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.

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.

Proso Millet Protein Elevates Plasma Level of High-Density Lipoprotein:A New Food Function of Proso Millet

We examined the effects of dietary proso-millet protein on plasma levels of high-density lipoprotein (HDL) cholesterol in different rats from animals reported in our previous studies. The results showed also, in this animal, that the ingestion of the millet protein elevates plasma levels of HDL-cholesterol like our earlier works. Taking into account the anti-atherogenic function of HDL, therefore, the millet protein would be useful as a new food ingredient which has the function that regulates cholesterol metabolism

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 highdensity 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 typeⅠsystems in the antiatherogenic HDL actions.In addition,the physiological significance of the existence of S1P in the HDL particles is discussed.

Reduced serum high-density lipoprotein cholesterol levels and aberrantly expressed cholesterol metabolism genes in colorectal cancer

BACKGROUND Colorectal cancer(CRC)is a common malignant tumor of the gastrointestinal tract.Lipid metabolism,as an important part of material and energy circulation,is well known to play a crucial role in CRC.AIM To explore the relationship between serum lipids and CRC development and identify aberrantly expressed cholesterol metabolism genes in CRC.METHODS We retrospectively collected 843 patients who had confirmed CRC and received surgical resection from 2013 to 2015 at the Cancer Hospital of the Chinese Academy of Medical Sciences as our research subjects.The levels of serum total cholesterol(TC),triglycerides,low-density lipoprotein cholesterol(LDL-C),highdensity lipoprotein cholesterol(HDL-C),LDL-C/HDL-C and clinical features were collected and statistically analyzed by SPSS.Then,we used the data from Oncomine to screen the differentially expressed genes(DEGs)of the cholesterol metabolism pathway in CRC and used Gene Expression Profiling Interactive Analysis to confirm the candidate DEGs.PrognoScan was used to analyze the prognostic value of the DEGs,and Search Tool for the Retrieval of Interacting Genes was used to construct the protein-protein interaction network of DEGs.RESULTS The serum HDL-C level in CRC patients was significantly correlated with tumor size,and patients whose tumor size was more than 5 cm had a lower serum HDL-C level(1.18±0.41 mmol/L vs 1.25±0.35 mmol/L,P<0.01)than their counterparts.In addition,TC/HDL(4.19±1.33 vs 3.93±1.26,P<0.01)and LDL-C/HDL-C(2.83±1.10 vs 2.61±0.96,P<0.01)were higher in patients with larger tumors.The levels of HDL-C(P<0.05),TC/HDL-C(P<0.01)and LDL-C/HDL-C(P<0.05)varied in different stages of CRC patients,and the differences were significant.We screened 14 differentially expressed genes(DEGs)of the cholesterol metabolism pathway in CRC and confirmed that lipoprotein receptor-related protein 8(LRP8),PCSK9,low-density lipoprotein receptor(LDLR),MBTPS2 and FDXR are upregulated,while ABCA1 and OSBPL1A are downregulated in cancer tissue.Higher expression of LDLR(HR=3.12,95%CI:1.77-5.49,P<0.001),ABCA1(HR=1.66,95%CI:1.11-2.48,P=0.012)and OSBPL1A(HR=1.38,95%CI:1.01-1.89,P=0.041)all yielded significantly poorer DFS outcomes.Higher expression of FDXR(HR=0.7,95%CI:0.47-1.05,P=0.002)was correlated with longer DFS.LDLR,ABCA1,OSBPL1A and FDXR were involved in many important cellular function pathways.CONCLUSION Serum HDL-C levels are associated with tumor size and stage in CRC patients.LRP8,PCSK9,LDLR,MBTPS2 and FDXR are upregulated,while ABCA1 and OSBPL1A are downregulated in CRC.Among them,LDLR,ABCA1,OSBPL1A and FDXR were valuable prognostic factors of DFS and were involved in important cellular function pathways.

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.

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.

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.

Advances in studies on the regulation of periodontal disease by high-density lipoprotein

Many studies in recent years have considered the potential relationship between periodontitis and lipid parameters.Currently,it is generally accepted that HDL(High-density lipoprotein)is one of the lipoproteins that play an important role in immunity and an important part of maintaining periodontal homeostasis.In this paper,the protective mechanism of HDL in periodontitis was discussed,and the adjuvant therapeutic effect of HDL in periodontitis with systemic disease was emphasized.

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.

High-density lipoprotein regulates angiogenesis by affecting autophagy via miRNA-181a-5p

We previously demonstrated that normal high-density lipoprotein(nHDL)can promote angiogenesis,whereas HDL from patients with coronary artery disease(d HDL)is dysfunctional and impairs angiogenesis.Autophagy plays a critical role in angiogenesis,and HDL regulates autophagy.However,it is unclear whether n HDL and d HDL regulate angiogenesis by affecting autophagy.Endothelial cells(ECs)were treated with n HDL and d HDL with or without an autophagy inhibitor.Autophagy,endothelial nitric oxide synthase(e NOS)expression,miRNA expression,nitric oxide(NO)production,superoxide anion(O2^(·-))generation,EC migration,and tube formation were evaluated.n HDL suppressed the expression of miR-181a-5p,which promotes autophagy and the expression of e NOS,resulting in NO production and the inhibition of O2^(·-)generation,and ultimately increasing in EC migration and tube formation.d HDL showed opposite effects compared to n HDL and ultimately inhibited EC migration and tube formation.We found that autophagy-related protein 5(ATG5)was a direct target of miR-181a-5p.ATG5 silencing or miR-181a-5p mimic inhibited n HDL-induced autophagy,e NOS expression,NO production,EC migration,tube formation,and enhanced O2^(·-)generation,whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of d HDL.ATG5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null(LDLr^(-/-))mice when compared to C57BL/6 mice.ATG5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr^(-/-)mice.Taken together,nHDL was able to stimulate autophagy by suppressing miR-181a-5p,subsequently increasing e NOS expression,which generated NO and promoted angiogenesis.In contrast,d HDL inhibited angiogenesis,at least partially,by increasing miR-181a-5p expression,which decreased autophagy and e NOS expression,resulting in a decrease in NO production and an increase in O2^(·-)generation.Our findings reveal a novel mechanism by which HDL affects angiogenesis by regulating autophagy and provide a therapeutic target for d HDL-impaired angiogenesis.

Carbamylated lipoproteins in diabetes

Diabetic dyslipidemia is characterized by quantitative and qualitative abnormalities in lipoproteins.In addition to glycation and oxidation,carbamylation is also a post-translational modification affecting lipoproteins in diabetes.Patients with type 2 diabetes(T2D)exhibit higher levels of carbamylated low-density lipoproteins(cLDL)and high-density lipoproteins(cHDL).Accumulating evidence suggests that cLDL plays a role in atherosclerosis in diabetes.cLDL levels have been shown to predict cardiovascular events and all-cause mortality.cLDL facilitates immune cell recruitment in the vascular wall,promotes accumulation of lipids in macrophages,and contributes to endothelial dysf-unction,endothelial nitric oxide-synthase(eNOS)inactivation and endothelial repair defects.Lastly,cLDL induces thrombus formation and platelet aggregation.On the other hand,recent data have demonstrated that cHDL serum level is independently associated with all-cause and cardiovascular-related mortality in T2D patients.This relationship may be causative since the atheroprotective properties of HDL are altered after carbamylation.Thus,cHDL loses the ability to remove cholesterol from macrophages,to inhibit monocyte adhesion and recruitment,to induce eNOS activation and to inhibit apoptosis.Taken together,it seems very likely that the abnormalities in the biological functions of LDL and HDL after carbamylation contribute to atherosclerosis and to the elevated cardiovascular risk in diabetes.

基于脂组学方法分析不同危险因素的脑卒中患者预后的研究

目的探讨基于脂组学方法分析不同危险因素的脑卒中患者预后的研究。方法回顾性分析九江市第一人民医院2021年2月至2023年2月收治的120例缺血性脑卒中(AIS)患者的临床资料治疗3个月后将其按预后情况分为良好组(n=82)和不良组(n=38)。分析患者年龄、性别、吸烟史、饮酒史、高血压、高脂血症、糖尿病、脑卒中家族遗传史、总胆固醇(TC)、三酰甘油(TG)、糖化血红蛋白(HbA1c)、低密度脂蛋白胆固醇(LDL-C)水平对AIS患者预后的影响。结果全部纳入研究的120例AIS患者中,有38例患者出现预后不良,发生率为31.67%;有82例预后良好,发生率为68.33%。单因素分析结果提示,两组性别、吸烟史、饮酒史、高血压、高脂血症、糖尿病、脑卒中家族遗传史比较,差异无统计学意义(P>0.05);两组患者年龄、TC、TG、HbA1c以及LDL-C比较,差异有统计学意义(P<0.05)。多因素分析结果提示,年龄(β=0.266,OR=1.304,95%CI=1.136~1.498)、HbA1c(β=0.838,OR=2.312,95%CI=1.269~4.212)、LDL-C(β=1.662,OR=5.269,95%CI=2.178~12.745)是AIS患者预后不良的危险因素(P<0.05)。结论年龄、HbA1c、LDL-C是AIS患者预后不良的危险因素。可根据上述因素进行针对性干预,以期减少AIS患者预后不良的发生率。

冠心病患者PCI术后5年再入院ISR发生危险因素分析

目的研究冠心病患者接受冠状动脉支架植入术后5年再入院患者发生支架内再狭窄(ISR)的危险因素。方法以2016年1月~2017年12月在火箭军特色医学中心首次接受药物洗脱支架植入术并于术后5年再次在中心接受冠状动脉造影的103例冠心病患者作为研究对象。根据冠状动脉造影结果,将他们分为支架内再狭窄(ISR)组(n=49)和非ISR组(n=54)。采用单因素分析比较两组之间的相关临床数据,并对具有统计学意义的有关因素进行Logistic回归分析。结果ISR组的低密度脂蛋白胆固醇(LDL-C)(P<0.05)、糖化血红蛋白(P<0.05)、D-二聚体水平(P<0.01)高于非ISR组,ISR组冠心病家族史比率、术后吸烟比率高于非ISR组(均P<0.05)。运用ROC曲线分析各因素对PCI术后ISR发生的预测价值,结果提示LDL-C在预测ISR存在时的ROC曲线下面积为0.943(P<0.01),最佳临界值为2.34 mmol/L,灵敏度为85.7%,特异度为94.4%;D-二聚体的ROC曲线下面积为0.778(P<0.01),最佳临界值为0.49μg/L,灵敏度为63.3%,特异度为85.2%;糖化血红蛋白的ROC曲线下面积为0.702(P<0.01),最佳临界值为7.45%,灵敏度为51.0%,特异度为98.1%。冠心病家族史的ROC曲线下面积为0.599(P=0.082),术后吸烟的ROC曲线下面积为0.716(P<0.01)。结论LDL-C、D-二聚体和糖化血红蛋白水平、冠心病家族史和术后吸烟是ISR的独立危险因素。

Glycation of high-density lipoprotein in type 2 diabetes mellitus

Objective To evaluate whether glycation of high-density lipoprotein （HDL） increases cardiovascular risk in patients with type 2 diabetes mellitus by altering its anti-atherogenic property.

Apolipoprotein A1,the neglected relative of Apolipoprotein E and its potential role in Alzheimer’s disease

Lipoproteins are multi-molecule assemblies with the primary function of transportation and processing of lipophilic substances within aqueous bodily fluids(blood,cerebrospinal fluid).Nevertheless,they also exert other physiological functions such as immune regulation.In particular,neurons are both sensitive to uncontrolled responses of the immune system and highly dependent on a controlled and sufficient supply of lipids.For this reason,the role of certain lipoproteins and their protein-component(apolipoproteins,Apo’s)in neurological diseases is perceivable.ApoE,for example,is well-accepted as one of the major risk factors for sporadic Alzheimer’s disease with a protective allele variant(ε2)and a risk-causing allele variant(ε4).ApoA1,the major protein component of high-density lipoproteins,is responsible for transportation of excess cholesterol from peripheral tissues to the liver.The protein is synthesized in the liver and intestine but also can enter the brain via the choroid plexus and thereby might have an impact on brain lipid homeostasis.This review focuses on the role of ApoA1 in Alzheimer’s disease and discusses whether its role within this neurodegenerative disorder is specific or represents a general neuroprotective mechanism.

Higher testosterone levels are associated with increased highdensity lipoprotein cholesterol in men with cardiovascular disease： results from the Massachusetts Male Aging Study

Aim： To study the relationship between circulating androgens （total testosterone [TT], free testosterone [IT] and dihydrotestosterone [DHT]） and high-density lipoprotein cholesterol （HDL-C） in men with and without cardiovascular disease （CVD）. Methods： Cross-sectional analyses included 1 661 baseline samples from the Massachusetts Male Aging Study （MMAS）, a population-based cohort of men ages 40-70 years. Serum hormones were measured by radioimmunoassay and HDL-C was determined following precipitation of the lower density lipoproteins. CVD was determined by self-report. Analyses were performed using multiple linear regression. Results： TT and HDL-C were positively correlated in the entire sample （r = 0.11, P = 0.0001）. After adjusting for confounders, we found this relationship was mostly limited to the 209 men with CVD. Among men with CVD, TT （P = 0.0004）, iT （P = 0.0172） and DHT （P = 0.0128） were all positively correlated with HDL-C, whereas in men without CVD only TT correlated with HDL-C （P = 0.0099）. Conclusion： Our results suggest that if androgens contribute to CVD in middle-aged men, the effect is not related to a suppressive effect of endogenous T on HDL-C. （Asian JAndrol 2008 Mar; 10： 193-200）

Lipoprotein in cholesterol transport: Highlights and recent insights into its structural basis and functional mechanism

Lipoproteins are protein-lipid macromolecular assemblies which are used to transport lipids in circulation and are key targets in cardiovascular disease （CVD）. The highly dynamic lipoprotein molecules are capable of adopting an array of conformations that is crucial to lipid transport along the cholesterol transport pathway, among which high-density lipopro- tein （HDL） and low-density lipoprotein （LDL） are major players in plasma cholesterol metabolism. For a more detailed illustration of cholesterol transport process, as well as the development of therapies to prevent CVD, here we review the functional mechanism and structural basis of lipoproteins in cholesterol transport, as well as their structural dynamics in the plasma lipoprotein （HDL and LDL） elevations, in order to obtain better quantitative understandings on structure-function relationship of lipoproteins. Finally, we also provide an approach for further research on the lipoprotein in cholesterol transport.