High-density lipoprotein and atherosclerosis: Roles of lipid transporters

Various previous studies have found a negative cor-relation between the risk of cardiovascular events and serum high-density lipoprotein(HDL) cholesterol levels. The reverse cholesterol transport, a pathway of choles-terol 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 trans-porters(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 mi-metic peptide, Fukuoka University ApoA-I Mimetic Pep-tide, effectively removes cholesterol via specific ABCA1 and other transporters, such as ABCG1, and has an an-tiatherosclerotic effect by enhancing the biological func-tions of HDL without changing circulating HDL choles-terol 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.

The role of low-density lipoprotein （LDL） and high-density lipoprotein （HDL） in comparison with whole egg yolk for sperm cryopreservation in rhesus monkeys

Low-density lipoprotein （LDL） extracted from hen egg yolk has recently been considered to be superior to whole egg yolk in sperm cryopreservation of various animal species. Meanwhile, there was a notion that high-density lipoprotein （HDL） in egg yolk may have a negative effect on post-thaw survival. The role of LDL and HDL in sperm cryopreservation of rhesus monkeys has not been explored. The present study evaluates their effect in comparison with egg yolk with or without the addition of permeable cryoprotectant （glycerol） on sperm cryopreservation of rhesus macaques. In addition, various additives intended to change the lipid composition of LDL-sperm membrane complex have also been tested for their effectiveness in preserving post-thaw viability. Our findings indicated that LDL is the main component in egg yolk that is responsible for its protective role for sperm cryopreservation in rhesus monkeys. Regardless of the presence or absence of glycerol, the protective role of LDL is similar to that of egg yolk and we did not observe any superiority in post-thaw survival with LDL when compared to egg yolk. Modifying the lipid composition of LDL-sperm membrane complex with the addition of cholesterol, cholesterol loaded cyclodextrin and phosphatidylcholine also did not yield any improvements in pest-thaw survival; while addition of methyl-β-cyclodextrin reduced post-thaw motility. HDL plays a neutral role in sperm cryopreservation of rhesus monkeys. The present study suggests that egg yolk may still hold advantages when compared with LDL as effective components in extenders for sperm cryopreservation in rhesus monkeys.

Effect of low high-density lipoprotein levels on mortality of septic patients: A systematic review and meta-analysis of cohort studies

BACKGROUND:An increase in high-density lipoprotein(HDL)is well associated with a decreased cardiovascular risk,especially atherosclerosis.Recent studies suggest that lower levels of HDL may also be associated with an increased risk of sepsis and an increased rate of mortality in septic patients.However,this conclusion remains controversial.METHODS:MEDLINE,EMBASE,and CENTRAL databases were searched from inception to September 30,2019.All studies were conducted to evaluate the correlation of lipoprotein levels and the risk and outcomes of sepsis in adult patients.The primary outcomes were the risk and mortality of sepsis.RESULTS:Seven studies comprising 791 patients were included.Lower levels of HDL had no marked relevance with the risk of sepsis(odds radio[OR]for each 1 mg/dL increase,0.94;95%CI 0.86–1.02;P=0.078),whereas lower HDL levels were related to an increased mortality rate in septic patients(OR for below about median HDL levels,2.00;95%CI 1.23–3.24;P=0.005).CONCLUSION:This meta-analysis did not reveal a signifi cant association between lower HDL levels and an increase in the risk of sepsis,whereas it showed that lower HDL levels are associated with a higher mortality rate in septic adult patients.These findings suggest that HDL may be considered as a promising factor for the prevention and treatment of sepsis in the future.

Bone and high-density lipoprotein:The beginning of a beautiful friendship

There is a tight link between bone and lipid metabolic pathways.In this vein,several studies focused on the exploration of high-density lipoprotein(HDL)in the pathobiology of bone diseases,with emphasis to the osteoarthritis(OA)and osteoporosis,the most common bone pathologies.Indeed,epidemiological and in vitro data have connected reduced HDL levels or dysfunctional HDL with cartilage destruction and OA development.Recent studies uncovered functional links between HDL and OA fueling the interesting hypothesis that OA could be a chronic element of the metabolic syndrome.Other studies have linked HDL to bone mineral density.Even though at epidemiological levels the results are conflicting,studies in animals as well as in vitro experiments have shown that HDL facilitates osteoblastogensis and bone synthesis and most probably affects osteoclastogenesis and osteoclast bone resorption.Notably,reduced HDL levels result in increased bone marrow adiposity affecting bone cells function.Unveiling the mechanisms that connect HDL and bone/cartilage homeostasis may contribute to the design of novel therapeutic agents for the improvement of bone and cartilage quality and thus for the treatment of related pathological conditions.

Role of sphingosine 1-phosphate in anti-atherogenic actions of high-density lipoprotein

The reverse cholesterol transport mediated by high-density lipoprotein (HDL) is an important mechanism for maintaining body cholesterol, and hence, the crucial anti-atherogenic action of the lipoprotein. Recent studies, however, have shown that HDL exerts a variety of anti-inflammatory and anti-atherogenic actions independently of cholesterol metabolism. The present review provides an overview of the roles of sphingosine 1-phosphate (S1P)/S1P receptor and apolipoprotein A-I/scavenger receptor class B type I systems in the anti-atherogenic HDL actions. In addition, the physiological significance of the existence of S1P in the HDL particles is discussed.

High-density Lipoprotein Cholesterol and In-hospital Mortality in Patients with Acute Aortic Dissection

The association between high-density lipoprotein cholesterol（HDL-C） and mortality in patients with acute aortic dissection（AAD） is unclear. From January 2007 to January 2014, a total of 928 consecutive AAD patients who were admitted within 48 h after the onset of symptoms were enrolled in the study. Patients were divided into two groups according to whether serum HDL-C level was below the normal lower limit or not. The Cox proportional hazard regression model was used to identify the predictive value of HDL-C for in-hospital mortality in patients with AAD. As compared with normal HDL-C group（n=585）, low HDL-C group（n=343） had lower levels of systolic blood pressure and hemoglobin and higher levels of leukocyte, alanine aminotransferase, blood glucose, blood urea nitrogen, creatinine and urea acid. Low HDL-C group had significantly higher in-hospital mortality than normal HDL-C group（21.6% vs. 12.6%, log-rank=10.869, P=0.001）. After adjustment for baseline variables including demographics and biologic data, the increased risk of in-hospital mortality in low HDL-C group was substantially attenuated and showed no significant difference（adjusted hazard ratio, 1.23; 95% confidence interval, 0.86–1.77; P=0.259）. Low HDL-C is strongly but not independently associated with in-hospital mortality in patients with AAD.

Pleiotropic effects of apolipoprotein A-Ⅱ on high-density lipoprotein functionality, adipose tissue metabolic activity and plasma glucose homeostasis

Apolipoprotein A-Ⅱ(APOA-Ⅱ) is the second most abundant apolipoprotein of high-density lipoprotein(HDL)synthesized mainly by the liver and to a much lesser extent by the intestine. Transgenic mice overexpressing human APOA-Ⅱ present abnormal lipoprotein composition and are prone to atherosclerosis, though in humans the role for APOA-Ⅱ in coronary heart disease remains controversial. Here, we investigated the effects of overexpressed APOA-Ⅱ on HDL structure and function, adipose tissue metabolic activity, glucose tolerance and insulin sensitivity. C57BL/6 mice were infected with an adenovirus expressing human APOA-Ⅱ or a control adenovirus Ad GFP, and five days post-infection blood and tissue samples were isolated. APOA-Ⅱ expression resulted in distinct changes in HDL apoproteome that correlated with increased antioxidant and anti-inflammatory activities. No effects on cholesterol efflux from RAW 264.7 macrophages were observed. Molecular analyses in white adipose tissue(WAT) indicated a stimulation of oxidative phosphorylation coupled with respiration for ATP production in mice overexpressing APOA-Ⅱ. Finally, overexpressed APOA-Ⅱ improved glucose tolerance of mice but had no effect on the response to exogenously administered insulin. In summary, expression of APOA-Ⅱ in C57BL/6 mice results in pleiotropic effects with respect to HDL functionality, adipose tissue metabolism and glucose utilization, many of which are beneficial to health.

Risk factors for low high-density lipoprotein among Asian Indians in the United States

AIM To examine the differences in metabolic risk factors(RFs) by gender in the Asian Indian(AI) population in the United States. METHODS Using cross-sectional data from 1038 randomly selected Asian Indians, we investigated the relationship between metabolic syndrome(Met S) RFs, cardiovascular disease,and diabetes. RESULTS A greater percent of women in this group had increased waist circumference and low high density lipoprotein(HDL) levels than men, but AI males had increased blood glucose, increased blood pressure, and increased triglycerides compared to females. Those individuals who met the Met S criteria had increased cardiovascular disease. One of the biggest single RFs for cardiovascular disease and diabetes reported in the literature for AIs is low HDL. CONCLUSION Our results show that lack of knowledge about diabetes, low physical activity, increased body mass index, and age were the factors most significantly correlated with low HDL in this population. Future studies and prospective trials are needed to further elucidate causes of the Met S and diabetes in AIs.

Relationship of Circulating High-Density Lipoprotein Cholesterol and Anemia

Circulating level of low HDLC （high-density lipoprotein cholesterol） represents a common critical risk factor for IHD （ischemic heart disease） and may further aggravate the condition in anemic subjects, as the presence of anemia itself is a threat to cardiovascular consequences. To investigate the relationship of circulating HDLC with anemia, first we determined the levels of total hemoglobin （Hb） in a total of 301 subjects （male, n = 158; female, n = 143） randomly, and then examined the circulating levels of HDLC in fasting condition. Age of the study subjects was 47.9 ~ 16.6 （mean ＋ SD） years. Both the male and female subjects were divided into three groups according to their levels of Hb. The relationship of circulating levels of HDLC with the levels of total Hb was statistically analyzed. In case of the male subjects, we found that the levels of HDLC differed significantly among the three groups with different levels of Hb （P = 0.0233） and decrease in the levels of HDLC correlated significantly with the gradual decrease of total Hb level （r = 0.2504; P = 0.0015）. In female subjects, we observed a similar trend of difference among the three groups （P = 0.0685）. However, decrease in the levels of HDLC correlated significantly with the gradual decrease of Hb level （r = 0,2199; P = 0.0083）. Altogether, this study demonstrates that decrease in the circulating HDLC is related to the gradual decrease of Hb level. This study also indicates that circulating level of HDLC may be influenced by the level of total Hb and reveals the cardiovascular risks in anemia as well.

A Possible Mechanism Linking Hyperglycemia and Reduced High-density Lipoprotein Cholesterol Levels in Diabetes

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.

High-density lipoprotein endocytosis in endothelial cells

AIM: To describe the way stations of high-density lipoprotein(HDL) uptake and its lipid exchange in endothelial cells in vitro and in vivo. METHODS: A combination of fluorescence microscopy using novel fluorescent cholesterol surrogates and electron microscopy was used to analyze HDL endocytosis in great detail in primary human endothelial cells. Further, HDL uptake was quantified using radio-labeled HDL particles. To validate the in vitro findings mice were injected with fluorescently labeled HDL and particle uptake in the liver was analyzed using fluorescencemicroscopy. RESULTS: HDL uptake occurred via clathrin-coated pits, tubular endosomes and multivesicular bodies in human umbilical vein endothelial cells. During uptake and resecretion, HDL-derived cholesterol was exchanged at a faster rate than cholesteryl oleate, resembling the HDL particle pathway seen in hepatic cells. In addition, lysosomes were not involved in this process and thus HDL degradation was not detectable. In vivo, we found HDL mainly localized in mouse hepatic endothelial cells. HDL was not detected in parenchymal liver cells, indicating that lipid transfer from HDL to hepatocytes occurs primarily via scavenger receptor, class B, type Ⅰ mediated selective uptake without concomitant HDL endocytosis. CONCLUSION: HDL endocytosis occurs via clathrincoated pits, tubular endosomes and multivesicular bodies in human endothelial cells. Mouse endothelial cells showed a similar HDL uptake pattern in vivo indicating that the endothelium is one major site of HDL endocytosis and transcytosis.

Hypercholesterolemia,low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9

Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol （LDL-C） are positively correlated with the risk of atherosclerosis. High plasma LDL concentrations in patients with hypercholesterolemia lead to build-up of LDL in the inner walls of the arteries, which becomes oxidized and promotes the formation of foam cells, consequently initiating atherosclerosis. Plasma LDL is mainly cleared through the LDL receptor （LDLR） pathway. Mutations in the LDLR cause familiar hyperch- olesterolemia and increase the risk of premature coronary heart disease. The expression of LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 （SREBP-2） and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 （PCSK9） and inducible degrader of the LDLR （IDOL）. In this review, we summarize the latest advances in the studies of PCSK9.

Influence of Oxidized Low Density Lipoprotein on the Proliferation of Human Artery Smooth Muscle Cells in vitro

The effects of oxidized low density lipoprotein （ox-LDL） on the proliferation of cultured human vascular smooth muscle cells （vSMC） were investigated in vitro. By using NaBr density gradient centrifugation, LDL was isolated and purified from human plasma. Ox-LDL was produced from LDL by being incubated with CuSO4. ox-LDL was then added to the culture medium at different concentrations （35, 60, 85, 110, 135 and 160μg/mL） for 7 days. The influence of ox-LDL on vSMC proliferation was observed in growth curve, mitosis index, and in situ determination of apoptosis. The data were analyzed with SPSS 10.0 software. The results showed that the ox-LDL produced in vitro had a good purity and optimal oxidative degree, which was similar to the intrinsic ox-LDL in atherosclerotic plaque, ox-LDL at a concentration of 35 μg/mL demonstrated the strongest proliferation inducement, and at a concentration of 135 μg/mL, ox-LDL could inhibit the growth of vSMC. ox-LDL at concentrations of 35 and 50 μg/mL presented powerful mitotic trigger, and with the increase of ox-LDL concentration, the mitotic index of vSMC was decreased gradually, ox-LDL at higher concentrations promoted more apoptotic vSMCs, ox-LDL at lower concentrations triggered proliferation of vSMCs, and at higher concentrations induced apoptosis in vSMCs, ox-LDL played a promotional role in the pathogenesis and development of atherosclerosis by affecting vSMC proliferation and apoptosis.

Antitumoral activity of low density lipoprotein-aclacinomycin complex in mice bearing H_(22) tumor

INTRODUCTIONCancer cells,which proliferate rapidly need largeamounts of cholesterol for new membrane synthesis,and high LDL receptor (LDLR) activity.LDL hasbeen proposed as a useful discriminatory vehicle forthe delivery of cytotoxic drugs to tumor cells.LDL presents many advantages as drug

A Modified Chitosan Adsorbent for Selective Removal of Low Density Lipoprotein

A modified chitosan adsorbent was synthesized through a simple preparation procedure, and it demonstrated good adsorption performance for selective removal of low density lipoprotein in human plasma. Phase inversion technique was employed to form chitosan beads, to which epoxy groups were then introduced by reacting with ethyleneglycol diglycidylether, and tryptophan was subsequently coupled to the epoxy-activated beads.

ASSOCIATION BETWEEN LOW- DENSITY LIPOPROTEIN RECEPTOR- RELATED PROTEIN GENE, BUTYRYLCHOLINESTERASE GENE AND ALZHEIMER'S DISEASE IN CHINESE

Objective. To research the relations between low- density lipoprotein receptor- related protein gene (LRP) polymorphism, butyrylcholinesterase gene (BchE) polymorphism and Alzheimer’s disease (AD) in Chinese. Methods. The gene polymorphisms of LRP and BchE were genotyped in 38 AD cases and 40 controls with polymerase chain reaction- restriction fragment length polymorphism (PCR- RFLP) methods. AD groups were classified according to the LRP C/C genotype and compared with matched controls. Results. AD group had higher frequencies of C/C homozygote (81.6％ vs 60.0％ , P< 0.05) and of C allele (89.5％ vs 76.3％ , P< 0.05),with no significant difference between any of these LRP genotypes classified AD groups and their respective control groups. Conclusions. A positive correlation was found between LRP gene polymorphism and AD, but not between BchE gene polymorphism and AD in Chinese AD cases.

Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion

Apolipoprotein B （apoB） is the main protein component of very low density lipoprotein （VLDL） and is necessary for the assembly and secretion of these triglyceride （TG）-rich particles. Following release from the liver, VLDL is converted to low density lipoprotein （LDL） in the plasma and increased production of VLDL can therefore play a detrimental role in cardiovascular disease. Increasing evidence has helped to establish VLDL assembly as a target for the treatment of dyslipidemias. Multiple factors are involved in the folding of the apoB protein and the formation of a secretion-competent VLDL particle. Failed VLDL assembly can initiate quality control mechanisms in the hepatocyte that target apoB for degradation. ApoB is a substrate for endoplasmic reticulum associated degradation （ERAD） by the ubiquitin proteasome system and for autophagy. Efficient targeting and disposal of apoB is a regu- lated process that modulates VLDL secretion and partitioning of TG. Emerging evidence suggests that significant overlap exists between these degradative pathways. For example, the insulin-mediated targeting of apoB to autop- hagy and postprandial activation of the unfolded protein response （UPR） may employ the same cellular machinery and regulatory cues. Changes in the quality control mechanisms for apoB impact hepatic physiology and pathology states, including insulin resistance and fatty liver. Insulin signaling, lipid metabolism and the hepatic UPR may impact VLDL production, particularly during the postprandial state. In this review we summarize our current understanding of VLDL assembly, apoB degradation, quality control mechanisms and the role of these processes in liver physiology and in pathologic states.

Effect of Curcumin on the Gene Expression of Low Density Lipoprotein Receptors

Objective： To investigate the molecular mechanisms and effective target ponits of lipid-lowering drug, Rhizoma Curcumae Longae, and study the effect of curcumin on the expression of low density lipoprotein （LDL） receptors in macrophages in mice. Methods. Macrophages in mice were treated with curcumin, which was purified from the ethanolly extraction of Rhizoma Curcumae Longae for 24 h. The LDL receptors expressed in the macrophages were determined by enzyme-linked immunosorbent assay （ELISA） and assay of Dil labeled LDL uptake by flow cytometer. Results： It was found for the first time that 10 μmol/L-50 μmol/L curcumin could obviously up-regulate the expression of LDL receptor in macrophages in mice, and a dose-effect relationship was demonstrated. Conclusion： One of the lipid-lowering mechanisms of traditional Chinese medicine, Rhizoma Curcumae Longae, was completed by the effect of curcumin through the up-regulation of the expression of LDL receptor.

Effects of Oxidized Low Density Lipoprotein on Transformation of Valvular Myofibroblasts to Osteoblast-like Phenotype

In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated with oxidized low density lipoprotein（ox-LDL, 50 mg/L）, and divided into four groups according to the ox-LDL treatment time： control group, ox-LDL 24-h group, ox-LDL 48-h group, and ox-LDL 72-h group. Wnt signal pathway blocker Dickkopf-1（DDK-1, 100 μg/L） was added in ox-LDL 72-h group. The expression of α-smooth muscle actin（α-SMA）, bone morphogenetic protein 2（BMP2）, alkaline phosphatase（ALP）, and osteogenic transcription factor Cbfa-1 was detected by Western blotting, and that of β-catenin, a key mediator of Wnt signal pathway by immunocytochemical staining method. The Wnt/β-catenin was observed and the transformation of myofibroblasts to the osteoblast-like phenotype was examined. The expression of α-SMA, BMP2, ALP and Cbfa-1 proteins in the control group was weaker than in the ox-LDL-treated groups. In ox-LDL-treated groups, the protein expression of α-SMA, BMP2, ALP, and Cbfa-1 was significantly increased in a time-dependent manner as compared with the control group, and there was significant difference among the three ox-LDL-treated groups（P〈0.05 for all）; β-catenin protein was also up-regulated in the ox-LDL-treated groups in a time-dependent manner as compared with the control group（P〈0.05）, and its transfer from cytoplasm to nucleus and accumulation in the nucleus were increased in the same fashion（P〈0.05）. After addition of DKK-1, the expression of α-SMA, bone-related proteins and β-catenin protein was significantly reduced as compared with ox-LDL 72-h group（P〈0.05）. The Wnt/ β-catenin signaling pathway may play an important role in transformation of valvular myofibroblasts to the osteoblast-like phenotype.

Effects of Oxidized Low Density Lipoprotein onthe Expression and Function of ABCA1 in Macrophages

Summary:In the present study, we examined the regulation of the expression and function of ABCA1 by modified LDL (ox-LDL) in vitro. After incubation with apoA-I for 24 h, RAW264.7 cells effluxed 37.65 % cholesterol loaded by acetyl LDL (ac-LDL), and 9.78 % cholesterol in ox-LDL group. The level of ABCA1 mRNA increased about three times either when cells were incubated with 100 μg /mL ac-LDL or with 100 μg /mL ox-LDL. However, the level of ABCA1 protein rose by 1.57 times in ac-LDL group and 1.26 times in ox-LDL group. These results demonstrated that ox-LDL had different effect on the expression and function of ABCA1, ox-LDL might decrease the cholesterol efflux mediated by ABCA1 through other unknown mechanisms.