Search

High-density lipoproteins (HDL) are a heterogeneous class of molecules whose main function is to remove excess cholesterol through a mechanism called reverse transport, in which cholesterol is transported from peripheral organs and from arterial foam cells to the liver, where it is subsequently eliminated with bile. While its ability to eliminate excess cholesterol has always been viewed as its main feature, its beneficial effects go beyond this single effect. Many of the proteins that are associated with HDL are responsible for anti-oxidant and anti-inflammatory properties. These proteins that are associated with HDL during its generation and remodelling, are referred to as 'protein cargo', which has been extensively analysed by mass spectrometry analysis in healthy and diseased individuals. In this review, we discuss the pathway that leads to HDL formation and its subsequent remodelling and catabolism with regards to the possible involvement of HDL 'protein cargo' in Alzheimer's disease., (© 2020 International Society for Neurochemistry.)

Background: Moderate alcohol intake in human increases HDL-cholesterol, and has protective effects against cardiovascular disease (CVD). Although de novo lipid synthesis inhibitors are highly effective in lowering total and LDL-cholesterol they have only modest effects on raising HDL-C. A better understanding of the mechanism of ethanol-mediated HDL-C regulation could suggest new therapeutic approaches for CVD., Methods: Human hepatoblastoma (HepG2) and colorectal epithelial adenocarcinoma (Caco-2) cells were incubated in the presence of varying concentrations of ethanol in the culture medium, with or without addition of de novo lipid synthesis (DNLS) inhibitors (atorvastatin and/or TOFA). ApoA1 protein was measured by Western blot, and RNA of lipid pathway genes APOA1, APOC3, APOA4, APOB100, HMGCR, LDLR, and SREBF2 by quantitative RT-PCR. Lipoproteins (VLDL, LDL, and HDL) and lipids were also monitored., Results: Ethanol stimulated ApoA1 protein (both cytoplasmic and secreted) and APOA1 RNA levels in HepG2 cells in a dose sensitive way, with ~ 50% upregulation at 100 mM ethanol in the medium. The effect was not observed in intestinal-derived Caco-2 cells. DNLS inhibitors did not block the upregulation of ApoA1 RNA by ethanol; TOFA alone produced a modest increase in ApoA1 RNA. Ethanol had no effect on ABCA1 protein levels. Addition of ethanol to the cell medium led to modest increases in de novo synthesis of total cholesterol, cholesteryl esters and triglycerides, and as expected these increases were blocked when the lipid synthesis inhibitors were added. Ethanol stimulated a small increase in HDL and VLDL but not LDL synthesis. Ethanol in the cell medium also induced modest but measurable increases in the RNA of APOC3, APOA4, APOB, LDLR, and HMGCR genes. Unlike APOA1, induction of RNA from APOC3 and APOA4 was also observed in Caco-2 cells as well as HepG2 cells., Conclusion: This study has verified the previously reported upregulation of APOA1 by exposure of HepG2, but not Caco-2 cells, to ethanol in the culture medium. It is shown for the first time that the effect is dependent on RNA polymerase II-mediated transcription, but not on de novo biosynthesis of cholesterol or fatty acids, and therefore is not a generalized metabolic response to ethanol exposure. Some other lipid pathway genes are also modulated by ethanol exposure of cells. The results reported here suggest that the proximal signaling molecule leading to increased APOA1 gene expression in response to ethanol exposure may be free acetate or acetyl-CoA., Take Home: Upregulation of ApoA1 gene expression in hepatoma cells in culture, upon exposure to moderate ethanol concentrations in the medium, occurs at the level of RNA and is not dependent on new cholesterol or fatty acid synthesis. The primary signaling molecule may be free acetate or acetyl-CoA. These results are important for understanding the mechanism by which moderate alcohol consumption leads to upregulation of serum HDL-cholesterol in humans, and suggests new approaches to targeting HDL as a risk factor for cardiovascular disease.

Fibroblast growth factor (FGF)19, an endocrine hormone produced in the gut, acts in the liver to control bile acid synthesis. NGM282, an engineered FGF19 analog, is currently in clinical development for treating nonalcoholic steatohepatitis. However, the molecular mechanisms that integrate FGF19 with cholesterol metabolic pathways are incompletely understood. Here, we report that FGF19 and NGM282 promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating LXR signaling while ameliorating hepatic steatosis. We further identify ABCA1 and FGF receptor 4 as mediators of this effect, and that administration of a HMG-CoA reductase inhibitor or a blocking antibody against proprotein convertase subtilisin/kexin type 9 abolished FGF19-associated elevations in total cholesterol, HDL cholesterol (HDL-C), and LDL cholesterol in db/db mice. Moreover, we show that a constitutively active MEK1, but not a constitutively active STAT3, mimics the effect of FGF19 and NGM282 on cholesterol change. In dyslipidemic Apoe -/- mice fed a Western diet, treatment with NGM282 dramatically reduced atherosclerotic lesion area in aortas. Administration of NGM282 to healthy volunteers for 7 days resulted in a 26% increase in HDL-C levels compared with placebo. These findings outline a previously unrecognized role for FGF19 in the homeostatic control of cholesterol and may have direct impact on the clinical development of FGF19 analogs., (Copyright © 2019 Zhou et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.)

Background & Objectives: Hepatic scavenger receptor class B1 (SR-B1), a high-density lipoprotein (HDL) receptor, is involved in the selective uptake of HDL-associated esterified cholesterol (EC), thereby regulates cholesterol homoeostasis and improves reverse cholesterol transport. Previously, we reported in euglycaemic obese rats (WNIN/Ob strain) that feeding of vitamin A-enriched diet normalized hypercholesterolaemia, possibly through hepatic SR-B1-mediated pathway. This study was aimed to test whether it would be possible to normalize hypercholesterolaemia in glucose-intolerant obese rat model (WNIN/GR/Ob) through similar mechanism by feeding identical vitamin A-enriched diet., Methods: In this study, 30 wk old male lean and obese rats of WNIN/GR-Ob strain were divided into two groups and received either stock diet or vitamin A-enriched diet (2.6 mg or 129 mg vitamin A/kg diet) for 14 wk. Blood and other tissues were collected for various biochemical analyses., Results: Chronic vitamin A-enriched diet feeding decreased hypercholesterolaemia and normalized abnormally elevated plasma HDL-cholesterol (HDL-C) levels in obese rats as compared to stock diet-fed obese groups. Further, decreased free cholesterol (FC) and increased esterified cholesterol (EC) contents of plasma cholesterol were observed, which were reflected in higher EC to FC ratio of vitamin A-enriched diet-fed obese rats. However, neither lecithin-cholesterol acyltransferase (LCAT) activity of plasma nor its expression (both gene and protein) in the liver were altered. On the contrary, hepatic cholesterol levels significantly increased in vitamin A-enriched diet fed obese rats. Hepatic SR-B1 expression (both mRNA and protein) remained unaltered among groups. Vitamin A-enriched diet fed obese rats showed a significant increase in hepatic low-density lipoprotein receptor mRNA levels, while the expression of genes involved in HDL synthesis, namely, ATP-binding cassette protein 1 (ABCA1) and apolipoprotein A-I, were downregulated. No such response was seen in vitamin A-supplemented lean rats as compared with their stock diet-fed lean counterparts., Interpretation & Conclusions: Chronic vitamin A-enriched diet feeding decreased hypercholesterolaemia and normalized HDL-C levels, possibly by regulating pathways involved in HDL synthesis and degradation, independent of hepatic SR-B1 in this glucose-intolerant obese rat model., Competing Interests: None.

Background: n-3 polyunsaturated fatty acids (PUFA) have previously been demonstrated in association with a reduced risk of chronic diseases, including insulin resistance, cancer and cardiovascular disease. In the present study, we analyzed the effects of n-3 PUFA-rich perilla oil (PO) and fish oil (FO) high fat diet intervention against the synthesis of hepatic high-density lipoprotein cholesterol (HDL-c) in obesity-insulin resistance model rats., Methods: In the modeling period, the male SD rats were randomly divided into 2 groups. The rats in the high fat (HF) group were given a high fat pure diet containing 20.62% lard. In the intervention period, the model rats were intervened with purified high-fat diets rich in PO or FO, containing same energy content with high fat pure diet in HF. After the intervention, the protein and mRNA expressions status of the key genes involved in synthesis of hepatic HDL-c were measured for further analytic comparison., Results: The obesity-insulin resistance model rats were characterized by surprisingly high levels of serum triglyceride (TG) and increased body weight (P < 0.05, each). After the intervention, there were no apparent changes in the serum HDL-c and total cholesterol (TCH). In addition, the FO could up-regulate the hepatic adenosine triphosphate (ATP) binding cassette transporter A1 (ABCA1) mRNA (P < 0.01) and protein expressions, as well as increase the level of serum apolipoprotein A-1 (apoA-1) (P < 0.0001), and elevate the hepatic apoA-1mRNA expression (P < 0.01). Different from FO, the PO specifically elevated the hepatic ABCA1mRNA expression (P < 0.01)., Conclusions: The FO high fat diets promoted the synthesis of HDL-c in the obesity-insulin resistance rats.

Mammalian cells synthesize various sterol molecules, including the C30 sterol, lanosterol, as cholesterol precursors in the endoplasmic reticulum. The build-up of precursor sterols, including lanosterol, displays cellular toxicity. Precursor sterols are found in plasma HDL. How these structurally different sterols are released from cells is poorly understood. Here, we show that newly synthesized precursor sterols arriving at the plasma membrane (PM) are removed by extracellular apoA-I in a manner dependent on ABCA1, a key macromolecule for HDL biogenesis. Analysis of sterol molecules by GC-MS and tracing the fate of radiolabeled acetate-derived sterols in normal and mutant Niemann-Pick type C cells reveal that ABCA1 prefers newly synthesized sterols, especially lanosterol, as the substrates before they are internalized from the PM. We also show that ABCA1 resides in a cholesterol-rich membrane domain resistant to the mild detergent, Brij 98. Blocking ACAT activity increases the cholesterol contents of this domain. Newly synthesized C29/C30 sterols are transiently enriched within this domain, but rapidly disappear from this domain with a half-life of less than 1 h. Our work shows that substantial amounts of precursor sterols are transported to a certain PM domain and are removed by the ABCA1-dependent pathway., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

Objective: The hypothesis that cholesterol that enters the cell within low-density lipoprotein (LDL) particles rapidly equilibrates with the regulatory pool of intracellular cholesterol and maintains cholesterol homeostasis by reducing cholesterol and LDL receptor synthesis was validated in the fibroblast but not in the hepatocyte. Accordingly, the present studies were designed to compare the effects of cholesterol that enters the hepatocyte within an LDL particle with those of cholesterol that enters via other lipoprotein particles., Approach and Results: We measured cholesterol synthesis and esterification in hamster hepatocytes treated with LDL and other lipoprotein particles, including chylomicron remnants and VLDL. Endogenous cholesterol synthesis was not significantly reduced by uptake of LDL, but cholesterol esterification (280%) and acyl CoA:cholesterol acyltransferase 2 expression (870%) were increased. In contrast, cholesterol synthesis was significantly reduced (70% decrease) with other lipoprotein particles. Furthermore, more cholesterol that entered the hepatocyte within LDL particles was secreted within VLDL particles (480%) compared with cholesterol from other sources., Conclusions: Much of the cholesterol that enters the hepatocyte within LDL particles is shunted through the cell and resecreted within VLDL particles without reaching equilibrium with the regulatory pool.

There has been strong evolutionary pressure to ensure that an animal cell maintains levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL)-cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

High-density lipoproteins play a central role in systemic cholesterol homeostasis by stimulating the efflux of excess cellular cholesterol and transporting it to the liver for biliary excretion. HDL has long been touted as the "good cholesterol" because of the strong inverse correlation of plasma HDL cholesterol levels with coronary heart disease. However, the disappointing outcomes of recent clinical trials involving therapeutic elevations of HDL cholesterol have called this moniker into question and revealed our lack of understanding of this complex lipoprotein. At the same time, the discovery of microRNAs (miRNAs) that regulate HDL biogenesis and function have led to a surge in our understanding of the posttranscriptional mechanisms regulating plasma levels of HDL. Furthermore, HDL has recently been shown to selectively transport miRNAs and thereby facilitate cellular communication by shuttling these potent gene regulators to distal tissues. Finally, that miRNA cargo carried by HDL may be altered during disease states further broadened our perspective of how this lipoprotein can have complex effects on target cells and tissues. The unraveling of how these tiny RNAs govern HDL metabolism and contribute to its actions promises to reveal new therapeutic strategies to optimize cardiovascular health.

Plasma HDL levels are inversely associated with atherosclerosis. Inbred mouse strains differ in plasma HDL levels and susceptibility to atherosclerosis. Atherosclerosis-susceptible C57BL/6J mice possess plasma HDL levels 2-fold lower than atherosclerosis-resistant FVB/NJ mice. Polymorphisms have been previously identified between the two mouse strains in the major HDL apolipoproteins, ApoA-I and ApoA-II, which may affect their function on HDL. To begin to understand the HDL differences, we here report on a detailed comparison of the lipid-associated functions of the two mouse ApoA-I proteins. We demonstrate that these polymorphisms significantly alter the protein self-association properties, the ability of the proteins to clear lipid micelles from solution, and their binding affinity for mature mouse HDL. The changes in lipid binding do not appear to alter the ability of the protein to promote cholesterol efflux from cells or the formation of nascent HDL from primary hepatocytes. These apolipoprotein polymorphisms do not change the rate at which HDL protein or cholesterol are catabolized in vivo. Although the presence of the polymorphisms in ApoA-I alters important factors in HDL formation, the basis for the differences in the HDL plasma levels observed in the various mouse strains is more complex and requires additional investigation.

The lipidation of apoA-I in liver greatly influences HDL biogenesis and plasma HDL levels by stabilizing the secreted apoA-I. Niacin is the most effective lipid-regulating agent clinically available to raise HDL. This study was undertaken to identify regulatory mechanisms of niacin action in hepatic lipidation of apoA-I, a critical event involved in HDL biogenesis. In cultured human hepatocytes (HepG2), niacin increased: association of apoA-I with phospholipids and cholesterol by 46% and 23% respectively, formation of lipid-poor single apoA-I molecule-containing particles up to ~2.4-fold, and pre β 1 and α migrating HDL particles. Niacin dose-dependently stimulated the cell efflux of phospholipid and cholesterol and increased transcription of ABCA1 gene and ABCA1 protein. Mutated DR4, a binding site for nuclear factor liver X receptor alpha (LXR α ) in the ABCA1 promoter, abolished niacin stimulatory effect. Further, knocking down LXR α or ABCA1 by RNA interference eliminated niacin-stimulated apoA-I lipidation. Niacin treatment did not change apoA-I gene expression. The present data indicate that niacin increases apoA-I lipidation by enhancing lipid efflux through a DR4-dependent transcription of ABCA1 gene in HepG2 cells. A stimulatory role of niacin in early hepatic formation of HDL particles suggests a new mechanism that contributes to niacin action to increase the stability of newly synthesized circulating HDL.

Objective: Cardiovascular disease (CVD) is the leading cause of death in patients with rheumatoid arthritis (RA). Disease-modifying therapies that improve risk factors for CVD, such as dyslipidemia, are desired. This study used an electronic health record to determine if hydroxychloroquine (HCQ) use was associated with an improvement in lipid levels in an inception RA cohort., Methods: All adult individuals with the initial diagnosis of RA between January 1, 2001, and March 31, 2008, were identified (n=1,539). Only patients with at least one lipid level post-RA diagnosis were included (n=706). Information on demographics, medical history, body mass index (BMI), laboratory measures, and medications were collected at office visits. Potential risk and protective factors for dyslipidemia were controlled for in linear mixed-effects regression models for low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, triglycerides, LDL/HDL, and total cholesterol/HDL., Results: Patients were 69% women and 98% white, with a median age of 65 years and a median BMI of 29.8 kg/m2. In the adjusted regression models, HCQ use was associated with the following average differences in lipids: LDL decrease of 7.55 mg/dl (P<0.001), HDL increase of 1.02 mg/dl (P=0.20), total cholesterol decrease of 7.70 mg/dl (P=0.002), triglycerides decrease of 10.91 mg/dl (P=0.06), LDL/HDL decrease of 0.136 (P=0.008), and total cholesterol/HDL decrease of 0.191 (P=0.006), which were stable over time., Conclusion: Use of HCQ in this RA cohort was independently associated with a significant decrease in LDL, total cholesterol, LDL/HDL, and total cholesterol/HDL. Considering these results, its safety profile, and low cost, HCQ remains a valuable initial or adjunct therapy in this patient population at high risk for CVD., (Copyright © 2011 by the American College of Rheumatology.)

Background: The antiatherogenic functions of high density lipoprotein (HDL-C) include its role in reverse cholesterol transport, but to what extent the concentration of HDL-C interferes with the whole-body cholesterol metabolism is unknown. Therefore, we measured markers of body cholesterol synthesis (desmosterol and lathosterol) and of intestinal cholesterol absorption (campesterol and β-sitosterol) in healthy subjects that differ according to their plasma HDL-C concentrations., Methods: Healthy participants presented either low HDL-C (< 40 mg/dl, n=33, 17 male and 16 female) or high HDL-C (> 60 mg/dl, n=33, 17 male and 16 female), BMI< 30 kg/m², were paired according to age and gender, without secondary factors that might interfere with their plasma lipid concentrations. Plasma concentrations of non-cholesterol sterols were measured by the combined GC-MS analysis., Results: Plasma desmosterol did not differ between the two groups; however, as compared with the high HDL-C participants, the low HDL-C participants presented higher concentration of lathosterol and lower concentration of the intestinal cholesterol absorption markers campesterol and β-sitosterol., Conclusion: Plasma concentrations of HDL, and not the activities of LCAT and CETP that regulate the reverse cholesterol transport system, correlate with plasma sterol markers of intestinal cholesterol absorption directly, and of cholesterol synthesis reciprocally., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: The effect of ABCA1 genetic variation on HDL-C levels has been widely documented, although studies in children are scarce. We recently found a frequent non-synonymous ABCA1 variant (R230C) exclusive to populations with Native American ancestry, associated with low HDL-C levels and other metabolic traits in adults., Methods: We genotyped R230C variant in 1253 healthy unrelated Mexican school-aged children aged 6-15 years (595 boys and 658 girls) to seek associations with HDL-C levels and other metabolic traits. HDL subclass distribution was analyzed in a subgroup of 81 age, gender and BMI-matched children., Results: Individuals carrying the C230 allele showed a significantly lower HDL-C levels (P=2.9x10(-8)), and higher TC/HDL-C ratio, BMI, BMI z-score and percent fat mass (P=0.001, 0.049, 0.032 and 0.039, respectively). HDL size was smaller in R230C heterozygotes as compared to R230R homozygotes (P<0.05). Moreover, the proportion of HDL(2b) was lower, while the proportion of HDL(3a) and HDL(3b) particles was higher in R230C heterozygous and/or C230C homozygous individuals as compared to R230R homozygotes (P<0.05)., Conclusions: Our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children., (Copyright 2010 Elsevier B.V. All rights reserved.)

Plasma levels of HDL cholesterol (HDL-C) have a strong inherited basis with heritability estimates of 40-60%. The well-established inverse relationship between plasma HDL-C levels and the risk of coronary artery disease (CAD) has led to an extensive search for genetic factors influencing HDL-C concentrations. Over the past 30 years, candidate gene, genome-wide linkage, and most recently genome-wide association (GWA) studies have identified several genetic variations for plasma HDL-C levels. However, the functional role of several of these variants remains unknown, and they do not always correlate with CAD. In this review, we will first summarize what is known about HDL metabolism, monogenic disorders associated with both low and high HDL-C levels, and candidate gene studies. Then we will focus this review on recent genetic findings from the GWA studies and future strategies to elucidate the remaining substantial proportion of HDL-C heritability. Comprehensive investigation of the genetic factors conferring to low and high HDL-C levels using integrative approaches is important to unravel novel pathways and their relations to CAD, so that more effective means of diagnosis, treatment, and prevention will be identified.

This study investigated the role of glucose in the biogenesis of high-density lipoprotein cholesterol (HDL-C). Mouse primary peritoneal macrophages were harvested and maintained in Dulbecco's modified Eagle's medium (DMEM) containing glucose of various concentrations. The cells were divided into 3 groups in terms of different glucose concentrations in the cultures: Control group (5.6 mmol/L glucose), high glucose concentration groups (16.7 mmol/L and 30 mmol/L glucose). ATP-binding cassette transporter A1 (ABCA1) mRNA expression in the macrophages was detected by semi-quantitative RT-PCR 24, 48 and 72 h after glucose treatment. The results showed that ABCA1 mRNA expression in the 16.7 mmol/L glucose group was not significantly different from that in the control group at all testing time points (P>0.05 for each). In the 30 mmol/L glucose group, macrophage ABCA1 mRNA expression was not changed significantly at 24 h (P=0.14), but was substantially decreased by 40.4% at 48 h (P=0.009) and by 48.1% at 72 h (P=0.015) as compared with that in the control group. It was concluded that ABCA1 is of vital importance for HDL-C biogenesis. High glucose may hamper HDL-C biogenesis by decreasing ABCA1 expression, which contributes to low HDL-C level in diabetes.

Objective: The authors hypothesized that high-pleasure low-arousal (HPLA) would predict a subsequent decrease of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TRI), as well as a subsequent increase of high-density lipoprotein cholesterol (HDL-C). The authors also hypothesized that high-pleasure high-arousal (HPHA) would have the opposite effects on these blood lipids, predicting a subsequent increase of LDL-C and TRI, and a decrease of HDL-C., Design: Participants were 990 male and 595 female apparently healthy employees who underwent a routine periodic health examination at two points in time, Time 1 (T1) and Time 2 (T2), about 24 months apart. Data were analyzed separately for the men and women, and the authors controlled for possible confounders shown in past research to be implicated with hyperlipidemia., Main Outcome Measures: HPHA and HPLA were assessed based on the Job-Related Affective Well-Being Scale, while LDL-C, TRI, and HDL-C were assessed based on fasting blood samples., Results: For the men, support for our hypotheses was found relative to HDL-C and TRI. The authors did not find support for our hypotheses for thee women., Conclusion: Our findings suggest that for men, the two types of positive affects may have opposite physiological consequences with respect to subsequent changes in blood lipid levels., (PsycINFO Database Record (c) 2009 APA, all rights reserved.)

Human endothelial lipase (EL) is a member of a family of lipases and phospholipases that are involved in the metabolism of plasma lipoproteins. EL displays a preference to hydrolyze lipids in HDL. We report here that a naturally occurring low frequency coding variant in the EL gene (LIPG), glycine-26 to serine (G26S), is significantly more common in African-American individuals with elevated HDL cholesterol (HDL-C) levels. To test the hypothesis that this variant results in reduced EL function, we extensively characterized and compared the catalytic and noncatalytic functions of the G26S variant and wild-type (WT) EL. While the catalytic-specific activity of G26S EL is similar to WT EL, its secretion is markedly reduced. Consistent with this observation, we found that carriers of the G26S variant had significantly reduced plasma levels of EL protein. Thus, this N-terminal variant results in reduced secretion of EL protein, plausibly leading to increased HDL-C levels.

Aims: Severe high-density lipoprotein cholesterol (HDL-C) deficiency is attributed to mutations in several genes and may contribute to the genetic basis of coronary artery disease. To identify the cellular basis of a novel HDL-deficiency phenotype, we screened 54 subjects of French Canadian ancestry with severe HDL deficiency., Methods and Results: We excluded individuals with mutations in genes currently associated with low HDL (ABCA1, LCAT, APOA-I, and SMPD1). We identified two patients in which cellular phospholipid efflux in the HDL biosynthesis process is impaired, whereas cholesterol efflux is normal. Two-dimensional gel electrophoresis analysis further showed that the two patients with impaired phospholipid efflux were defective primarily in the larger alpha-HDL subpopulations. In fibroblasts from affected subjects, oxysterol stimulation resulted in increased ABCA1 protein expression and normalized their defective phospholipid efflux defect., Conclusion: Our results indicate for the first time in humans that phospholipid and cholesterol efflux are two separate and distinct processes in cellular HDL biosynthesis. They further show for the first time that normal cellular phospholipid efflux is necessary for the formation of larger alpha-HDL particles. The defect in phospholipid efflux is due to defective ABCA1 protein regulation and can be corrected by treatment with physiological oxysterols, a current therapeutic target of interest, that may, with further studies, be used to raise HDL levels in patients with severe HDL deficiencies.

The ATP-binding cassette transporter A1 (ABCA1) has an essential role in the formation of nascent high-density lipoprotein particles and also participates in the cholesterol efflux from macrophages in the artery wall. Several substances, such as statins, or even gene variants are able to modulate ABCA1 expression. There is strong evidence that statin treatment downregulates the ABCA1 expression in nonloaded macrophages. Interestingly, in cholesterol-loaded macrophages, which are more relevant to atherogenesis, this effect is lost. We observed an inhibitory effect of atorvastatin in peripheral blood mononuclear cells of hypercholesterolemic individuals. Moreover, in these individuals, the ABCA1 -14C>T polymorphism was associated with high baseline gene-expression levels. Other studies are needed to evaluate how relevant these findings are to the formation of arterial foam cells in vivo.

Background: Rosiglitazone is an agonist of the peroxisome proliferator-activated receptor (PPAR) gamma that may modify HDL metabolism in humans, but this effect has not been completely elucidated. Therefore, we determined the effect of rosiglitazone on apo AI turnover, HDL structure, and PON1 plasma activity., Methods: Kinetic studies of HDL-apo AI radiolabeled with (125)I were performed in 7 chow-fed, male, New Zealand white rabbits after 6 weeks of 0.32 mg/kg/d rosiglitazone-treatment vs. vehicle-treated rabbits (n=11). HDL size distribution was determined by polyacrylamide gradient electrophoresis and paraoxonase-1 (PON1); plasma activity was assessed spectrophotometrically using phenylacetate as substrate., Results: Fractional catabolic rate (FCR) of HDL apo AI was higher in the rosiglitazone-treated group than in the control group (0.031+/-0.004 vs. 0.025+/-0.006 pools/h, respectively, p<0.05). The mean apo AI production rate (PR) was 62% higher in the rosiglitazone group as compared to controls (0.918+/-0.238 vs. 0.564+/-0.160 mg/kg/h, p<0.01). Accordingly, apo AI plasma levels in rosiglitazone-treated animals were about 37% higher than in the control group. Rosiglitazone-induced changes in apo AI turnover appeared concomitantly with a significant increase of phospholipids and a decrease in colesteryl esters content of the HDL. Compositional changes resulted in a relative increase of the HDL3b and HDL3c subfractions and a significant enhancement of the plasma PON1 activity (488.5+/-138.2 vs. 595.2+/-179.4 micromol/min/ml, p<0.05)., Conclusions: Rosiglitazone increased apo AI plasma concentrations, resulting from an enhancement of apo AI synthesis, and induced the synthesis of smaller HDL particles with a concomitant increase of plasma PON1 activity. These modifications may contribute to the anti-atherogenic potential of rosiglitazone.

Apolipoprotein (apo) A-I is a key HDL protein participating in the process of reverse cholesterol transport. A small part of plasma apo A-I exists as free protein which is a substrate for generation of discoid HDL precursors, containing small amounts of phospholipids and free cholesterol. The cycling of apo A-I between precursor and mature forms of HDL is an essential element of HDL remodeling in plasma. The second most abundant protein of human HDL is apo A-II, nevertheless, it is present only in about half of the HDL particles in plasma. The mechanism mediating the formation of HDL containing apo A-I and apo A-II is unknown. The role of apo A-II in reverse cholesterol transport generates controversy. Different observations indicate either proatherogenic or proinflammatory properties of apo A-II. Also the participation of apo A-II in plasma HDL remodeling remains unclear. Apo A-II maybe a factor stabilizing HDL particles. This protein may also take part in regulation of VLDL metabolism. The review presents current knowledge concerning participation of apo A-I and apo A-II in plasma HDL remodeling.

The molecular mechanism by which nascent HDL forms via the interaction of apolipoprotein A-I (apoA-I) and transmembrane ABCA1 is poorly understood. Here, because ABCA1 has been reported to localize to acidic intracellular compartments, including the Golgi and endosome, we studied the interaction of apoA-I with model membranes under acidic conditions. Pure phosphatidylcholine liposomes were persistent against apoA-I at pH levels above 5.0, but were progressively transformed into reconstituted HDLs (rHDLs) by apoA-I at lower pH. Circular dichroism spectral measurements and 8-anilino-1-naphthalenesulfonic acid fluorescence measurements of lipid-free apoA-I ascribed this accelerated rHDL formation to the conformational change of the protein into a rather hydrophobic alpha-helical structure under acidic conditions. The addition of phosphatidylserine (PS) increased acidity at the bilayer surface and enabled the formation of discoidal rHDLs even at the pH of the endosome and slightly lower pH of the Golgi. These results suggest the following new scenario of nascent HDL formation: ABCA1, which colocalizes with apoA-I in acidic intracellular compartments, including the Golgi and endosome, increases acidity at the membrane surface on the luminal side by PS translocase activity and causes apoA-I to form nascent HDL.

Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.

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

Subnormal levels of HDL cholesterol constitute a major cardiovascular risk factor. Inhibitors of cholesteryl ester transfer protein (CETP) are presently the most potent HDL-raising agents. Torcetrapib was the first CETP inhibitor to enter a large-scale, prospective, placebo-controlled interventional trial, which was prematurely terminated in December 2006 because of excess cardiovascular and noncardiovascular mortality in the active treatment group. Therapy with torcetrapib was associated with considerable increases in aldosterone level and blood pressure and changes in serum electrolytes indicative of mineralocorticoid excess. These findings indicate that torcetrapib has off-target toxic effects unrelated to HDL raising that involve the activation of mineralocorticoid receptors by aldosterone and result in the induction of hypertension. In contrast with torcetrapib, other CETP inhibitors such as JTT-705 and MK-825 do not increase blood pressure in humans, an observation which discounts a class effect. The available data do not, however, exclude potential adverse effects of CETP inhibition such as the generation of HDL particles that have deficient biological activities and a deleterious impact on reverse cholesterol transport and steroid metabolism. Normalization of both defective HDL function and diminished HDL levels should, therefore, be the focus of pharmacological HDL raising in future studies.

Background: Although ischemic preconditioning (PC) is known to confer cardioprotection in healthy subjects, it is unclear whether this phenomenon exists in the presence of hyperlipidaemia. The goal of this study was to determine whether the cardioprotective effect of PC is affected by hyperlipidaemia in a guinea pig model., Methods: We investigated the influence of preconditioning in normo- and hyperlipidaemic animals on papillary muscle contractility and myocardial damage as expressed by the percentage of apoptotic cells. Guinea pigs were fed a normal diet or a hyperlipidaemic diet for 5 weeks. Experiments were performed on papillary muscles subjected to experimental ischemia-reperfusion with or without prior PC., Results: The dietary treatment resulted in significant changes in lipid parameters, which had not affected the functionality of the right ventricle papillary muscle, both at basal conditions and in response to ischemia-reperfusion injury. However, it was found that the hyperlipidaemic diet had an effect on ischemia-induced apoptosis. Papillary muscles of hyperlipidaemic animals with higher HDL plasma concentrations were less susceptible to ischemia-reperfusion injury., Conclusions: This study demonstrates that hyperlipidaemia does not alter the benefits of ischemic preconditioning such as a reduction of apoptosis and preservation of myocardial contractility. Additionally, it has been shown that plasma HDL may protect cardiomyocytes against ischemia-induced apoptosis.

Background: High-density lipoprotein (HDL) could enhance inflammation in atherogenesis when inflammatory response is present, and the activity of paraoxonase and antioxidant in HDL in the elderly is significantly decreased. There might be a different role for high-density lipoprotein cholesterol (HDL-C) between different age groups in patients with coronary heart disease (CHD)., Methods: For this study, 225 inpatients with CHD (coronary atherosclerosis stenosis >/= 50% on >/= 1 major coronary arteries by coronary angiography), and 80 without CHD; 120 resting unstable angina patients, and 68 with stable angina were consecutively recruited. Risk factors were analyzed for CHD and resting unstable angina., Results: High-density lipoprotein cholesterol in resting unstable angina was higher than that in stable angina (1.24 +/- 1.05 versus 1.05 +/- 0.29 mmol/L, p = 0.032). After adjustment for age, sex, physical inactivity, hypertension, diabetes, C-reactive protein, triglycerides, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) the adjusted odds ratio (OR) (95% CI) of resting unstable angina was 10.19 (2.18-47.6, p = 0.003) for HDL-C. Risk factors were further investigated in different age groups. Adjusted OR of CHD associated with HDL-C in < 55-year-old group was 0.09 (0.01-0.66, p = 0.018), in >/= 55-year-old group it was 0.55 (0.08-3.82, p > 0.05). Adjusted OR of resting unstable angina associated with high HDL-C was 19.24 (2.86-129.4, p = 0.002) in patients aged >/= 55 years., Conclusions: Elevated HDL-C might be an independent risk factor for resting unstable angina, even though HDL-C could play a much more important role in protection against coronary stenosis in younger or middle-aged persons.

Objective: To examine the effect of the I405V and TaqIB polymorphisms of cholesteryl ester transfer protein (CETP) on the lipid response after simvastatin treatment in 180 hypercholesterolaemic patients., Methods: Hypercholesterolaemic patients (n = 180) attending the lipid clinic at the Onassis Cardiac Surgery Center were genotyped and their response to simvastatin was evaluated., Results: Sequence variations in the CETP gene influenced the effect of lipid-lowering treatment. Specifically, the I allele of the I405V polymorphism was associated with a greater reduction in triglyceride (TG; p = 0.04) and a significant increase in high-density lipoprotein cholesterol (HDL-C) levels (p = 0.05) after treatment compared with the V allele., Conclusions: The authors' findings suggest that CETP I405V polymorphism modifies the effect of simvastatin on TG reduction and HDL-C elevation; the carriers of the I allele responded better to treatment. These findings need to be confirmed in larger studies.

Currently, low density lipoprotein cholesterol (LDL-C) levels are the main, if not the only, lipid target in the effort to reduce cardiovascular disease (CVD) morbidity and mortality. Several primary and secondary CVD prevention trials with statins shaped current guidelines and provided detailed targets across a range of CVD risk categories. These targets can be attained using effective statins or combination therapy. However, the net benefit in CVD risk reduction may be improved if we address other lipid risk factors. High density lipoprotein cholesterol (HDL-C) emerges from epidemiological studies as the most promising target. This review links the increase in HDL-C levels with clinical benefit from "old" (e.g. sustained release niacin) and new treatment options. Synthetically produced recombined apolipoprotein A-I Milano administered intravenously seems to have a marked effect in reducing the atheroma burden. The anti-cholesterol ester transfer protein (CETP) vaccine (CETi-1) produces auto-antibodies against CETP thus increasing the cholesterol ester content in HDL particles. CETP inhibitors (e.g. JTT-705 and torcetrapib) seem to be the most promising regimen to increase HDL-C levels. Torcetrapib (already in phase IIIa studies) can substantially increase HDL-C levels (up to 106%), alone or in combination with atorvastatin. HDL-C strategies, in combination with effective statins, are a new drug target aimed at a further reduction in CVD morbidity and mortality compared with statin monotherapy.

Apolipoprotein (apo) AI and apoB are the major apolipoproteins of high-density lipoprotein (HDL) and low-density lipoprotein (LDL), respectively. ApoB assembles the precursor of LDL, very-low-density lipoprotein (VLDL), in the liver. The assembly starts with the formation of a primordial particle, which is converted to VLDL2. The VLDL2 particle is then transferred to the Golgi apparatus and can either be secreted or converted to triglyceride-rich VLDL1. We have reviewed this assembly process, the process involved in the storage of triglycerides in cytosolic lipid droplets, and the relationship between these two processes. We also briefly discuss the formation ofHDL. ApoB mediates the interaction between LDL and the arterial wall. Two regions in apoB are involved in this binding. This interaction and its role in the development of atherosclerosis are reviewed. ApoB can be used to measure the number of LDL or VLDL particles present in plasma, as there is one molecule of apoB on each particle. By contrast, the amount of cholesterol and other lipids on each particle varies under different conditions. We address the possibility of using apoAl and apoB levels to estimate the risk of development of cardiovascular diseases and to monitor intervention to treat these diseases.

The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.

Clinical and epidemiological studies showed an inverse relationship between the level of high-density lipoprotein (HDL) cholesterol and the development of atherosclerosis. This fact aroused more interest in HDLs and it was found that these lipoproteins have significance in malignant diseases. In this review the biochemical classification of plasma lipoproteins, the structure of HDL, and the structural characterization of HDL-apolipoproteins are presented. The synthesis of HDL cholesterol and factors that regulate their structure and function are also considered. We discuss the antiatherogenic activity of HDL through its reverse cholesterol transport and antioxidant, anti-inflammatory, antithrombotic, and profibrinolytic effects.

Objective: Inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), an enzyme in the cholesterol synthesis pathway, has the unique ability to inhibit cholesterol synthesis while simultaneously enhancing oxysterol synthesis. Our objectives were to determine, in vivo, if a novel OSC inhibitor reduced low-density lipoprotein (LDL) cholesterol and to define the mechanism(s) involved., Methods and Results: Miniature pigs received the OSC inhibitor RO0717625 or placebo and a diet containing fat (34% of energy) and 400 mg per day of cholesterol. Treatment decreased plasma total cholesterol (-20%) and LDL cholesterol (-29%). Apolipoprotein B (apoB) kinetic parameters were determined. Very low-density lipoprotein (VLDL) apoB pool size decreased 22% because of inhibition of VLDL production (-43%). LDL apoB pool size decreased 22% because of a 1.5-fold increase in fractional catabolic rate (FCR). The increased FCR was associated with a 2-fold increase in hepatic LDL receptor mRNA. Hepatic total and microsomal cholesterol were reduced by 16% and 27%, respectively. Plasma lathosterol concentrations decreased 57%, reflecting inhibition of hepatic cholesterol synthesis. Treatment reduced plasma plant sterols and decreased postprandial cholesterol transport in chylomicrons., Conclusions: A novel OSC inhibitor, RO0717625, decreased VLDL and LDL apoB100 through decreased VLDL production and enhanced LDL clearance. Thus, OSC represents a potential therapeutic target for dyslipidemia.

Purpose of Review: Even with the aggressive reduction of LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. The Armed Forces Regression Study was a randomized, double-blind, placebo-controlled trial of combination drug therapy aimed at raising HDL-cholesterol in patients with angiographically evident coronary artery disease. Drug therapy ultimately resulted in regression of the angiographic lesions and a reduction in cardiovascular events. This review places the Armed Forces Regression Study within the context of other recent studies., Recent Findings: In the past few years a number of other important papers have further defined the important role HDL-cholesterol plays in the pathobiology of atherosclerosis. These studies have focused on three general areas: HDL-cholesterol metabolism and the reverse cholesterol transport pathway; novel therapeutic interventions and their effects on coronary artery disease as assessed through non-invasive imaging modalities; and finally a re-analysis of previous outcomes trials with established HDL-cholesterol modifying agents., Summary: The results of the Armed Forces Regression Study fit nicely within the evolving paradigm of targeting HDL-cholesterol in patients at risk of cardiovascular events. The use of niacin and well-tolerated fibrates as an adjunct to statins or as primary therapy in patients intolerant of statins appears reasonable in patients with low levels of HDL-cholesterol and at high risk of cardiovascular events. The further development of novel therapeutic approaches, in addition to broadening our pharmacological armamentarium, should further advance our understanding of HDL-cholesterol.

Purpose of Review: Mammalian somatic cells do not catabolize cholesterol and therefore need to export it for sterol homeostasis at the levels of cells and whole bodies. This mechanism may reduce intracellularly accumulated cholesterol in excess, and thereby would contribute to the prevention or cure of the initial stage of atherosclerotic vascular lesions., Recent Findings: HDL is thought to play a main role in this reaction on the basis of epidemiological evidence and in-vitro experimental data. Two independent mechanisms have been identified for this reaction. One is non-specific diffusion-mediated cholesterol 'efflux' from the cell surface, and cholesterol is trapped by various extracellular acceptors including lipoproteins. Extracellular cholesterol esterification on HDL provides a driving force for the net removal of cell cholesterol, and some cellular factors may enhance this reaction. The other mechanism is an apolipoprotein-mediated process to generate HDL by removing cellular phospholipid and cholesterol. This reaction is mediated by a membrane protein ABCA1, and lipid-free or lipid-poor helical apolipoproteins recruit cellular phospholipid and cholesterol to assemble HDL particles. The reaction is composed of two elements: the assembly of HDL particles with phospholipid by apolipoprotein, and cholesterol enrichment in HDL. ABCA1 is essential for the former step, and the latter step requires further intracellular events., Summary: ABCA1 is a rate-limiting factor of HDL assembly and is regulated by transcriptional factors and posttranscriptional factors. Posttranscriptional regulation of ABCA1 involves the modulation of its calpain-mediated degradation.

Forty-nine ABC protein genes exist on human chromosomes. Eukaryotic ABC proteins were originally recognized as drug efflux pumps involved in the multidrug resistance of cancer cells. However, it is now realized that one of their major physiological roles is cellular lipid transport and homeostasis, and their dysfunction is often associated with human diseases. ABCA1 and ABCA7 mediate the apolipoprotein-dependent formation of a high-density lipoprotein-cholesterol complex. ABCA3 is indispensable for pulmonary surfactant secretion. ABCG5 and ABCG8 are involved in the secretion of plant sterols and cholesterol into bile. However, the primary substrates and mechanism of action of these ABC proteins have not been precisely defined. In this review article, we first describe the general structure and functions of eukaryotic ABC proteins. The current model of ABCA1 functionality is then explained based on studies on a topological model, subcellular localization, apoA-I dependence of HDL formation, functional defects of Tangier disease mutants, and ATP hydrolysis of purified ABCA1. ABCA1 is supposed to function as a transporter of lipids as well as a receptor for apoA-I. ABCA3 is likely involved in accumulating phospholipids and cholesterol in lamellar bodies and in generating multivesicular structures.

Purpose of Review: ATP-binding cassette transporter AI (ABCA1)-mediated assembly of phospholipid and free cholesterol with apoA-I plays an important role in HDL biogenesis. This review focuses on recent progress in ABCA1-mediated HDL formation and regulation of ABCA1 expression., Recent Findings: Studies of hepatic ABCA1 overexpression suggest that the liver is a major site for HDL formation. Lipidation of apoA-I by ABCA1 increases its potential for reverse cholesterol transport based on the following findings: (1) apoA-I/lipid complexes formed by ABCA1 are better acceptors of cellular lipid via non-ABCA1-mediated efflux pathways than lipid-free apoA-I in vitro and (2) lipidation of apoA-I prevents it from rapidly associating with plasma HDL in vivo, resulting in more available nascent pre-beta HDL for cellular lipid efflux. Several novel regulatory mechanisms for ABCA1 at the post-transcriptional level have been identified recently. Interaction of apoA-I with ABCA1 prevents phosphorylation of a sequence rich in proline, glutamic acid, serine and threonine in a cytoplasmic domain of ABCA1, resulting in less degradation by calpain proteolysis and increased surface expression of ABCA1. In addition, destabilization and decreased cellular surface expression of ABCA1 protein by unsaturated fatty acids have been identified., Summary: Initial lipidation of apoA-I by hepatic ABCA1 is critical for plasma HDL formation because it enables pre-beta HDL to function more efficiently as a cholesterol acceptor for other pathways of cholesterol efflux in the reverse cholesterol transport pathway and prevents apoA-I from rapidly associating with preexisting plasma HDL particles, resulting in greater availability of pre-beta HDL particles for cholesterol efflux.

Apolipoprotein A-I (APOA1 gene, apoA-I protein) is the major protein for plasma high density lipoprotein (HDL). The relationship of APOA1-75G/A polymorphism with lipid profile and coronary artery disease (CAD) is unclear. Out of 370 individuals initially recruited, 164 angiographically proven CAD patients (>/= 70% stenosis) and 36 individuals with normal coronaries or insignificant CAD (NCAD,

Keto-substituted hydrocarbons with 11-19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g, 14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f, 14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 1 g dose-dependently modified non-HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2-3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.

A large body of evidence from numerous, well-controlled, randomized trials demonstrates that treatment with statins reduce morbidity and mortality from cardiovascular disease (CVD). Although these observations are important and have resulted in the adoption of standard of care approaches to the management of CVD risk, they do not tell the whole story. When reviewing these landmark trials it is clear that on average two thirds of events are not prevented. This leads to the evaluation of risk beyond low-density lipoprotein cholesterol. This review focuses on the association of low high-density lipoprotein (HDL) cholesterol and increased CVD risk, the published trials that study the effect of raising HDL cholesterol on CVD outcomes, and the novel approaches toward HDL cholesterol raising that are on the horizon.

Little information is available on cholesterol absorption and synthesis in human type 1 diabetes. We studied these variables using serum cholesterol precursor sterol ratios to cholesterol as surrogate markers of cholesterol synthesis and those of cholestanol and plant sterols to reflect cholesterol absorption in seven type 1 diabetic subjects and in five age- and body weight-matched control subjects. Total and lipoprotein cholesterol levels were similar, but triglycerides in intermediate-density lipoprotein (IDL) and LDL were higher in type 1 diabetic than in control subjects. Most of the marker sterols were transported by LDL and HDL in both groups. The percentage of esterified cholesterol was lower in triglyceride-rich lipoproteins in diabetic patients than in control subjects. The ratios of the absorption marker sterols in serum were higher, and those of the synthesis markers were lower in type 1 diabetic than in control subjects. The increased cholestanol ratios were seen in all lipoproteins, and those of free and total plant sterols were mainly in LDL, whereas the decreased free and total synthesis markers were mainly in all lipoproteins. In conclusion, high absorption and low synthesis marker sterols seem to characterize human type 1 diabetes. These findings could be related to low expression of ABC G/5 G/8 genes, resulting in high absorption of cholesterol and sterols in general and low synthesis of cholesterol compared with type 2 diabetes.

Thirty four healthy young volunteers (22 men, 12 women; age 25.7 +/- 5.8 years; BMI 20.8 +/- 2.3 kg/m2) participated in a randomized controlled cross-over trial on the effect of consuming one boiled egg every day for 8 wk on the serum lipid profile. The only significant change after 8 wk of egg consumption was an elevation of the total cholesterol/HDL cholesterol ratio. However, scrutiny of individual responses revealed that twelve of the subjects (10 men, 2 women) had a greater than 15% rise in the LDL cholesterol level after 8 wk of egg consumption. These subjects, considered hyperresponders, showed significant increases (P < 0.025) at both 4 wk and 8 wk after egg consumption in total cholesterol and LDL cholesterol levels, and at 8 wk in total cholesterol/HDL cholesterol ratio. The remaining 22 hyporesponders showed no change in any of the variables measured at 4 wk or 8 wk after egg consumption. In view of the high nutritional value of eggs, a blanket ban on eggs is not justified. However, since up to one-third of the population may be hyperresponders, knowing the response of an individual is important before making the egg a regular item of the diet.