Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
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 atheroscleros...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.展开更多
Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive...Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke.Therefore,OLR1 is likely involved in the progress of intracerebral hemorrhage.In this study,we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model.OLR1 small interfering RNA(10μL;50 pmol/μL)was injected into the right basal ganglia to knock down OLR1.Twenty-four hours later,0.5 U collagenase type VII was injected to induce intracerebral hemorrhage.We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma,neuron loss,inflammatory reaction,and oxidative stress in rat brain tissue.We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway.Therefore,silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage.These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.展开更多
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） re...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.展开更多
Objective To investigate the association between low-density lipoprotein receptor-related protein 5 （LRPS） variants （rs12363572 and rs4930588） and type 2 diabetes mellitus （T2DM） in Han Chinese. Methods A total ...Objective To investigate the association between low-density lipoprotein receptor-related protein 5 （LRPS） variants （rs12363572 and rs4930588） and type 2 diabetes mellitus （T2DM） in Han Chinese. Methods A total of 1842 T2DM cases （507 newly diagnosed cases and 1335 previously diagnosed cases） and 7777 controls were included in this case-control study. PCR-RFLP was conducted to detect the genotype of the two single nucleotide polymorphisms （SNPs）. Odds ratios （ORs） and 95% confidence intervals （95% CIs） were calculated to describe the strength of the association by logistic regression. Results In the study subjects, neither rs12363572 nor rs4930588 was significantly associated with T2DM, even after adjusting for relevant covariates. When stratified by body mass index （BMI）, the two SNPs were also not associated with T2DM. Among the 3 common haplotypes, only haplotype ~ was associated with reduced risk of T2DM （OR 0.820, 95% CI 0.732-0.919）. In addition, rs12363572 was associated with BMI （P〈0.001） and rs4930588 was associated with triglyceride levels （P=0.043） in 507 newly diagnosed T2DM cases but not in healthy controls. Conclusion No LRP5 variant was found to be associated with T2DM in Han Chinese, but haplotype TT was found to be associated with T2DM.展开更多
To explore the functions of very low density lipoprotein receptor (VLDL-R) subtype II in lipoprotein metabolism and foam cells formation, the recombinant plasmid with the two subtypes cDNA was constructed respectively...To explore the functions of very low density lipoprotein receptor (VLDL-R) subtype II in lipoprotein metabolism and foam cells formation, the recombinant plasmid with the two subtypes cDNA was constructed respectively, the ldl-A7 cell lines were transfected and two cell lines expressing VLDL-R were obtained: one stably expressing the VLDLR with the O-linked sugar region (type I VLDLR) and the other without the O-linked sugar region (type II VLDLR). In the study on binding of VLDLR to their nuclein labeled natural ligands (VLDL and β-VLDL), it was found that surface binding of 125I-VLDL or 125I-β-VLDL of ldl-A7 cells transfected with type I VLDLR recombinant (ldl-A7-VRI) was more higher than that of ldl-A7 cells transfected with type II VLDLR recombinant (ldl-A7-VRII). After being incubated with VLDL for different time, the contents of triglyceride and total cholesterol in cells were mensurated, and the formation of foam cells and accumulation of lipid in cells was observed by oil-red O staining. The results showed that the contents of triglyceride and total cholesterol in ldl-A7-VR I were much higher than those in ldl-A7-VR II, and ldl-A7-VR I could transform into foam cells notably. It was suggested that type I VLDLR binds with relative higher affinity to VLDL and β-VLDL, and internalizes much more lipoprotein into cells. As a result, we can conclude that type I VLDLR plays a more important role in lipoprotein metabolism and foam cells formation than type II VLDLR.展开更多
Infection by hepatitis C virus(HCV), a plus-stranded RNA virus that can cause cirrhosis and hepatocellular carcinoma, is one of the major health problems in the world. HCV infection is considered as a multistep comple...Infection by hepatitis C virus(HCV), a plus-stranded RNA virus that can cause cirrhosis and hepatocellular carcinoma, is one of the major health problems in the world. HCV infection is considered as a multistep complex process and correlated with abnormal metabolism of lipoprotein. In addition, virus attacks hepatocytes by the initial attaching viral envelop glycoprotein E1/E2 to receptors of lipoproteins on host cells. With the development of HCV model system, mechanisms of HCV cell entry through lipoprotein uptake and its receptor have been extensively studied in detail. Here we summarize recent knowledge about the role of lipoprotein receptors, scavenger receptor class B type Ⅰ and low-density lipoprotein receptor in the entry of HCV, providing a foundation of novel targeting therapeutic tools against HCV infection.展开更多
Objectives Bai Ku Yao(White-trousers Yaos)is a special branch of Yao minority in China.They are now living in both Lihu and Baxu villages,Nandan County,Guangxi,China.The population size is about 30,000.The special cus...Objectives Bai Ku Yao(White-trousers Yaos)is a special branch of Yao minority in China.They are now living in both Lihu and Baxu villages,Nandan County,Guangxi,China.The population size is about 30,000.The special customs and culture of Bai Ku Yao,including their special clothing,intra-ethnic marriages and alcohol intake are still completely conserved to the present day.In previous epidemiologic studies,we found that the serum lipid levels and the prevalence of hyperlipidaemia were lower in Bai Ku Yao than in Han Chinese from the same region.This ethnic difference in serum lipid profiles is still not well known.We hypothesized that there may be significant differences in some genetic polymorphismsssociation of low density lipoprotein receptor(LDL-R)genepolymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 1024 subjects of Bai Ku Yao and 792 participants of Han Chinese were stud-ied by a stratified randomized cluster sampling.Epidemiological survey was carried out using internationally standardized methods.Information on demographics,socioeconomic status,and lifestyle factors was collected with standardized questionnaires.The height,weight,waist circumference,blood pressure,and serum total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),apolipoprotein(Apo)A1,and ApoB were measured.Body massindex(BMI,kg/m2)was calculated.Genotyping of the LDL-RAvaⅡwas performed by polymerse chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing.Results(l)The height,weight,serum TC,HDL-C,LDL-C,ApoAl levels and the ratio of ApoAl to ApoB were lower in Bai Ku Yao than in Han Chinese(P【0.01 for all),whereas the percentage of subjects who consumed alcohol or smoked cigarettes was higher in Bai Ku Yao than in Han Chinese(P【0.01 for each).(2)The frequency of A+allele in Bai Ku Yao was 34.5%,and the frequencies of A-A-,A-A+and A+A+genotypes were 42.6%,45.9%and 11.5%;respectively.The frequency of A+allele in Han Chinese was 19.3%(P【0.001),and the frequencies of A-A-,A-A+and A+A+genotypes were 64.9%,31.6%and 3.5%(P【0.001);respectively.The frequencies of A-A-,A-A+and A+A+genotypes in Bai Ku Yao were significant difference between males and females,between normal TC and high TC subgroup,and between normal LDL-C and high LDL-C subgroup(P【0.05 for all),whereas the frequencies of A-and A+?alleles in Han Chinese were significant difference between males and females(P【0.05).(3)Serum LDL-C levels in Bai Ku Yao were significant difference among the A-A-,A-A+and A+A+genotypes(P【0.05),the A+carriers had higher serum LDL-C levels.Serum HDL-C levels in Han Chiese were significant difference among the A-A-,A-A+and A+A+genotypes(P【0.01),the A+carriers had higher serum HDL-C levels.(4)After adjusting other factors,the prevalence of LDL-C abnormality was still higher in Han Chiese than in Bai Ku Yao.The prevalence of TC abnormality in Han Chinese was almost twice high as in Bai Ku Yao.The age and diet were common risk factor for TC abnormality.No effect of AvaⅡgenotype or alcohol consumption on the TC abnormality was found,but the combination of geno-type and alcohol consumption can increase the prevalence of TC abnormality[Exp(B)=(1.154)].Age was negatively cor-related with TG level.Conclusions Serum TC and LDL-C levels were lower in Bai Ku Yao than in Han Chinese.There were significant differences in the AvaⅡallele and genotype frequencies between the he A+carriers in Bai Ku Yao had higher serum LDL-C levels,whereas the A+carriers in Han had higher serum HDL-C levels.Interactions between alcohol consumption or cigarette smoking and the LDL-R AvaⅡgenotype were also observed.The differences in the serum lipid profiles between the two ethnic groups might partly result from different genotypic frequency of LDL-R AvaⅡpolymorphism or differentgene-enviromental interactions.Bai Ku Yao and Han population,the frequency of A+allele was higher in Bai Ku Yao than in Han.T between the two ethnic groups.Therefore,the aim of the present study was to detect the.展开更多
Objective To investigate the inhibitory effects of aqueous turmeric extract (AqT) and serum of rats orally treated with ethanol extract of turmeric (SeT) on proliferation of vascular smooth muscle cells (VSMC) and i...Objective To investigate the inhibitory effects of aqueous turmeric extract (AqT) and serum of rats orally treated with ethanol extract of turmeric (SeT) on proliferation of vascular smooth muscle cells (VSMC) and its effects on the expression of low density lipoprotein receptor (LDL R) antigen on the surface of smooth muscle cells. Methods Enzyme linked immunosorbent assay (ELISA) for the expression of LDL R protein and thiazolyl blue (MTT) assay for the proliferation of VSMC were used in this study. Results Both aqueous turmeric extract (AqT) and serum of rats orally treated with ethanol extract of turmeric (SeT) could inhibit 10% serum activated proliferation of VSMC. The inhibition shown in both experiments was dose dependent with an inhibitory rate of 18.9% at 20 mg/ml AqT and rate of 20.1% at 10% SeT respectively. AqT up regulated the expression of LDL R protein with a highest rate at 5 mg/ml AqT in 3% lipoprotein deficient serum (LPDS). SeT did not show significant effect on the expression of LDL R on the surface of VSMC. Conclusion The extracts of turmeric may be extended to decrease the risk of atherosclerosis (AS).展开更多
Background Low-density lipoprotein （LDL） receptor is normally regulated via a feedback system that is dependent on intracellular cholesterol levels. We have demonstrated that cytokines disrupt cholesterol-mediated L...Background Low-density lipoprotein （LDL） receptor is normally regulated via a feedback system that is dependent on intracellular cholesterol levels. We have demonstrated that cytokines disrupt cholesterol-mediated LDL receptor feedback regulation causing intracellular accumulation of unmodified LDL in peripheral cells. Liver is the central organ for lipid homeostasis. The aim of this study was to investigate the regulation of cholesterol exogenous uptake via LDL receptor and its underlying mechanisms in human hepatic cell line （HepG2） cells under physiological and inflammatory conditions. Methods Intracellular total cholesterol （TC）, free cholesterol （FC） and cholesterol ester （CE） were measured by an enzymic assay. Oil Red O staining was used to visualize lipid droplet accumulation in cells. Total cellular RNA was isolated from cells for detecting LDL receptor, sterol regulatory element binding protein （SREBP）-2 and SREBP cleavage-activating protein （SCAP） mRNA levels using real-time quantitative PCR. LDL receptor and SREBP-2 protein expression were examined by Western blotting. Confocal microscopy was used to investigate the translocation of SCAP-SREBP complex from the endoplasmic reticulum （ER） to the Golgi by dual staining with anti-human SCAP and anti-Golgin antibodies. Results LDL loading increased intracellular cholesterol level, thereby reduced LDL receptor mRNA and protein expression in HepG2 cells under physiological conditions. However, interleukin 1β （IL-1β） further increased intracellular cholesterol level in the presence of LDL by increasing both LDL receptor mRNA and protein expression in HepG2. LDL also reduced the SREBP and SCAP mRNA level under physiological conditions. Exposure to IL-1β caused over-expression of SREBP-2 and also disrupted normal distribution of SCAP-SREBP complex in HepG2 by enhancing translocation of SCAP-SREBP from the ER to the Golgi despite a high concentration of LDL in the culture medium. Conclusions IL-1β disrupts cholesterol-mediated LDL receptor feedback regulation by enhancing SCAP-SREBP complex translocation from the ER to the Golgi, thereby increasing SREBP-2 mediated LDL receptor expression even in the presence of high concentration of LDL. This results in LDL cholesterol accumulation in hepatic cells via LDL receptor pathway under inflammatory stress.展开更多
Objective： To explore the polymorphism of low density lipoprotein receptor （LDL-R） genes Pvu Ⅱ end Ave Ⅱ in e population with phlegm-dampness constitution （PDC）. Methods： Polymorphism of LDL-R genes at Pvu Ⅱ ...Objective： To explore the polymorphism of low density lipoprotein receptor （LDL-R） genes Pvu Ⅱ end Ave Ⅱ in e population with phlegm-dampness constitution （PDC）. Methods： Polymorphism of LDL-R genes at Pvu Ⅱ end Ave Ⅱ of 48 persons with gentle constitution （GC） end 61 with PDC were analyzed with PCR-RELP technique, end their serum contents of lipids end glucose were determined end compared as well. Results： The A＋ ellelic end P- ellelic frequency were higher end the P＋ ellelic frequency was lower in subjects with PDC then those in subjects with GC, which were 0.3083 vs 0.1771, 0.9098 vs 0.7708 end 0.0902 vs 0.2292, respectively, ell showing significant difference between the two groups （P〈0.05）. Comparison of the two groups in serum levels of triglyceride （TG）, fasting blood glucose, 2 h postprandial blood glucose, end 2 h postprandial insulin showed that ell the parameters were higher in subjects with PDC then in subjects with GC respectively, showing significant difference （P〈0.05）. Conclusion： PDC is related with the P- end A＋ ellelic frequency of higher LDL-R genes at Pvu Ⅱ end Ave Ⅱ, therefore, the polymorphism of LDL-R genes could be taken as one of the genetic markers for PDC, end humans with PDC ere more liable to suffer from blood lipids end glucose disorder then those with GC.展开更多
Alphaviruses are a group of important viruses that cause significant diseases in humans.Among them,Semliki Forest vi-rus(SFV)not only causes symptoms such as joint pain but also infects neuron cells and induces enceph...Alphaviruses are a group of important viruses that cause significant diseases in humans.Among them,Semliki Forest vi-rus(SFV)not only causes symptoms such as joint pain but also infects neuron cells and induces encephalitis in rodents.Recently,the very-low-density lipoprotein receptor(VLDLR)was identified as the cellular receptor for SFV entry.In this study,we present the cryo-electron microscopy structure of SFV bound to human VLDLR.VLDLR targets E1-DIII region of SFV using its membrane-distal LDLR class A(LA)repeats.Structural and functional analyses emphasize the synergistic role of multiple VLDLR repeats in the SFV entry.Remarkably,VLDLR’s binding mode to SFV closely mirrors that of minor group human rhinoviruses but differs significantly from other alphaviruses’interactions with receptors in the canyon re-gion of the E protein.We also assessed SFV binding to VLDLR or apolipoprotein E receptor 2(ApoER2)proteins in horses and mosquitoes and revealed their use of multiple but different LA repeats for binding.Our findings illuminate SFV’s cross-species infectivity,offering insights into potential antiviral strategies against alphavirus infections.展开更多
Objective: The objective of the study was to explore the regulatory mechanism of the Xiaozheng Tongluo method on lipid metabolism in liver tissue based on the sterol regulatory element-binding protein-2/(SREBP2)/3-hyd...Objective: The objective of the study was to explore the regulatory mechanism of the Xiaozheng Tongluo method on lipid metabolism in liver tissue based on the sterol regulatory element-binding protein-2/(SREBP2)/3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGCR)/low-density lipoprotein receptor(LDLR) signaling pathway. Materials and Methods: C57BL/6 mice were selected as the blank group. The apolipoprotein E-deficient(Apo E^(-/-)) mice were randomly divided into the model group, traditional Chinese medicine(TCM) group, and control group. The general condition of the mice was determined by the mouse's state and liver weight. Liver hematoxylin and eosin staining and Oil Red O staining were used to observe the pathological changes and lipid droplet deposition of the liver. The protein expression levels of SREBP2, HMGCR, and LDLR were detected by Western blotting and polymerase chain reaction. Results:(1) The rats in the model group were in poor condition, and their liver weight increased significantly. Compared with the model group, the condition of the TCM group and the control group improved to varying degrees, and their liver weight decreased significantly.(2) Compared with the normal group, the hepatocytes in the model group were arranged in a disorderly manner,and the red-stained lipids of stem cells increased significantly. Compared with the model group, the degree of liver lesions in the control group and TCM group was reduced, and the red-stained lipid of hepatocytes was significantly reduced.(3) Compared with the blank group, the expression of SREBP2 and HMGCR protein in the model group increased significantly, and the expression of LDLR protein decreased significantly(P < 0.05).Compared with the model group, the expression of SREBP2 and HMGCR protein in the TCM group decreased significantly, and the expression of LDLR protein increased significantly(P < 0.05). Conclusions: The method detailed in this paper can increase the expression of SREBP2 and HMGCR protein and decrease the expression of LDLR protein, thus regulating liver cholesterol metabolism and delaying the progression of atherosclerosis.展开更多
Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibrobl...Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibroblasts,neurons,astrocytes,macrophages,smooth muscle cells,and malignant cells.Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression.For example,LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase(MMP)-2and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor,the serine/threonine protein kinase signaling pathway,and the expression of Caspase-3.LRPI-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion.In addition,LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1CpG islands.Furthermore,a novel fusion gene,LRP1-SNRNP25,promotes osteosarcoma cell invasion and migration.Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.展开更多
The present study found that conditioned media from Kupffer cells preincubated with acetylated LDL or acetylated LDL and zymosan increased the number of HDL receptors on hepatocytes, using the method of conditioned me...The present study found that conditioned media from Kupffer cells preincubated with acetylated LDL or acetylated LDL and zymosan increased the number of HDL receptors on hepatocytes, using the method of conditioned media transfer. This indicated that the transferable factors produced by Kupffer cells modulate HDL receptors on hepatocytes.展开更多
Background Lipid abnormalities are often complicated by renal dysfunction. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the first-line choice for lowering cholesterol levels. The present ...Background Lipid abnormalities are often complicated by renal dysfunction. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the first-line choice for lowering cholesterol levels. The present study was designed to investigate whether statins could prevent and invert the development of renal injury in cholesterol-fed rabbits and to find the possible mechanism of their effects by detecting gene and protein expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the renal artery.Methods Twenty-four male New Zealand white rabbits were divided into three groups: (1) control group, regular granules chow; (2) HC-diet group, granules chow with 1% cholesterol and 5% lard oil; and (3) fluvastatin group, 1% cholesterol and 5% lard oil diet plus fluvastatin (10 mg·kg -1 ·d -1 ) . After 16 weeks, serum total cholesterol (TC), low-density lipoprotein(LDL) and creatinine (Cr) levels were measured. Renal hemodynamics and function, mainly including glomerular filtration rate (GFR) in vivo were quantified using 99m Tc-DTPA single photon emission computed tomograph ( 99m Tc-DTPA SPECT). The thickness of the renal artery intima was quantitated in HE-stained segments by histomorphometry. Gene expression of LOX-1 in the renal artery was examined by semi-quantitative RT-PCR and its protein expression was evaluated by immunohistochemistry.Results High cholesterol diet induced hypercholesterolemia (HC) complicated by renal dysfunction with increased levels of serum lipid and Cr, decreased GFR and delayed excretion and extensively thickened renal arterial intima in the HC-diet group. Rabbits in the control group showed a minimal LOX-1 expression (mRNA and protein) in the endothelium and neointima of the renal artery. Intimal proliferation of the renal artery in the HC-diet group was associated with a marked increase of LOX-1 expression (protein and mRNA). Treatment with fluvastatin improved renal function, attenuated intimal proliferation of the renal artery and markedly decreased the enhanced LOX-1 expression in the endothelium and neointima of the renal artery in rabbits. Conclusions Fuvastatin treatment could prevent the development of renal injury in patients with HC and early atherosclerosis (AS). This beneficial effect might be mediated by its pleiotropic effects including a decrease in total cholesterol exposure level and prevention of LOX-1 expression in atherosclerotic arteries.展开更多
Objective To review the recent research progress in lectin-like oxidized low-density lipoprotein receptor-1 （LOX-1） including its protein, ligands, expression and pathophysiological significance. Data sources Inform...Objective To review the recent research progress in lectin-like oxidized low-density lipoprotein receptor-1 （LOX-1） including its protein, ligands, expression and pathophysiological significance. Data sources Information included in this article was identified by searching of PUBMED （1997-2006） online resources using the key term LOX-1. Study selection Mainly original milestone articles and critical reviews written by major pioneer investigators of the field were selected. Results The key issues related to the LOX-1 protein as well as ligands for LOX-1. Factors regulating the expression of LOX-1 were summarized. The pathophysiological functions of LOX-1 in several diseases were discussed. Conclusions Identification of LOX-1 and a definition of its biological role in pathophysiologic states provide deeper insight into the pathogenesis of some cardiovascular diseases especially in atherosclerosis and provide a potential selective therapeutic approach. LOX-1 is unlocking and drugs targeting LOX-1 might be a promising direction to explore.展开更多
The role of very low density lipoprotein receptor (LVLDR) in the process of foam cell formation was investigated. After the primary cultured mouse peritoneal macrophages were incubated with VLDL, β VLDL or low densi...The role of very low density lipoprotein receptor (LVLDR) in the process of foam cell formation was investigated. After the primary cultured mouse peritoneal macrophages were incubated with VLDL, β VLDL or low density lipoprotein (LDL), respectively for 24 h and 48 h, foam cells formation was identified by oil red O staining and cellular contents of triglyceride (TG) and total cholesterol (TC) were determined. The mRNA levels of LDLR, LDLR related protein (LRP) and VLDLR were detected by semi quantitative RT PCR. The results demonstrated that VLDL, β VLDL and LDL could increase the contents of TG and TC in macrophages. Cells treated with VLDL or β VLDL showed markedly increased expression of VLDLR and decreased expression of LDLR, whereas LRP was up regulated slightly. For identifying the effect of VLDL receptor on cellular lipid accumulation, ldl A7 VR cells, which expresses VLDLR and trace amount of LRP without functional LDLR, was used to incubate with lipoproteins for further examination. The results elucidated that the uptake of triglyceride rich lipoprotein mediated by VLDLR plays an important role in accumulation of lipid and the formation of foam cells.展开更多
This study examined the effect of insulin on the expression of very low density lipoprotein receptor (VLDLR) subtypes of SGC7901 cells and discussed its biological implication.In vitro, moderately or poorly-differenti...This study examined the effect of insulin on the expression of very low density lipoprotein receptor (VLDLR) subtypes of SGC7901 cells and discussed its biological implication.In vitro, moderately or poorly-differentiated human gastric adenocarcinoma cell line SGC7901 was incubated with insulin for different lengths of time, and then the expression of protein and RNA level in VLDLR subtypes were detected by Western blotting and real-time PCR, respectively.The results showed that, at certain time interval, insulin could down-regulate expression of type Ⅰ VLDLR and up-regulate the expression of type Ⅱ VLDLR in SGC7901 cells, at both protein and RNA level.We are led to conclude that insulin serves as a regulator in maintaining the balance between glucose and lipid metabolism in vivo, possibly through its effect on the differential expression of VLDLR subtypes.展开更多
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金D.W.Z.is a Scholar of the Alberta Heritage Foundation for Medical Research and is supported in part by a Canadian Institutes of Health Research New Investigator AwardZhang laboratory is supported by Canadian Foundation for Innovation,grants from a Grant-in-Aidfor Heart and Stroke Foundation of CanadaPfizer Canada, the Canadian Institutes of Health Research(MOP 93794), and Mazankowski Alberta Heart Institute
文摘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.
基金supported by the National Natural Science Foundation of China,No.81971125(to ZYH).
文摘Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke.Therefore,OLR1 is likely involved in the progress of intracerebral hemorrhage.In this study,we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model.OLR1 small interfering RNA(10μL;50 pmol/μL)was injected into the right basal ganglia to knock down OLR1.Twenty-four hours later,0.5 U collagenase type VII was injected to induce intracerebral hemorrhage.We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma,neuron loss,inflammatory reaction,and oxidative stress in rat brain tissue.We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway.Therefore,silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage.These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.
文摘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.
基金supported by the National Natural Science Foundation of China(No.81072359)Natural Science Foundation of Guangdong Province(No.S2013010016791)+1 种基金Science and Technology Development Foundation of Shenzhen(No.JCYJ20120613112221107 and JCYJ20130326110246234)Natural Science Foundation of Shenzhen University(No.801-00035911)
文摘Objective To investigate the association between low-density lipoprotein receptor-related protein 5 （LRPS） variants （rs12363572 and rs4930588） and type 2 diabetes mellitus （T2DM） in Han Chinese. Methods A total of 1842 T2DM cases （507 newly diagnosed cases and 1335 previously diagnosed cases） and 7777 controls were included in this case-control study. PCR-RFLP was conducted to detect the genotype of the two single nucleotide polymorphisms （SNPs）. Odds ratios （ORs） and 95% confidence intervals （95% CIs） were calculated to describe the strength of the association by logistic regression. Results In the study subjects, neither rs12363572 nor rs4930588 was significantly associated with T2DM, even after adjusting for relevant covariates. When stratified by body mass index （BMI）, the two SNPs were also not associated with T2DM. Among the 3 common haplotypes, only haplotype ~ was associated with reduced risk of T2DM （OR 0.820, 95% CI 0.732-0.919）. In addition, rs12363572 was associated with BMI （P〈0.001） and rs4930588 was associated with triglyceride levels （P=0.043） in 507 newly diagnosed T2DM cases but not in healthy controls. Conclusion No LRP5 variant was found to be associated with T2DM in Han Chinese, but haplotype TT was found to be associated with T2DM.
基金This project was supported by a grant from National Natu-ral Sciences Foundation of China (No .30300134)
文摘To explore the functions of very low density lipoprotein receptor (VLDL-R) subtype II in lipoprotein metabolism and foam cells formation, the recombinant plasmid with the two subtypes cDNA was constructed respectively, the ldl-A7 cell lines were transfected and two cell lines expressing VLDL-R were obtained: one stably expressing the VLDLR with the O-linked sugar region (type I VLDLR) and the other without the O-linked sugar region (type II VLDLR). In the study on binding of VLDLR to their nuclein labeled natural ligands (VLDL and β-VLDL), it was found that surface binding of 125I-VLDL or 125I-β-VLDL of ldl-A7 cells transfected with type I VLDLR recombinant (ldl-A7-VRI) was more higher than that of ldl-A7 cells transfected with type II VLDLR recombinant (ldl-A7-VRII). After being incubated with VLDL for different time, the contents of triglyceride and total cholesterol in cells were mensurated, and the formation of foam cells and accumulation of lipid in cells was observed by oil-red O staining. The results showed that the contents of triglyceride and total cholesterol in ldl-A7-VR I were much higher than those in ldl-A7-VR II, and ldl-A7-VR I could transform into foam cells notably. It was suggested that type I VLDLR binds with relative higher affinity to VLDL and β-VLDL, and internalizes much more lipoprotein into cells. As a result, we can conclude that type I VLDLR plays a more important role in lipoprotein metabolism and foam cells formation than type II VLDLR.
基金Supported by The Ministry of Education,Culture,Sports,Science and Technology to Hitomi Imachi,Koji Murao,Japan,Nos.24591352,15K09415National Natural Science Foundation of China to Huanxiang Zhang,Nos.31371407 and 31071220
文摘Infection by hepatitis C virus(HCV), a plus-stranded RNA virus that can cause cirrhosis and hepatocellular carcinoma, is one of the major health problems in the world. HCV infection is considered as a multistep complex process and correlated with abnormal metabolism of lipoprotein. In addition, virus attacks hepatocytes by the initial attaching viral envelop glycoprotein E1/E2 to receptors of lipoproteins on host cells. With the development of HCV model system, mechanisms of HCV cell entry through lipoprotein uptake and its receptor have been extensively studied in detail. Here we summarize recent knowledge about the role of lipoprotein receptors, scavenger receptor class B type Ⅰ and low-density lipoprotein receptor in the entry of HCV, providing a foundation of novel targeting therapeutic tools against HCV infection.
文摘Objectives Bai Ku Yao(White-trousers Yaos)is a special branch of Yao minority in China.They are now living in both Lihu and Baxu villages,Nandan County,Guangxi,China.The population size is about 30,000.The special customs and culture of Bai Ku Yao,including their special clothing,intra-ethnic marriages and alcohol intake are still completely conserved to the present day.In previous epidemiologic studies,we found that the serum lipid levels and the prevalence of hyperlipidaemia were lower in Bai Ku Yao than in Han Chinese from the same region.This ethnic difference in serum lipid profiles is still not well known.We hypothesized that there may be significant differences in some genetic polymorphismsssociation of low density lipoprotein receptor(LDL-R)genepolymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 1024 subjects of Bai Ku Yao and 792 participants of Han Chinese were stud-ied by a stratified randomized cluster sampling.Epidemiological survey was carried out using internationally standardized methods.Information on demographics,socioeconomic status,and lifestyle factors was collected with standardized questionnaires.The height,weight,waist circumference,blood pressure,and serum total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),apolipoprotein(Apo)A1,and ApoB were measured.Body massindex(BMI,kg/m2)was calculated.Genotyping of the LDL-RAvaⅡwas performed by polymerse chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing.Results(l)The height,weight,serum TC,HDL-C,LDL-C,ApoAl levels and the ratio of ApoAl to ApoB were lower in Bai Ku Yao than in Han Chinese(P【0.01 for all),whereas the percentage of subjects who consumed alcohol or smoked cigarettes was higher in Bai Ku Yao than in Han Chinese(P【0.01 for each).(2)The frequency of A+allele in Bai Ku Yao was 34.5%,and the frequencies of A-A-,A-A+and A+A+genotypes were 42.6%,45.9%and 11.5%;respectively.The frequency of A+allele in Han Chinese was 19.3%(P【0.001),and the frequencies of A-A-,A-A+and A+A+genotypes were 64.9%,31.6%and 3.5%(P【0.001);respectively.The frequencies of A-A-,A-A+and A+A+genotypes in Bai Ku Yao were significant difference between males and females,between normal TC and high TC subgroup,and between normal LDL-C and high LDL-C subgroup(P【0.05 for all),whereas the frequencies of A-and A+?alleles in Han Chinese were significant difference between males and females(P【0.05).(3)Serum LDL-C levels in Bai Ku Yao were significant difference among the A-A-,A-A+and A+A+genotypes(P【0.05),the A+carriers had higher serum LDL-C levels.Serum HDL-C levels in Han Chiese were significant difference among the A-A-,A-A+and A+A+genotypes(P【0.01),the A+carriers had higher serum HDL-C levels.(4)After adjusting other factors,the prevalence of LDL-C abnormality was still higher in Han Chiese than in Bai Ku Yao.The prevalence of TC abnormality in Han Chinese was almost twice high as in Bai Ku Yao.The age and diet were common risk factor for TC abnormality.No effect of AvaⅡgenotype or alcohol consumption on the TC abnormality was found,but the combination of geno-type and alcohol consumption can increase the prevalence of TC abnormality[Exp(B)=(1.154)].Age was negatively cor-related with TG level.Conclusions Serum TC and LDL-C levels were lower in Bai Ku Yao than in Han Chinese.There were significant differences in the AvaⅡallele and genotype frequencies between the he A+carriers in Bai Ku Yao had higher serum LDL-C levels,whereas the A+carriers in Han had higher serum HDL-C levels.Interactions between alcohol consumption or cigarette smoking and the LDL-R AvaⅡgenotype were also observed.The differences in the serum lipid profiles between the two ethnic groups might partly result from different genotypic frequency of LDL-R AvaⅡpolymorphism or differentgene-enviromental interactions.Bai Ku Yao and Han population,the frequency of A+allele was higher in Bai Ku Yao than in Han.T between the two ethnic groups.Therefore,the aim of the present study was to detect the.
文摘Objective To investigate the inhibitory effects of aqueous turmeric extract (AqT) and serum of rats orally treated with ethanol extract of turmeric (SeT) on proliferation of vascular smooth muscle cells (VSMC) and its effects on the expression of low density lipoprotein receptor (LDL R) antigen on the surface of smooth muscle cells. Methods Enzyme linked immunosorbent assay (ELISA) for the expression of LDL R protein and thiazolyl blue (MTT) assay for the proliferation of VSMC were used in this study. Results Both aqueous turmeric extract (AqT) and serum of rats orally treated with ethanol extract of turmeric (SeT) could inhibit 10% serum activated proliferation of VSMC. The inhibition shown in both experiments was dose dependent with an inhibitory rate of 18.9% at 20 mg/ml AqT and rate of 20.1% at 10% SeT respectively. AqT up regulated the expression of LDL R protein with a highest rate at 5 mg/ml AqT in 3% lipoprotein deficient serum (LPDS). SeT did not show significant effect on the expression of LDL R on the surface of VSMC. Conclusion The extracts of turmeric may be extended to decrease the risk of atherosclerosis (AS).
基金This study was supported by grants from the National Natural Science Foundation of China(Key Program,No.30530360)the National Basic Research Program of China(No.2006CB503907)Royal Free Hospital Special Trustees grant
文摘Background Low-density lipoprotein （LDL） receptor is normally regulated via a feedback system that is dependent on intracellular cholesterol levels. We have demonstrated that cytokines disrupt cholesterol-mediated LDL receptor feedback regulation causing intracellular accumulation of unmodified LDL in peripheral cells. Liver is the central organ for lipid homeostasis. The aim of this study was to investigate the regulation of cholesterol exogenous uptake via LDL receptor and its underlying mechanisms in human hepatic cell line （HepG2） cells under physiological and inflammatory conditions. Methods Intracellular total cholesterol （TC）, free cholesterol （FC） and cholesterol ester （CE） were measured by an enzymic assay. Oil Red O staining was used to visualize lipid droplet accumulation in cells. Total cellular RNA was isolated from cells for detecting LDL receptor, sterol regulatory element binding protein （SREBP）-2 and SREBP cleavage-activating protein （SCAP） mRNA levels using real-time quantitative PCR. LDL receptor and SREBP-2 protein expression were examined by Western blotting. Confocal microscopy was used to investigate the translocation of SCAP-SREBP complex from the endoplasmic reticulum （ER） to the Golgi by dual staining with anti-human SCAP and anti-Golgin antibodies. Results LDL loading increased intracellular cholesterol level, thereby reduced LDL receptor mRNA and protein expression in HepG2 cells under physiological conditions. However, interleukin 1β （IL-1β） further increased intracellular cholesterol level in the presence of LDL by increasing both LDL receptor mRNA and protein expression in HepG2. LDL also reduced the SREBP and SCAP mRNA level under physiological conditions. Exposure to IL-1β caused over-expression of SREBP-2 and also disrupted normal distribution of SCAP-SREBP complex in HepG2 by enhancing translocation of SCAP-SREBP from the ER to the Golgi despite a high concentration of LDL in the culture medium. Conclusions IL-1β disrupts cholesterol-mediated LDL receptor feedback regulation by enhancing SCAP-SREBP complex translocation from the ER to the Golgi, thereby increasing SREBP-2 mediated LDL receptor expression even in the presence of high concentration of LDL. This results in LDL cholesterol accumulation in hepatic cells via LDL receptor pathway under inflammatory stress.
基金Supported by the State Administration of TCM (No.2003LHR18)
文摘Objective： To explore the polymorphism of low density lipoprotein receptor （LDL-R） genes Pvu Ⅱ end Ave Ⅱ in e population with phlegm-dampness constitution （PDC）. Methods： Polymorphism of LDL-R genes at Pvu Ⅱ end Ave Ⅱ of 48 persons with gentle constitution （GC） end 61 with PDC were analyzed with PCR-RELP technique, end their serum contents of lipids end glucose were determined end compared as well. Results： The A＋ ellelic end P- ellelic frequency were higher end the P＋ ellelic frequency was lower in subjects with PDC then those in subjects with GC, which were 0.3083 vs 0.1771, 0.9098 vs 0.7708 end 0.0902 vs 0.2292, respectively, ell showing significant difference between the two groups （P〈0.05）. Comparison of the two groups in serum levels of triglyceride （TG）, fasting blood glucose, 2 h postprandial blood glucose, end 2 h postprandial insulin showed that ell the parameters were higher in subjects with PDC then in subjects with GC respectively, showing significant difference （P〈0.05）. Conclusion： PDC is related with the P- end A＋ ellelic frequency of higher LDL-R genes at Pvu Ⅱ end Ave Ⅱ, therefore, the polymorphism of LDL-R genes could be taken as one of the genetic markers for PDC, end humans with PDC ere more liable to suffer from blood lipids end glucose disorder then those with GC.
基金supported by the National Natural Science Foundation of China (82072290,82122040,and 32100129)supported by CAS Project for Young Scientists in Basic Research (YSBR-010)the Youth Innovation Promotion Association CAS (Y2021033).
文摘Alphaviruses are a group of important viruses that cause significant diseases in humans.Among them,Semliki Forest vi-rus(SFV)not only causes symptoms such as joint pain but also infects neuron cells and induces encephalitis in rodents.Recently,the very-low-density lipoprotein receptor(VLDLR)was identified as the cellular receptor for SFV entry.In this study,we present the cryo-electron microscopy structure of SFV bound to human VLDLR.VLDLR targets E1-DIII region of SFV using its membrane-distal LDLR class A(LA)repeats.Structural and functional analyses emphasize the synergistic role of multiple VLDLR repeats in the SFV entry.Remarkably,VLDLR’s binding mode to SFV closely mirrors that of minor group human rhinoviruses but differs significantly from other alphaviruses’interactions with receptors in the canyon re-gion of the E protein.We also assessed SFV binding to VLDLR or apolipoprotein E receptor 2(ApoER2)proteins in horses and mosquitoes and revealed their use of multiple but different LA repeats for binding.Our findings illuminate SFV’s cross-species infectivity,offering insights into potential antiviral strategies against alphavirus infections.
基金supported by the Science and Technology Support Program Project of the Hebei Provincial Department of Science and Technology (No. 19277753D)the Scientific Research Project of the Hebei Administration of TCM (No. 2019004, No. 2019066)
文摘Objective: The objective of the study was to explore the regulatory mechanism of the Xiaozheng Tongluo method on lipid metabolism in liver tissue based on the sterol regulatory element-binding protein-2/(SREBP2)/3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGCR)/low-density lipoprotein receptor(LDLR) signaling pathway. Materials and Methods: C57BL/6 mice were selected as the blank group. The apolipoprotein E-deficient(Apo E^(-/-)) mice were randomly divided into the model group, traditional Chinese medicine(TCM) group, and control group. The general condition of the mice was determined by the mouse's state and liver weight. Liver hematoxylin and eosin staining and Oil Red O staining were used to observe the pathological changes and lipid droplet deposition of the liver. The protein expression levels of SREBP2, HMGCR, and LDLR were detected by Western blotting and polymerase chain reaction. Results:(1) The rats in the model group were in poor condition, and their liver weight increased significantly. Compared with the model group, the condition of the TCM group and the control group improved to varying degrees, and their liver weight decreased significantly.(2) Compared with the normal group, the hepatocytes in the model group were arranged in a disorderly manner,and the red-stained lipids of stem cells increased significantly. Compared with the model group, the degree of liver lesions in the control group and TCM group was reduced, and the red-stained lipid of hepatocytes was significantly reduced.(3) Compared with the blank group, the expression of SREBP2 and HMGCR protein in the model group increased significantly, and the expression of LDLR protein decreased significantly(P < 0.05).Compared with the model group, the expression of SREBP2 and HMGCR protein in the TCM group decreased significantly, and the expression of LDLR protein increased significantly(P < 0.05). Conclusions: The method detailed in this paper can increase the expression of SREBP2 and HMGCR protein and decrease the expression of LDLR protein, thus regulating liver cholesterol metabolism and delaying the progression of atherosclerosis.
基金the National Natural Science Foundation of China(81372872 to J.Yang,81402215 to X.Du,and 81320108022 to K.Chen)funds from the University Cancer Foundation via the Sister Institution Network Fund at the Tianjin Medical University Cancer Institute and Hospital,Fudan University Shanghai Cancer Center,and University of Texas MD Anderson Cancer Centersupported by the program for Innovative Research Team in University in China(IRT1076 to K.Chen)
文摘Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibroblasts,neurons,astrocytes,macrophages,smooth muscle cells,and malignant cells.Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression.For example,LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase(MMP)-2and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor,the serine/threonine protein kinase signaling pathway,and the expression of Caspase-3.LRPI-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion.In addition,LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1CpG islands.Furthermore,a novel fusion gene,LRP1-SNRNP25,promotes osteosarcoma cell invasion and migration.Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.
文摘The present study found that conditioned media from Kupffer cells preincubated with acetylated LDL or acetylated LDL and zymosan increased the number of HDL receptors on hepatocytes, using the method of conditioned media transfer. This indicated that the transferable factors produced by Kupffer cells modulate HDL receptors on hepatocytes.
文摘Background Lipid abnormalities are often complicated by renal dysfunction. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the first-line choice for lowering cholesterol levels. The present study was designed to investigate whether statins could prevent and invert the development of renal injury in cholesterol-fed rabbits and to find the possible mechanism of their effects by detecting gene and protein expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the renal artery.Methods Twenty-four male New Zealand white rabbits were divided into three groups: (1) control group, regular granules chow; (2) HC-diet group, granules chow with 1% cholesterol and 5% lard oil; and (3) fluvastatin group, 1% cholesterol and 5% lard oil diet plus fluvastatin (10 mg·kg -1 ·d -1 ) . After 16 weeks, serum total cholesterol (TC), low-density lipoprotein(LDL) and creatinine (Cr) levels were measured. Renal hemodynamics and function, mainly including glomerular filtration rate (GFR) in vivo were quantified using 99m Tc-DTPA single photon emission computed tomograph ( 99m Tc-DTPA SPECT). The thickness of the renal artery intima was quantitated in HE-stained segments by histomorphometry. Gene expression of LOX-1 in the renal artery was examined by semi-quantitative RT-PCR and its protein expression was evaluated by immunohistochemistry.Results High cholesterol diet induced hypercholesterolemia (HC) complicated by renal dysfunction with increased levels of serum lipid and Cr, decreased GFR and delayed excretion and extensively thickened renal arterial intima in the HC-diet group. Rabbits in the control group showed a minimal LOX-1 expression (mRNA and protein) in the endothelium and neointima of the renal artery. Intimal proliferation of the renal artery in the HC-diet group was associated with a marked increase of LOX-1 expression (protein and mRNA). Treatment with fluvastatin improved renal function, attenuated intimal proliferation of the renal artery and markedly decreased the enhanced LOX-1 expression in the endothelium and neointima of the renal artery in rabbits. Conclusions Fuvastatin treatment could prevent the development of renal injury in patients with HC and early atherosclerosis (AS). This beneficial effect might be mediated by its pleiotropic effects including a decrease in total cholesterol exposure level and prevention of LOX-1 expression in atherosclerotic arteries.
文摘Objective To review the recent research progress in lectin-like oxidized low-density lipoprotein receptor-1 （LOX-1） including its protein, ligands, expression and pathophysiological significance. Data sources Information included in this article was identified by searching of PUBMED （1997-2006） online resources using the key term LOX-1. Study selection Mainly original milestone articles and critical reviews written by major pioneer investigators of the field were selected. Results The key issues related to the LOX-1 protein as well as ligands for LOX-1. Factors regulating the expression of LOX-1 were summarized. The pathophysiological functions of LOX-1 in several diseases were discussed. Conclusions Identification of LOX-1 and a definition of its biological role in pathophysiologic states provide deeper insight into the pathogenesis of some cardiovascular diseases especially in atherosclerosis and provide a potential selective therapeutic approach. LOX-1 is unlocking and drugs targeting LOX-1 might be a promising direction to explore.
文摘The role of very low density lipoprotein receptor (LVLDR) in the process of foam cell formation was investigated. After the primary cultured mouse peritoneal macrophages were incubated with VLDL, β VLDL or low density lipoprotein (LDL), respectively for 24 h and 48 h, foam cells formation was identified by oil red O staining and cellular contents of triglyceride (TG) and total cholesterol (TC) were determined. The mRNA levels of LDLR, LDLR related protein (LRP) and VLDLR were detected by semi quantitative RT PCR. The results demonstrated that VLDL, β VLDL and LDL could increase the contents of TG and TC in macrophages. Cells treated with VLDL or β VLDL showed markedly increased expression of VLDLR and decreased expression of LDLR, whereas LRP was up regulated slightly. For identifying the effect of VLDL receptor on cellular lipid accumulation, ldl A7 VR cells, which expresses VLDLR and trace amount of LRP without functional LDLR, was used to incubate with lipoproteins for further examination. The results elucidated that the uptake of triglyceride rich lipoprotein mediated by VLDLR plays an important role in accumulation of lipid and the formation of foam cells.
基金supported by grants from National Natural Sciences Foundation of China (No.39970307)Hubei Provincial Natural Sciences Foundation of China (No.2005ABA092)
文摘This study examined the effect of insulin on the expression of very low density lipoprotein receptor (VLDLR) subtypes of SGC7901 cells and discussed its biological implication.In vitro, moderately or poorly-differentiated human gastric adenocarcinoma cell line SGC7901 was incubated with insulin for different lengths of time, and then the expression of protein and RNA level in VLDLR subtypes were detected by Western blotting and real-time PCR, respectively.The results showed that, at certain time interval, insulin could down-regulate expression of type Ⅰ VLDLR and up-regulate the expression of type Ⅱ VLDLR in SGC7901 cells, at both protein and RNA level.We are led to conclude that insulin serves as a regulator in maintaining the balance between glucose and lipid metabolism in vivo, possibly through its effect on the differential expression of VLDLR subtypes.
