrophages. rHDL also increased vascular mRNA expression of RCT transporters, ABCA1 and ABCG1, in Trail−/−Apoe−/− but not in Apoe−/− mice. Conclusions. rHDL improves features of diabetes-associated atherosclerosis in mice. These findings support the therapeutic potential of rHDL in the treatment of atherosclerosis and associated diabetic complications. More studies are warranted to understand rHDL's mechanism of action.

EARLY TIME RESTRICTED FEEDING IMPROVES HIGH DENSITY LIPOPROTEIN FUNCTION IN GERIATRIC MONKEYS

Ageing conveys the greatest risk for cardiovascular disease (CVD) development, which is the dominant cause of mortality in developed nations. High density lipoprotein (HDL) particles mediate reverse cholesterol transport, are anti-inflammatory and their function predicts CVD. We observed lower plasma cholesterol efflux capacity in geriatric vervet monkeys (p=0.03) when consuming either healthy or Western diets. Adult (n=16) and geriatric (n=19) monkeys were stratified into groups fed Western diet on ad libitum (Ad Lib) or early time restricted feeding (eTFR) schedules. eTRF supplied excess food only between 6am to 2pm. Housing, seasonality and fasting conditions for data and sample collections were equivalent. After 6 months, cholesterol efflux to HDL was greater in eTRF monkeys (p=0.01), with no age by group interaction. Efflux media and plasma was chromatographically separated to confirm labelled cholesterol, and enzymatically measured cholesterol, respectively, was affiliated with HDL particles. eTRF monkeys had higher total plasma cholesterol levels (p=0.03) which was due to greater cholesterol amounts associated with only HDL, and resulted in HDL particles that were larger. eTRF resulted in robustly better HDL function such that measures from geriatric individuals were comparable to younger adults. Additionally, no differences in adiposity was observed in eTRF monkeys. Few interventions are known to raise HDL levels, and more importantly, are confirmed to improve HDL function. Our study is to date the largest, longest, controlled eTRF evaluation in primates and we show that positive biological effects are observable in HDL isolated from both adult and geriatric individuals independently of weight change.

Apolipoprotein AI) Promotes Atherosclerosis Regression in Diabetic Mice by Suppressing Myelopoiesis and Plaque Inflammation.

Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering. Aortic arches containing plaques developed in Ldlr-/- mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined. Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus. Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.

130 Toremifene Citrate Improves High-Density Lipoprotein Levels in Men on Testosterone Replacement Therapy

Decreases in high-density lipoprotein (HDL) levels have been observed in men on testosterone therapy (TTh). Niacin is commonly used as a therapy for low HDL, although its side effect (SE) profile often leads to frequent discontinuation. Toremifine citrate is an oral selective estrogen modulator (SERM) that is well tolerated and can improve lipid profiles by raising HDL levels in both breast and prostate cancer patients. Here we assess the role of toremifene in the management of HDL abnormalities in men on TRT. Determine the effect of torimifene citrate on the HDL levels of hypogonadal men on TTh compared to both niacin and control groups. Men on TTh with low HDL levels (<39 mg/dL) at a single andrology clinic treated between October 2015 and August 2017 treated with either toremifine (60 mg daily), niacin (titrated to 1,000 mg daily over 2 months) plus krill oil (1,000 mg daily) (NKO), or no treatment (patient refusal) were reviewed in a retrospective intent-to-treat analysis. Patient age, type of TTh, length of follow-up, and baseline and subsequent non-fasting lipid panels, total testosterone (TT) levels, and estrogen (E) levels were determined. Analysis of variance (ANOVA) was used to determine differences between groups.

Dysfunctional high density lipoprotein failed to rescue the function of oxidized low density lipoprotein-treated endothelial progenitor cells: a novel index for the prediction of HDL functionality

Lipid metabolic disorders play critical roles in atherogenesis. Traditionally, it has been suggested that reduced high density lipoprotein (HDL) levels might be an important morbidity indicator for cardiovascular diseases. Therefore, it has been argued that therapeutically raising HDL levels may reduce atherogenesis in patients with dyslipidemia. However, recent clinical trials to elevate serum HDL levels by pharmacologic approaches failed to demonstrate clinical efficacy. Thus, to investigate the functionality of HDL and to explore the possible clinical relevance as well as to define an effective indicator that can represent HDL function may provide another key and reference to disclose the clinical treatment of dyslipidemia. We analyzed the association between the data of dichlorofluorescein assay (assay the functionality of HDL), the effect of HDL on oxidized low density lipoprotein (oxLDL)-stimulated endothelial progenitor cells (EPCs) in vitro, levels of circulating EPCs, and ex vitro EPC colony forming units of each case, we defined the indicator (relative HDL index (RHDL index) = dichlorofluorescein assay result of each subject/dichlorofluorescein assay reading of our young healthy controls) that may represent functionality of HDL. HDL from healthy adults protected oxLDL-treated EPCs by modulating p38 mitogen-activated protein kinase and Rho activation and by promoting nitric oxide production. HDL from subject with RHDL index ≧2 also failed to restore the functionality of oxLDL-treated EPCs via cell-signaling pathways in vitro. The RHDL index significantly correlated with patients' circulating EPC number or EPC colony forming units ex vivo. In conclusions, we explored the RHDL index as a score to predict a patient's EPC functions in vivo and ex vitro.

Abstract 21040: MicroRNA-144 Antagonism Promotes Regression of Atherosclerosis

Introduction: Removal of cholesterol from atherosclerotic lesions remains an unmet therapeutic need. The ATP Binding Cassette Transporter A1 (ABCA1) plays a key role in the efflux of cholesterol from macrophages, therefore strategies that increase macrophage ABCA1 levels are likely to be atheroprotective. Methods and Results: To determine the long-term efficacy of anti-microRNA-144 (miR-144) therapy on the progression of atherosclerosis, we first treated Ldlr -/- mice with saline, control anti-miR, or anti-miR-144 oligonucleotides once a week for 16 weeks. Second, to determine the potential of miR-144 antagonism as an interventional atherosclerosis therapeutic, we treated Low-density lipoprotein receptor null ( Ldlr -/- ) mice with established atherosclerotic plaques with anti-miR-144 for 4 weeks, in a model of atherosclerosis regression. All anti-miR-144-treated mice showed an increase in circulating high-density lipoprotein (HDL) levels. In the model of atherosclerosis regression, anti-miR-144-treated mice also showed enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with these observations, anti-miR-144-treated mice showed reductions in atherosclerotic burden. Notably, in addition to increasing circulating HDL levels and reverse cholesterol transport, miR-144 antagonism significantly remodeled the HDL particle proteome in both progression and regression models of atherosclerosis. Conclusions: These studies establish that raising HDL levels and altering HDL particle properties by anti-miR-144 treatment promotes reverse cholesterol transport and atherosclerosis regression, and suggest it may be a promising interventional therapeutic strategy to treat atherosclerotic disease.

Aktivitas Hipolipidemik dan Indeks Aterogenik yang Rendah Ekstrak Air Daun Tapak Dara pada Tikus Hiperkolesterolemia

Catharanthus roseus is one plant recognized as medical potential which can decrease cholesterol. Thepresent study was carried out to evaluate the effect of aqueous leaf extracts of C. roseus on plasma lipidprofil levels in rats cholesterol rich diet and atherogenic index. This study was carried out on 15 SpraqueDawley male rats randomly distributed into five groups (n=3). Rats hypercholesterolemic wereadministrated cholesterol rich diet containing 1% (w/w). Normal control group with normal diet whitoutextracts (K1), positive control hypercholesterolemic group (K2) with cholesterol rich diet whitout extracts,and others three groups (K3-K5) were feed high cholesterol and 1 mL of aqueous leaf extracts of C. roseuswith a dose of 20% (w/v), 40% (w/v) and 80% (w/v) respectively, administered twice daily 1 mL orally.Treatment was given for 28 days. After treatment, the plasma lipids profile such cholesterol total, highdensity lipoprotein (HDL), low density lipoprotein (LDL), triglyceride (TGA) level were measured. Theresults showed that during the period of treatment with cholesterol rich diet have produced under condition hypercholesterolemic of rats with average cholesterol levels of 124.33 ± 4.04 mg/dL (K2 group). Treatmentwith extract dose of 80% showed the best results among the other doses in reducing levels of total cholesterol,triglycerides, LDL and raise HDL levels. Extract treatment dose of 80% up to four weeks resulted incholesterol total (79.33±3.51 mg/dL), TGA (72.33±6.65 mg/dL), HDL (55.00±3.60 mg/dL), and LDL(9.87±5.34mg/dL). In addition, value ratio of cholesterol:HDL was 1.4: 1 and atherogenic index value was0.44. These results suggest that extracts of leaf C. roseus optimum doses 80% (w/v) has hipolipidemicactivity in hypercholesterolemic rats and it has low atherogenic index value.

Triglycerides on the rise: should we swap seats on the seesaw?

For decades, cardiovascular risk attributed to lipids beyond low-density lipoprotein (LDL) has focused appropriately on high-density lipoprotein (HDL). Indubitable observational data show a consistent inverse relationship between baseline HDL-C concentrations and cardiovascular risk. Yet, fidelity as a prospective risk marker does not guaranty that an analyte either lies in a causal pathway for disease, or that its therapeutic manipulation will yield clinical benefits. Indeed, multiple strategies to raise HDL levels therapeutically have thus far failed to forestall events in clinical trials [e.g. currently available fibrates, niacin, and the investigated cholesteryl ester transfer protein (CETP) inhibitors]. We await eagerly with an open mind, however, results from the ongoing outcome trials with two additional CETP inhibitors. We also recognize that steady-state concentrations of HDL-C in plasma likely do not reflect the flux of HDL particles, their potential for mediating reverse cholesterol transport, and other putative functions of HDL subclasses. For example, a large body of in vitro and experimental animal studies indicates that HDL particles may have many beneficial actions beyond reverse cholesterol transport. These putative properties of HDL particles include anti-oxidant and anti-inflammatory effects, attributes not assessed by the simple laboratory measurement of HDL-C. These functional facets of HDL may provide novel targets for therapeutic manipulation in a more subtle fashion in the future. Yet, concordant with the data from clinical intervention trials showing lack of benefit (or even harm) with current approaches to pharmacological boosting of HDL-C, recent genetic studies have also cast doubt on HDL-C as a causal risk factor.1 While HDL-C has stood in the spotlight, centre stage, triglycerides have tarried in the wings as a causal cardiovascular risk factor. Adjustment for …

High DHA dosage from algae oil improves postprandial hypertriglyceridemia and is safe for type-2 diabetics

Postprandial refers to diet induced changes in plasma concentrations of sugars, amino acids and fats be- tween 0 and 6 h following a meal. This review details the fat transport through lipoprotein particles and triglyceride frac- tions in the postprandial plasma. The long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is more active in postprandial plasma and is more abundantly incorporated into the surface phospholipid fraction of lipoproteins. A survey of controlled clinical trials in the literature demon- strates that 1,000 mg to 2,000 mg DHA daily is effective to treat hypertriglyceridemia (HTG), mixed dyslipidemia and most effectively controls elevated postprandial triglycerides (TG). TG is a marker for total fat in circulation. Omega-3 fatty acids lower fasting and postprandial TG, an activity first discovered in 1971 in Greenlandic Inuits. Low TG and high DHA were coincident with the absence of type 2 diabetes. It is now known that DHA is the major structural and functional omega-3 component of lipoproteins in hu- man plasma. DHA is the omega-3 to most substantially increase by mass in the phospholipid fraction of very low- density lipoproteins (VLDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). DHA is most effective at raising HDL levels and improves the omega-3 index in red blood cells (RBC). DHA intake also correlates with greater than 25 % reductions of fasting TG and greater than 40 % reductions in postprandial TG. Postprandial HTG is common in the type 2 diabetes; therefore, we considered the safety of DHA from Schizochytrium sp. algae oil and the evidence for risk reduction of coronary vascular disease (CVD) and type 2 diabetes. Recent clinical trials suggest high DHA intake from Chromista algae controls plasma TG, but does not appear to control glucocentric markers or cholesterol levels. DHA directly affects postprandial TG transport, but has little effect on insulin function and insulin resistance. Applications for use in South Asian diabetics are considered. 1,200 mg algae DHA daily over 3 months is an optimized program for direct control of postprandial HTG and is safe for type 2 diabetics.

The Best Way to Improve HDL is to Lower LDL Levels.

ObjectiveAnalyses of HDL function.IntroductionPopulation studies have shown that plasma levels of HDL (high density lipoprotein) inversely correlate with the prevalence of coronary heart disease. Plasma HDL cholesterol levels in an individual however, does not necessarily correlate with the risk for coronary heart disease. Many patients with high HDL, present with coronary events and many individuals with low HDL cholesterol do not develop coronary complications. Our group previously demonstrated that HDL composition and function could be more important than HDL cholesterol levels. Under excessive inflammatory pressure unsaturated fatty acids in HDL can undergo oxidative modification. Protective enzymes including paraoxonase, LCAT and PLTP can be inactivated by oxidative modification reducing HDL's anti inflammatory properties. This results in HDL not being able to protect LDL from oxidative modification.MethodsFasting plasma from patients with documented coronary disease were analyzed for their ability to prevent LDL modification.ResultsWe demonstrated that among coronary patients over 69 per cent had non protective HDL while among healthy controls 4.5 per cent had dysfunctional HDL.ConclusionWhile there are effective medications for lowering LDL cholesterol (namely statins) there are few or no satisfactory drugs for raising HDL levels.

High Density Lipoprotein: A Therapeutic Target in Type 2 Diabetes

High density lipoproteins (HDLs) have a number of properties that have the potential to inhibit the development of atherosclerosis and thus reduce the risk of having a cardiovascular event. These protective effects of HDLs may be reduced in patients with type 2 diabetes, a condition in which the concentration of HDL cholesterol is frequently low. In addition to their potential cardioprotective properties, HDLs also increase the uptake of glucose by skeletal muscle and stimulate the synthesis and secretion of insulin from pancreatic β cells and may thus have a beneficial effect on glycemic control. This raises the possibility that a low HDL concentration in type 2 diabetes may contribute to a worsening of diabetic control. Thus, there is a double case for targeting HDLs in patients with type 2 diabetes: to reduce cardiovascular risk and also to improve glycemic control. Approaches to raising HDL levels include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. There is an ongoing search for HDL-raising drugs as agents to use in patients with type 2 diabetes in whom the HDL level remains low despite lifestyle interventions.

Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice: a clue to the disputed effect of statins on HDL

Besides a significant reduction of low-density lipoprotein (LDL) cholesterol, statins moderately increase high-density lipoprotein (HDL) levels. In vitro studies have indicated that this effect may be the result of an increased expression of apolipoprotein (apo)A-I, the main protein component of HDL. The aim of the present study was to investigate in vivo the effect of rosuvastatin on apoA-I expression and secretion in a transgenic mouse model for human apoA-I. Human apoA-I transgenic mice were treated for 28 days with 5, 10 or 20 mg·kg(-1) ·day(-1) of rosuvastatin, the most effective statin in raising HDL levels. Possible changes of apoA-I expression by treatment were investigated by quantitative real-time RT-PCR on RNA extracted from mouse livers. The human apoA-I secretion rate was determined in primary hepatocytes isolated from transgenic mice from each group after treatment. Rosuvastatin treatment with 5 and 10 mg·kg(-1) ·day(-1) did not affect apoA-I plasma levels, whereas a significant decrease was observed in mice treated with 20 mg·kg(-1) ·day(-1) of rosuvastatin (-16%, P < 0.01). Neither relative hepatic mRNA concentrations of apoA-I nor apoA-I secretion rates from primary hepatocytes were influenced by rosuvastatin treatment at each tested dose. In human apoA-I transgenic mice, rosuvastatin treatment does not increase either apoA-I transcription and hepatic secretion, or apoA-I plasma levels. These results support the hypothesis that other mechanisms may account for the observed HDL increase induced by statin therapy in humans.

Effects of High-Density Lipoproteins on Pancreatic β-Cell Insulin Secretion

Type 2 diabetes is characterized by impaired beta-cell secretory function, insulin resistance, reduced high-density lipoprotein (HDL) levels, and increased cardiovascular risk. Given the current interest in therapeutic interventions that raise HDLs levels, this study investigates the effects of HDLs on insulin secretion from beta-cells. Incubation of Min6 cells and primary islets under basal or high-glucose conditions with either apolipoprotein (apo) A-I or apoA-II in the lipid-free form, as a constituent of discoidal reconstituted HDLs (rHDLs), or with HDLs isolated from human plasma increased insulin secretion up to 5-fold in a calcium-dependent manner. The increase was time and concentration dependent. It was also K(ATP) channel and glucose metabolism dependent under high-glucose, but not low-glucose, conditions. The lipid-free apolipoprotein-mediated increase in insulin secretion was ATP binding cassette (ABC) transporter A1 and scavenger receptor-B1 dependent. The rHDL-mediated increase in insulin secretion was ABCG1 dependent. Exposure of beta-cells to lipid-free apolipoproteins also increased insulin mRNA expression and insulin secretion without significantly depleting intracellular insulin or cholesterol levels. These results establish that lipid-free and lipid-associated apoA-I and apoA-II increase beta-cell insulin secretion and indicate that interventions that raise HDLs levels may be beneficial in type 2 diabetes.

The promise of apolipoprotein A-I mimetics

Synthetic high-density lipoprotein (HDL) and apolipoprotein (apo) A-I mimetic peptides emulate many of the atheroprotective biological functions attributed to HDL and can modify atherosclerotic disease processes. Administration of these agents as HDL replacement or modifying therapy has tremendous potential of providing new treatments for cardiovascular disease. Progress in the understanding of these agents is discussed in this review. Prospective, observational, and interventional studies have convincingly demonstrated that elevated serum levels of high-density lipoprotein-cholesterol (HDL-C) are associated with reduced risk for coronary heart disease (CHD). Although traditional pharmacological agents have shown modest utility in raising HDL levels and reducing CHD risk, use of HDL and apo A-I mimetics provides novel therapies to not only increase HDL levels, but to also influence HDL functionality. Evidence developed over the last several years has identified a number of pathways affected by synthetic HDL and apoA-I mimetic peptides, including enhancing reverse cholesterol transport and reducing oxidation and inflammation that directly influence the progression and regression of atherosclerotic disease. Clinical trials of relatively short-term synthetic HDL infusion into patients with CHD demonstrate beneficial effects. Use of apo A-I mimetic peptides could potentially overcome some of the limitations associated with use of the intact apo. Studies to establish the most efficacious peptides, optimal dosing regimens, and routes of administration are needed. Use of apo A-I mimetic peptides shows great promise as a therapeutic modality for HDL replacement and enhancing HDL function in treatment of patients with CHD.

Niacin for stroke prevention: evidence and rationale.

Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased atherothrombotic events, including stroke. Niacin is a safe and effective means of raising HDL, yet its role in stroke prevention is not well characterized. The purpose of the study is to determine the role of niacin in stroke prevention. A search of the PUBMED database using the keywords niacin, stroke, atherosclerosis, and/or carotid artery was undertaken to identify studies for review. National guidelines from the American Heart Association and National Cholesterol Education Program were reviewed. Treatment of low serum HDL (<40 mg/dL) is an identified goal of dyslipidemic therapy. Niacin is effective in raising HDL levels and reducing cardiovascular events in individuals with high vascular risk and can be used for treatment of stroke patients with low serum HDL. Niacin can be used safely in combination with statins, the first-line dyslipidemic treatment for secondary stroke risk reduction, with increased efficacy. Studies are needed to better define the role for niacin in secondary stroke prevention. Treatment of stroke patients with extended-release (ER) of niacin, alone or in combination with statins, should be considered in stroke patients with atherosclerotic mechanisms with low serum HDL-C levels.

Effect of Obesity on High‐density Lipoprotein Metabolism

Reduced levels of high-density lipoproteins (HDL) in non-obese and obese states are associated with increased risk for the development of coronary artery disease. Therefore, it is imperative to determine the mechanisms responsible for reduced HDL in obese states and, conversely, to examine therapies aimed at increasing HDL levels in these individuals. This paper examines the multiple causes for reduced HDL in obese states and the effect of exercise and diet--two non-pharmacologic therapies--on HDL metabolism in humans. In general, the concentration of HDL-cholesterol is adversely altered in obesity, with HDL-cholesterol levels associated with both the degree and distribution of obesity. More specifically, intra-abdominal visceral fat deposition is an important negative correlate of HDL-cholesterol. The specific subfractions of HDL that are altered in obese states include the HDL2, apolipoprotein A-I, and pre-beta1 subfractions. Decreased HDL levels in obesity have been attributed to both an enhancement in the uptake of HDL2 by adipocytes and an increase in the catabolism of apolipoprotein A-I on HDL particles. In addition, there is a decrease in the conversion of the pre-beta1 subfraction, the initial acceptor of cholesterol from peripheral cells, to pre-beta2 particles. Conversely, as a means of reversing the decrease in HDL levels in obesity, sustained weight loss is an effective method. More specifically, weight loss achieved through exercise is more effective at raising HDL levels than dieting. Exercise mediates positive effects on HDL levels at least partly through changes in enzymes of HDL metabolism. Increased lipid transfer to HDL by lipoprotein lipase and reduced HDL clearance by hepatic triglyceride lipase as a result of endurance training are two important mechanisms for increases in HDL observed from exercise.

ApoA-I

See related article, pages 564–571 A link between homocysteine and atherothrombotic vascular disease was first suggested by McCully more than 30 years ago.1 The vascular lesions observed by McCully in children with inborn errors of homocysteine metabolism were fibrotic rather than lipid rich, suggesting the possibility that hyperhomocysteinemia may produce vascular pathology through a mechanism independent of altered lipid metabolism. Since that time, many epidemiological studies have confirmed that elevated plasma levels of total homocysteine (tHcy) are associated with an increased risk of coronary events, stroke, and venous thromboembolism.2–4 Most of the epidemiological data indicate that elevation of plasma tHcy is not associated with a significant change in plasma total cholesterol but is negatively associated with high density lipoprotein (HDL) cholesterol.5–7 An effect of homocysteine on HDL metabolism could be clinically important, because HDL protects from vascular disease not only by facilitating reverse cholesterol transport8 but also through its direct antiinflammatory properties.9 During the past decade, the development of animal models has led to rapid progress in defining the pathophysiological consequences of hyperhomocysteinemia in vivo. Experimental approaches to induce hyperhomocysteinemia in animals include the use of diets that are high in methionine and/or low in folate, as well as genetic approaches, such as the generation of knockout mice with targeted disruption of the cystathionine β-synthase ( Cbs ),10 methylene tetrahydrofolate reductase ( Mthfr ),11 or methionine synthase ( Mtr )12 genes. Like hyperhomocysteinemic humans, hyperhomocysteinemic animals develop endothelial dysfunction, hepatic lipid accumulation, and decreased plasma HDL cholesterol with minimal changes in plasma …