Phospholipase A2 group IIA correlates with circulating high-density lipoprotein cholesterol and modulates cholesterol efflux possibly through regulation of PPAR-γ/LXR-α/ABCA1 in macrophages.

BACKGROUND: Secretory phospholipase A2 group IIA (sPLA2-IIA) is an independent risk factor for cardiovascular disease, but its role on high-density lipoprotein cholesterol (HDL-C) level has not been clarified. The aim of the present study was to explore the association between circulating sPLA2-IIA and HDL-C, and to evaluate if sPLA2-IIA enhances cholesterol efflux capacity through regulation of peroxisome proliferator-activated receptor γ (PPAR-γ), liver X receptor α (LXR-α), and ATP-binding cassette A1 (ABCA1). METHODS: 131 patients with coronary artery disease were enrolled. The plasma level of sPLA2-IIA was tested with enzyme-linked immunosorbent assay kit, and serum lipids were assessed by biochemical analyzer. Human monocyte-macrophage cell line THP-1 was co-incubated with sPLA2-IIA in the presence/absence of selective PPAR-γ antagonist GW9662 in vitro. Real-time PCR and Western-blot were employed to measure the mRNA and protein expressions of PPAR-γ, LXR-α, and ABCA1, respectively. The cholesterol efflux was evaluated by using an assay kit. RESULTS: In subjects, circulating level of sPLA2-IIA was positively related with that of HDL-C (r = 0.196, p = 0.024). The plasma level of sPLA2-IIA was significantly higher in the high HDL-C (≥ 1.04 mmol/L) group (7477.828 pg/mL) than that in low HDL-C (< 1.04 mmol/L) group (5836.92 pg/mL, p = 0.004). For each increase of 1 pg/µl in sPLA2-IIA level, the adjusted odds ratio for HDL-C ≥ 1.04 mmol/L was 1.143. Co-incubation of THP-1 cells with sPLA2-IIA resulted in increased expressions of PPAR-γ, LXR-α, and ABCA1, as well as enhanced cholesterol efflux capacity, that were all reversed by administration of GW9662. CONCLUSIONS: Circulating sPLA2-IIA was positively associated with HDL-C. PPAR-γ/LXR-α/ABCA1 might be responsible for sPLA2-IIA-regulated cholesterol efflux in macrophages.

Curcumin ameliorates lipid metabolic disorder and cognitive dysfunction via the ABCA1 transmembrane transport system in APP/PS1 double transgenic mice.

The disorder of lipid metabolism, especially cholesterol metabolism, can promote Alzheimer's Disease. Curcumin can ameliorate lipid metabolic disorder in the brain of Alzheimer's Disease patients, while the mechanism is not clear. APP/PS1 (APPswe/PSEN1dE9) double transgenic mice were divided into dementia, low-dose, and high-dose groups and then fed for six months with different dietary concentrations of curcumin. Morris water maze was used to evaluate the transgenic mice's special cognitive and memory ability in each group. In contrast, the cholesterol oxidase-colorimetric method was used to measure total serum cholesterol and high-density lipoprotein levels. Immunohistochemistry was used to evaluate the expression of liver X receptor-ß, ATP binding cassette A1 and apolipoprotein A1 of the hippocampus and Aß42 in the brains of transgenic mice. The mRNA and protein expression levels of liver X receptor-ß, retinoid X receptor-α and ATP binding cassette A1 were evaluated using qRT-PCR and Western blotting, respectively. Curcumin improved the special cognitive and memory ability of transgenic Alzheimer's Disease Mice. The total serum cholesterol decreased in Alzheimer's Disease mice fed the curcumin diet, while the high-density lipoprotein increased. The curcumin diet was associated with reduced expression of Aß and increased expression of liver X receptor-ß, ATP binding cassette A1, and apolipoprotein A1 in the CA1 region of the hippocampus. The mRNA and protein levels of retinoid X receptor-α, liver X receptor-ß, and ATP binding cassette A1 were higher in the brains of Alzheimer's Disease mice fed the curcumin diet. Our results point to the mechanism by which curcumin improves lipid metabolic disorders in Alzheimer's Disease via the ATP binding cassette A1 transmembrane transport system.

ABCA1- and ABCG1-mediated cholesterol efflux capacity of cerebrospinal fluid is impaired in Alzheimer's disease.

HDL-like particles in human cerebrospinal fluid (CSF) promote the efflux of cholesterol from astrocytes toward the neurons that rely on this supply for their functions. We evaluated whether cell cholesterol efflux capacity of CSF (CSF-CEC) is impaired in Alzheimer's disease (AD) by analyzing AD (n = 37) patients, non-AD dementia (non-AD DEM; n = 16) patients, and control subjects (n = 39). As expected, AD patients showed reduced CSF Aß 1-42, increased total and phosphorylated tau, and a higher frequency of the apoε4 genotype. ABCA1- and ABCG1-mediated CSF-CEC was markedly reduced in AD (-73% and -33%, respectively) but not in non-AD DEM patients, in which a reduced passive diffusion CEC (-40%) was observed. Non-AD DEM patients displayed lower CSF apoE concentrations (-24%) compared with controls, while apoA-I levels were similar among groups. No differences in CSF-CEC were found by stratifying subjects for apoε4 status. ABCG1 CSF-CEC positively correlated with Aß 1-42 (r = 0.305, P = 0.025), while ABCA1 CSF-CEC inversely correlated with total and phosphorylated tau (r = -0.348, P = 0.018 and r = -0.294, P = 0.048, respectively). The CSF-CEC impairment and the correlation with the neurobiochemical markers suggest a pathophysiological link between CSF HDL-like particle dysfunction and neurodegeneration in AD.

Hypoalphalipoproteinemia and BRAFV600E Mutation Are Major Predictors of Aortic Infiltration in the Erdheim-Chester Disease.

Objective- Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. Approach and Results- An analysis of plasma lipid levels indicated that male ECD patients carrying the BRAFV600E (B-Raf proto-oncogene, serine/threonine kinase) mutation exhibited hypoalphalipoproteinemia, as demonstrated by low plasma HDL-C (high-density lipoprotein cholesterol) levels. Capacity of sera from male BRAFV600E ECD patients to mediate free cholesterol efflux from human macrophages was reduced compared with control individuals. Cardiovascular involvement was detected in 84% of the ECD patients, and we reported that the presence of the BRAFV600E mutation and hypoalphalipoproteinemia is an independent determinant of aortic infiltration in ECD. Phenotyping of blood CD14+ cells, the precursors of histiocytes, enabled the identification of a specific inflammatory signature associated with aortic infiltration which was partially affected by the HDL phenotype. Finally, the treatment with vemurafenib, an inhibitor of the BRAFV600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions- Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAFV600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14+ cells into the aorta.

Apolipoprotein A-I configuration and cell cholesterol efflux activity of discoidal lipoproteins depend on the reconstitution process.

Discoidal high-density lipoproteins (D-HDL) are critical intermediates in reverse cholesterol transport. Most of the present knowledge of D-HDL is based on studies with reconstituted lipoprotein complexes of apolipoprotein A-I (apoA-I) obtained by cholate dialysis (CD). D-HDL can also be generated by the direct microsolubilization (DM) of phospholipid vesicles at the gel/fluid phase transition temperature, a process mechanistically similar to the "in vivo" apoAI lipidation via ABCA1. We compared the apoA-I configuration in D-HDL reconstituted with dimyristoylphosphatidylcholine by both procedures using fluorescence resonance energy transfer measurements with apoA-I tryptophan mutants and fluorescently labeled cysteine mutants. Results indicate that apoA-I configuration in D-HDL depends on the reconstitution process and are consistent with a "double belt" molecular arrangement with different helix registry. As reported by others, a configuration with juxtaposition of helices 5 of each apoAI monomer (5/5 registry) predominates in D-HDL obtained by CD. However, a configuration with helix 5 of one monomer juxtaposed with helix 2 of the other (5/2 registry) would predominate in D-HDL generated by DM. Moreover, we also show that the kinetics of cholesterol efflux from macrophage cultures depends on the reconstitution process, suggesting that apoAI configuration is important for this HDL function.

Influence of apolipoprotein A-I and apolipoprotein A-II availability on nascent HDL heterogeneity.

It is important to understand HDL heterogeneity because various subspecies possess different functionalities. To understand the origins of HDL heterogeneity arising from the existence of particles containing only apoA-I (LpA-I) and particles containing both apoA-I and apoA-II (LpA-I+A-II), we compared the abilities of both proteins to promote ABCA1-mediated efflux of cholesterol from HepG2 cells and form nascent HDL particles. When added separately, exogenous apoA-I and apoA-II were equally effective in promoting cholesterol efflux, although the resultant LpA-I and LpA-II particles had different sizes. When apoA-I and apoA-II were mixed together at initial molar ratios ranging from 1:1 to 16:1 to generate nascent LpA-I+A-II HDL particles, the particle size distribution altered, and the two proteins were incorporated into the nascent HDL in proportion to their initial ratio. Both proteins formed nascent HDL particles with equal efficiency, and the relative amounts of apoA-I and apoA-II incorporation were driven by mass action. The ratio of lipid-free apoA-I and apoA-II available at the surface of ABCA1-expressing cells is a major factor in determining the contents of these proteins in nascent HDL. Manipulation of this ratio provides a means of altering the relative distribution of LpA-I and LpA-I+A-II HDL particles.

A novel dammarane triterpenoid alleviates atherosclerosis by activating the LXRα pathway.

BACKGROUND: We have previously demonstrated that ginsenoside compound K can attenuate the formation of atherosclerotic lesions. Therefore, ginsenoside compound K has potential for atherosclerosis therapy. How to improve the druggability and enhance the antiatherosclerotic activity of ginsenoside compound K are the core problems in the prevention and treatment of atherosclerosis. CKN is a ginsenoside compound K derivative that was previously reported to have excellent antiatherosclerotic activity in vitro, and we have applied for international patents for it. METHODS: Male C57BL/6 ApoE-/- mice were fed a high-fat and high-choline diet to induce atherosclerosis and were subjected to in vivo studies. In vitro, the CCK-8 method was applied to evaluate cytotoxicity in macrophages. Foam cells were utilized, and cellular lipid determination was performed for in vitro studies. The area of atherosclerotic plaque and fatty infiltration of the liver were measured by image analysis. Serum lipid and liver function were determined by a seralyzer. Immunofluorescence and western blot analysis were conducted to explore the alterations in the expression levels of lipid efflux-related proteins. Molecular docking, reporter gene experiments and cellular thermal shift assays were used to verify the interaction between CKN and LXRα. RESULTS: After confirming the therapeutic effects of CKN, molecular docking, reporter gene experiments and cellular thermal shift assays were used to predict and investigate the antiatherosclerotic mechanisms of CKN. CKN exhibited the greatest potency, with a 60.9% and 48.1% reduction in en face atherosclerotic lesions on the thoracic aorta and brachiocephalic trunk, reduced plasma lipid levels and decreased foam cell levels in the vascular plaque content in HHD-fed ApoE-/- mice. Moreover, CKN in the present study may exert its antiatherosclerotic effects through activated ABCA1 by promoting LXRα nuclear translocation and reducing the adverse effects of LXRα activation. CONCLUSIONS: Our results revealed that CKN prevented the formation of atherosclerosis in ApoE-/- mice by activating the LXRα pathway.

New Strategies to Promote Macrophage Cholesterol Efflux.

The capacity of macrophages to dispose of cholesterol deposited in the atherosclerotic plaque depends on their ability to activate cholesterol efflux pathways. To develop athero-protective therapies aimed at promoting macrophage cholesterol efflux, cholesterol metabolism in THP-1 monocyte-derived macrophages has been extensively studied, but the intrinsic sensitivity of monocytes and the lack of a standardized procedure to differentiate THP-1 monocytes into macrophages have made it difficult to utilize THP-1 macrophages in the same or similar degree of differentiation across studies. The variability has resulted in lack of understanding of how the differentiation affects cholesterol metabolism, and here we review and investigate the effects of THP-1 differentiation on cholesterol efflux. The degree of THP-1 differentiation was inversely associated with ATP binding cassette A1 (ABCA1) transporter-mediated cholesterol efflux. The differentiation-associated decrease in ABCA1-mediated cholesterol efflux occurred despite an increase in ABCA1 expression. In contrast, DSC1 expression decreased during the differentiation. DSC1 is a negative regulator of the ABCA1-mediated efflux pathway and a DSC1-targeting agent, docetaxel showed high potency and efficacy in promoting ABCA1-mediated cholesterol efflux in THP-1 macrophages. These data suggest that pharmacological targeting of DSC1 may be more effective than increasing ABCA1 expression in promoting macrophage cholesterol efflux. In summary, the comparison of THP-1 macrophage subtypes in varying degrees of differentiation provided new insights into cholesterol metabolism in macrophages and allowed us to identify a viable target DSC1 for the promotion of cholesterol efflux in differentiated macrophages. Docetaxel and other pharmacological strategies targeting DSC1 may hold significant potential for reducing atherogenic cholesterol deposition.

Polyunsaturated fatty acids and modulation of cholesterol homeostasis in THP-1 macrophage-derived foam cells.

Transformation of macrophages to foam cells is determined by the rates of cholesterol uptake and efflux. This study uses a real time RT-PCR technique to investigate the role of conjugated linoleic acid (CLA), α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) in the regulation of the ATP-binding cassette A1 (ABCA1) and liver X receptor α (LXR) genes, which are involved in cholesterol homeostasis. Accordingly, these fatty acids significantly reduced the total, free and esterified cholesterols within the foam cells. While the expression of the ABCA1 and LXRα genes was increased in the presence of the pharmacological LXRα ligand, T0901317, their mRNA expression was not significantly affected by CLA, ALA and EPA. These results suggest that although polyunsaturated fatty acids have an effect on cholesterol homeostasis, they cannot change the expression of the ABCA1 and LXRα genes. Alternatively, several other genes and proteins may be involved.

Interaction between an ATP-Binding Cassette A1 (ABCA1) Variant and Egg Consumption for the Risk of Ischemic Stroke and Carotid Atherosclerosis: a Family-Based Study in the Chinese Population.

AIM: ATP-binding cassette A1 (ABCA1) plays an important role in reducing the risk of stroke. Egg is the major source of dietary cholesterol and is known to be associated with the risk of stroke and atherosclerosis. We aimed to assess the effects of interaction between an ABCA1 variant (rs2066715) and egg consumption on the risk of ischemic stroke (IS), carotid plaque, and carotid-intima media thickness (CIMT) in the Chinese population. METHODS: In total, 5869 subjects (including 1213 IS cases) across 1128 families were enrolled and divided into two groups based on the median egg consumption (4 eggs per week). In the analyses for the presence of carotid plaque and CIMT, 3171 out of 4656 IS-free controls without self-reported history of coronary heart disease and lipid-lowering medications were included. Multilevel logistic regression models were used to model the genetic association of rs2066715 with the risk of IS, and mixed-effect linear regression for the genetic association of rs2066715 with carotid plaque, and CIMT. The gene-by-egg cross-product term was included in the regression model for interaction analysis. RESULTS: We found that rs2066715 was associated with the increased risk of carotid plaque among those who consumed ＜4 eggs per week after adjustment (odds ratio [95% confidence interval]: 1.61 [1.08, 2.39], P =0.019). A significant effect of interaction between rs2066715 and egg consumption on the risk of carotid plaque was identified (P =0.011). CONCLUSION: rs2066715 was found to interact with egg consumption in modifying the risk of carotid plaque in the Chinese population.

Downregulation of ABCA1 and ABCG1 transporters by simvastatin in cholangiocarcinoma cells.

Disturbances in cholesterol homeostasis of the bile duct epithelium, including transport interruption and the hyperaccumulation of intracellular cholesterol can lead to the initiation and progression of cholangiocarcinoma (CCA). Statins, which are lipid-lowering drugs, have been previously documented to exhibit anti-cancer properties. The role of statins in CCA cell cholesterol transport through the expression and function of ATP-binding cassette (ABC) A1 and ABCG1 was investigated in the current study. In four CCA cell lines, ABCA1 and ABCG1 expression was identified. However, neither ABCG5 nor ABCG8 expression was observed. Immunocytochemistry revealed that the expression of ABCA1 was localized in the proximity of the nucleus, while ABCG1 was more dispersed throughout the cytoplasm of KKU-100 cells. A cholesterol efflux assay was performed using bodipy cholesterol, and the translocation of cholesterol via ABCA1 and ABCG1 to Apo-A1 and high density lipoprotein was confirmed, respectively. Simvastatin and atorvastatin demonstrated the inhibitory effects on CCA cell viability. A reduction in intracellular lipid level and a lower expression of ABCA1 and ABCG1 were observed in KKU-100 cells under simvastatin treatment. The pre-exposure of KKU-100 cells to cholesterol diminished the statin effect. Furthermore, when KKU-100 cells were pre-loaded with cholesterol, ABCA1 and ABCG1-mediated exports were unaffected even though they were treated with simvastatin. The results of the current study indicated the limitations of the use of statin in CCA therapy, particularly under hypercholesterolemia conditions.

Effects of fish and krill oil on gene expression in peripheral blood mononuclear cells and circulating markers of inflammation: a randomised controlled trial.

Marine n-3 (omega-3) fatty acids alter gene expression by regulating the activity of transcription factors. Krill oil is a source of marine n-3 fatty acids that has been shown to modulate gene expression in animal studies; however, the effect in humans is not known. Hence, we aimed to compare the effect of intake of krill oil, lean and fatty fish with a similar content of n-3 fatty acids, and high-oleic sunflower oil (HOSO) with added astaxanthin on the expression of genes involved in glucose and lipid metabolism and inflammation in peripheral blood mononuclear cells (PBMC) as well as circulating inflammatory markers. In an 8-week trial, healthy men and women aged 18-70 years with fasting TAG of 1·3-4·0 mmol/l were randomised to receive krill oil capsules (n 12), HOSO capsules (n 12) or lean and fatty fish (n 12). The weekly intakes of marine n-3 fatty acids from the interventions were 4654, 0 and 4103 mg, respectively. The mRNA expression of four genes, PPAR γ coactivator 1A (PPARGC1A), steaoryl-CoA desaturase (SCD), ATP binding cassette A1 (ABCA1) and cluster of differentiation 40 (CD40), were differently altered by the interventions. Furthermore, within-group analyses revealed that krill oil down-regulated the mRNA expression of thirteen genes, including genes involved in glucose and cholesterol metabolism and ß-oxidation. Fish altered the mRNA expression of four genes and HOSO down-regulated sixteen genes, including several inflammation-related genes. There were no differences between the groups in circulating inflammatory markers after the intervention. In conclusion, the intake of krill oil and HOSO with added astaxanthin alter the PBMC mRNA expression of more genes than the intake of fish.

Effects of ABCA1 R219K Polymorphism and Serum Lipid Profiles on Mild Cognitive Impairment in Type 2 Diabetes Mellitus.

Background: Accumulated evidence suggests that adverse lipid changes are risk factors for type 2 diabetes mellitus (T2DM) and neurodegenerative disorders. The ATP-binding cassette A1 transporter (ABCA1) gene contributes to both lipid processing and amyloid-ß formation and thus shows promise as a biological target in the pathology of mild cognitive impairment (MCI) in T2DM. Objective: This study aimed to investigate the interactions among lipids, ABCA1 R219K polymorphism, and cognitive function in T2DM. Methods: Clinical parameters, including lipids, were measured. The testing scores of different cognitive domains were recorded, and the ABCA1 R219K polymorphisms were analyzed. Results: A total of 226 patients, including 124 MCI patients and 102 controls, were enrolled in this study. T2DM patients with MCI showed lower cognitive functions, serum high-density lipoprotein (HDL-c), and apolipoprotein A1 (apoA-I) levels; and higher total cholesterol level than the controls. Serum HDL-c (P = 0.001) and apoA-I (P = 0.016) were positively associated with the MoCA score in MCI patients. Further stratification analyses revealed that the subjects with higher HDL-c concentration showed better attention and memory for verbal, visual, and logical functions than the group with lower HDL-c concentration (P < 0.05). No significant differences were observed among the distributions of ABCA1 R219K variants between MCI patients and controls; however, the KK genotype carriers presented higher apoA-I levels than those with RR genotype in MCI individuals. Conclusion: This study does not support the association between R219K polymorphism and T2DM-related MCI. However, our data suggested that the serum HDL-c level might positively influence cognition, especially memory function, in T2DM patients. Further studies are needed to determine the interaction between lipids and ABCA1 genotype and its effect on cognition in T2DM patients. Trial registration: Advanced Glycation End Products Induced Cognitive Impairment in Diabetes: BDNF Signal Meditated Hippocampal Neurogenesis ChiCTR-OCC-15006060; http://www.chictr.org.cn/showproj.aspx?proj=10536.

The integration of epigenetics and genetics in nutrition research for CVD risk factors.

There is increasing evidence documenting gene-by-environment (G × E) interactions for CVD related traits. However, the underlying mechanisms are still unclear. DNA methylation may represent one of such potential mechanisms. The objective of this review paper is to summarise the current evidence supporting the interplay among DNA methylation, genetic variants, and environmental factors, specifically (1) the association between SNP and DNA methylation; (2) the role that DNA methylation plays in G × E interactions. The current evidence supports the notion that genotype-dependent methylation may account, in part, for the mechanisms underlying observed G × E interactions in loci such as APOE, IL6 and ATP-binding cassette A1. However, these findings should be validated using intervention studies with high level of scientific evidence. The ultimate goal is to apply the knowledge and the technology generated by this research towards genetically based strategies for the development of personalised nutrition and medicine.

High-density lipoprotein-based drug discovery for treatment of atherosclerosis.

INTRODUCTION: Although there has been great progress achieved by the use of intensive statin therapy, the burden of atherosclerotic cardiovascular disease (CVD) remains high. This has initiated the search for novel high-density lipoprotein (HDL)-based therapeutics. Recent years have witnessed a shift from traditional raising HDL-C levels to enhancing HDL functionality, in which the process of reverse cholesterol transport (RCT) has acquired much attention. AREAS COVERED: In this review, the authors describe the key factors involved in RCT process for potential drug targets to reduce the CVD risk. Furthermore, the review provides a summary of the effective screening methods that have been developed to target RCT and their applications. This review also introduces some new strategies currently being clinically developed, which have the potential to improve HDL function in the RCT process. EXPERT OPINION: It is rational that the functionality of HDL is more important than the plasma HDL-C level in the evaluation of pharmacological treatment in atherosclerosis. HDL-based strategies designed to promote macrophage RCT are a major area of current drug discovery and development for atherosclerotic diseases. A better understanding of the functionality of HDL and its relationship with atherosclerosis will expand our knowledge of the role of HDL in lipid metabolism, holding promise for a future successful HDL-based therapy.

High-density lipoprotein and atherosclerosis: Roles of lipid transporters.

Various previous studies have found a negative correlation between the risk of cardiovascular events and serum high-density lipoprotein (HDL) cholesterol levels. The reverse cholesterol transport, a pathway of cholesterol from peripheral tissue to liver which has several potent antiatherogenic properties. For instance, the particles of HDL mediate to transport cholesterol from cells in arterial tissues, particularly from atherosclerotic plaques, to the liver. Both ATP-binding cassette transporters (ABC) A1 and ABCG1 are membrane cholesterol transporters and have been implicated in mediating cholesterol effluxes from cells in the presence of HDL and apolipoprotein A-I, a major protein constituent of HDL. Previous studies demonstrated that ABCA1 and ABCG1 or the interaction between ABCA1 and ABCG1 exerted antiatherosclerotic effects. As a therapeutic approach for increasing HDL cholesterol levels, much focus has been placed on increasing HDL cholesterol levels as well as enhancing HDL biochemical functions. HDL therapies that use injections of reconstituted HDL, apoA-I mimetics, or full-length apoA-I have shown dramatic effectiveness. In particular, a novel apoA-I mimetic peptide, Fukuoka University ApoA-I Mimetic Peptide, effectively removes cholesterol via specific ABCA1 and other transporters, such as ABCG1, and has an antiatherosclerotic effect by enhancing the biological functions of HDL without changing circulating HDL cholesterol levels. Thus, HDL-targeting therapy has significant atheroprotective potential, as it uses lipid transporter-targeting agents, and may prove to be a therapeutic tool for atherosclerotic cardiovascular diseases.

Vitamin E: a dark horse at the crossroad of cancer management.

It appears that the story on vitamin E and its role in human health remains incomplete. It is apparent that vitamin E supplementation involves many variables, some of which include its uptake from the intestine, the preference for α-tocopherol, transport by tocopherol specific proteins and lipid transporters and the differential metabolism of different vitamin E isoforms. The fundamental differences within population genetics can have significant implications for the effect that dietary supplementation might have on human health. When evaluating the efficacy of vitamin E prophylactic or therapeutic use in previous and future studies, it is critical to consider dosage to be administered, form of vitamin E and source (such as whether from synthetic or purified from natural sources). Further studies are needed to determine the effects of all vitamin E isoforms on cell growth, tumorigenicity, to clarify its possible use as an adjuvant to existing chemotherapeutics. The Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study Group and Selenium and Vitamin E Cancer Prevention Trial (SELECT) studies along with the numerous studies of vitamin E should help guide the next chapter of vitamin E research.

The high-fat high-fructose hamster as an animal model for niacin's biological activities in humans.

OBJECTIVE: Niacin has been used for more than 50 years to treat dyslipidemia, yet the mechanisms underlying its lipid-modifying effects remain unknown, a situation stemming at least in part from a lack of validated animal models. The objective of this study was to determine if the dyslipidemic hamster could serve as such a model. MATERIALS/METHODS: Dyslipidemia was induced in Golden Syrian hamsters by feeding them a high-fat, high-cholesterol, and high-fructose (HF/HF) diet. The effect of high-dose niacin treatment for 18 days and 28 days on plasma lipid levels and gene expression was measured. RESULTS: Niacin treatment produced significant decreases in plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and free fatty acids (FFA), but had no measureable effect on high-density lipoprotein cholesterol (HDL-C) in the dyslipidemic hamster. Niacin treatment also produced significant increases in hepatic adenosine ATP-Binding Cassette A1 (ABCA1) mRNA, ABCA1 protein, apolipoprotein A-I (Apo A-I) mRNA, and adipose adiponectin mRNA in these animals. CONCLUSIONS: With the exception of HDL-C, the lipid effects of niacin treatment in the dyslipidemic hamster closely parallel those observed in humans. Moreover, the effects of niacin treatment on gene expression of hepatic proteins related to HDL metabolism are similar to those observed in human cells in culture. The HF/HF-fed hamster could therefore serve as an animal model for niacin's lowering of proatherogenic lipids and mechanisms of action relative to lipid metabolism.

Effects of artesunate and ursolic acid on hyperlipidemia and its complications in rabbit.

OBJECTIVE: To find the novel hypolipidemic agents, the effects of ursolic acid and artesunate on hyperlipidemia and its complications were determined in rabbit fed with Western-type diet. METHODS AND RESULTS: New Zealand rabbits fed a Western-type diet developed a hyperlipidemia. Rabbits received ursolic acid (25mg/kg) or artesunate (25mg/kg) alone, or in combination (12.5+12.5mg/kg), to prevent hyperlipidemia. Ursolic acid or artesunate alone significantly decreased the plasma cholesterol and triglyceride in rabbits. Furthermore, they both attenuated liver steatosis and reduced the area of aortic root lesions. The combination of ursolic acid and artesunate was more potent than either agent alone, which indicates a strong synergistic effect. CONCLUSION: The hypolipidemic effect of artesunate is firstly reported. Its combination with ursolic acid might have the potential to further develop for the treatment of atherosclerosis.

Fatty acids affect micellar properties and modulate vitamin D uptake and basolateral efflux in Caco-2 cells.

We have recently shown that vitamin D3 (cholecalciferol) absorption is not a simple passive diffusion but involves cholesterol transporters. As free fatty acids (FAs) modulate cholesterol intestinal absorption and metabolism, we hypothesized that FAs may also interact with vitamin D absorption. Effects of FAs were evaluated at different levels of cholecalciferol intestinal absorption. First, the physicochemical properties of micelles formed with different FAs were analyzed. The micelles were then administered to human Caco-2 cells in culture to evaluate FA effects on (i) cholecalciferol uptake and basolateral efflux and (ii) the regulation of genes coding proteins involved in lipid absorption process. Micellar electric charge was correlated with both FA chain length and degree of unsaturation. Long-chain FAs at 500 µM in mixed micelles decreased cholecalciferol uptake in Caco-2 cells. This decrease was annihilated as soon as the long-chain FAs were mixed with other FAs. Oleic acid significantly improved cholecalciferol basolateral efflux compared to other FAs. These results were partly explained by a modulation of genes coding for lipid transport proteins such as Niemann-pick C1-like 1 and scavenger receptor class B type I. The data reported here show for the first time that FAs can interact with cholecalciferol intestinal absorption at different key steps of the absorption process. Cholecalciferol intestinal absorption may thus be optimized according to oil FA composition.