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
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...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.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
Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capac...Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capacity of human peripheral blood monocytes to express MCP-1 and effects of native very low density lipoprotein (VLDL) and oxidized VLDL(OX-VLDL) on the expression. The total RNA was extracted from cultured monocytes, which were exposed to VLDL and OX-VLDL, and the media conditioned by monocytes were collected. MCP-1 mRNA expression was examined by Northern blot analysis. MCP-1 protein in conditioned media was determined by using sandwich ELISA. The results showed that monocytes can express MCP-1 after a 24 h incubation at 37℃，and the expression was markedly increased by a exposure to OX-VLDL, whereas the expression was slightly increased when exposed to VLDL. It suggests that the capacity of monocytes to produce MCP-1 that recruits and activates circulating monocytes may be of considerable importance in atherogenesis, and oxidation of VLDL enhances its potential to promote atherogenesis.展开更多
Nonalcoholic fatty liver disease （NAFLD）, an pathologies characterized by fatty accumulation in escalating health problem worldwide, covers a spectrum of hepatocytes in early stages, with potential progression to li...Nonalcoholic fatty liver disease （NAFLD）, an pathologies characterized by fatty accumulation in escalating health problem worldwide, covers a spectrum of hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellu- lar role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metab- olism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD.展开更多
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...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.展开更多
报告一例常染色体隐性遗传发病的骨质疏松症-假性胶质瘤综合征。先证者女性,23岁,父母非近亲结婚,出生后发现双目失明,婴儿期因发现右眼视网膜母细胞瘤行右眼球摘除术,9岁开始反复发生轻微外力骨折,诊断为成骨不全。查体发现脊柱侧凸畸...报告一例常染色体隐性遗传发病的骨质疏松症-假性胶质瘤综合征。先证者女性,23岁,父母非近亲结婚,出生后发现双目失明,婴儿期因发现右眼视网膜母细胞瘤行右眼球摘除术,9岁开始反复发生轻微外力骨折,诊断为成骨不全。查体发现脊柱侧凸畸形、胸廓畸形、双上肢肘外翻、四肢关节韧带松弛。双能X线吸收检测仪(dual energy X-ray absorptiometry,DXA)骨密度明显低于同龄人,腰椎1-4骨密度Z值-5,左髋骨密度Z值-1.8。X线摄片示全身骨小梁稀疏。Sanger测序显示低密度脂蛋白受体相关蛋白-5(lowdensity lipoprotein receptor-related protein 5,LRP5)基因的6号外显子和23号外显子发生复合杂合突变,导致p.Pro382Leu+p.Cys1611LeufsX33。本文通过文献复习对该病的临床表现和诊疗特点进行讨论及总结,以期帮助临床医生提高对这一疾病的认识。展开更多
目的分析低密度脂蛋白受体相关蛋白5(low density lipoprotein receptor related protein 5,LRP5)rs556442、rs312778位点基因多态性及突变在绝经后女性2型糖尿病(type 2 diabetes mellitus,T2DM)患者中骨量异常的意义。方法收集2021年...目的分析低密度脂蛋白受体相关蛋白5(low density lipoprotein receptor related protein 5,LRP5)rs556442、rs312778位点基因多态性及突变在绝经后女性2型糖尿病(type 2 diabetes mellitus,T2DM)患者中骨量异常的意义。方法收集2021年5月至2023年5月新疆石河子地区的142例绝经后女性资料进行回顾性分析,分为正常对照组(A组,n=29)、T2DM组(B组,n=30)、骨量降低组(C组,n=28)、骨量降低+T2DM组(D组,n=55)。收集记录相关基线资料,运用全自动生化测定仪测定受试者血糖、血脂及骨代谢指标。通过双能X线骨密度仪测定骨密度(bone mineral density BMD),LRP5基因位点多态性采用飞行时间质谱法(MALDI-TOF-MS)测定,采用SNPscan技术对上述SNP位点进行基因分型。结果①四组基线资料比较,绝经年限、年龄及腰臀比(waist hip ratio,WHR)比较差异具有统计学意义(P<0.05);②与A组相比,B组的空腹血糖(FPG)、糖化血红蛋白(HbA1c)升高(P<0.05);D组的FPG、HbA1c的血清学水平升高,甘油三酯(TG)血清学水平降低(P<0.05);③rs556442位点:与A组相比,D组基因型分布(AA/AG/GG基因型)有统计学意义(P<0.05);rs312778位点组间基因型(CC/CT/TT基因型)及等位基因分布频率均无统计学意义(P>0.05);④rs556442位点:与AA基因型相比,B、C组AG/GG基因型的股骨颈BMD水平降低;D组AG/GG型的HDL血清学水平降低(P<0.05)。rs312778位点:与CC基因型相比,A组HbA1C、FPG血清学水平较CT/TT基因型低(P<0.05);D组CT/TT基因型的低密度脂蛋白(LDL)血清学水平升高(P<0.05);⑤多元线性回归分析:rs556442位点,TG增加是腰L_(1~4)BMD降低的危险因素(P<0.05);rs312778位点,体质量指数(body mass index,BMI)降低是腰L_(1~4)及股骨颈BMD降低的危险因素,TG增加是腰L_(1~4)BMD降低的危险因素(P<0.05);⑥在rs556442、rs312778位点骨量异常与基因型分布均无统计学意义(P>0.05)。结论新疆石河子地区绝经后T2DM女性患者LRP5基因rs556442、rs312778基因位点的突变可能与骨量降低有关。展开更多
目的探讨微小RNA-370-3p(miR-370-3p)和低密度脂蛋白受体相关蛋白6(LRP6)对胎儿生长受限(FGR)孕妇的临床诊断价值。方法选取2020年6月—2022年6月期间产检并确诊为FGR的孕妇96例为观察组,另选取同期产检的健康孕妇96例作为对照组,记录...目的探讨微小RNA-370-3p(miR-370-3p)和低密度脂蛋白受体相关蛋白6(LRP6)对胎儿生长受限(FGR)孕妇的临床诊断价值。方法选取2020年6月—2022年6月期间产检并确诊为FGR的孕妇96例为观察组,另选取同期产检的健康孕妇96例作为对照组,记录两组分娩孕周、1 min Apgar评分、5 min Apgar评分、新生儿体重、胎盘质量,依据美国妇产科学院(ACOG)标准将观察组划分为FGR组、严重FGR组。qRT-PCR法检测血清miR-370-3p和LRP6 mRNA表达水平;血清miR-370-3p和LRP6 mRNA水平与分娩孕周、1 min Apgar评分、5 min Apgar评分、新生儿体重、胎盘质量的相关性采用Pearson法分析;miR-370-3p和LRP6 mRNA对FGR的诊断价值采用ROC曲线评估。结果两组孕妇年龄、分娩孕周、是否初产的比例差异有统计学意义(P<0.05);观察组miR-370-3p显著高于对照组,LRP6显著低于对照组(P<0.05);严重FGR组miR-370-3p显著高于FGR组,LRP6显著低于FGR组(P<0.05);对照组与观察组新生儿体重、1 min Apgar评分、5 min Apgar评分及胎盘质量之间差异有统计学意义(P<0.05);miR-370-3p与LRP6之间呈负相关(r=-0.692,P<0.05),miR-370-3p与分娩孕周、新生儿体重、1 min Apgar评分、5 min Apgar评分、胎盘质量均呈负相关(r=-0.401、-0.382、-0.425、-0.484、-0.504,均P<0.05),LRP6与分娩孕周、新生儿体重、1 min Apgar评分、5 min Apgar评分、胎盘质量均呈正相关(r=0.306、0.412、0.512、0.612、0.419,均P<0.05);ROC曲线显示,miR-370-3p对FGR诊断的AUC为0.877(95%CI:0.821~0.919),截断值为1.40,其敏感度、特异性分别为67.71%、93.75%;LRP6对FGR诊断的AUC为0.838(95%CI:0.778~0.887),截断值为0.83,其敏感度、特异性分别为84.37%、71.87%;二者联合对FGR诊断的AUC为0.923(95%CI:0.875~0.956),明显高于二者单独诊断(Z联合vs miR-370-3P=2.811、P=0.005;Z联合vs LRP6=3.372、P=0.001),其敏感度、特异性分别为85.42%、87.50%。结论FGR患者血清miR-370-3p高表达、LRP6低表达,二者联合对FGR具有一定诊断价值。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
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.
文摘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.
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Monocyte chemoattractant protein-1(MCP-1), a potent chemoattractant, is thought to play an important role in migration of monocytes into atherosclerotic lesions. The present study was designed to investigate the capacity of human peripheral blood monocytes to express MCP-1 and effects of native very low density lipoprotein (VLDL) and oxidized VLDL(OX-VLDL) on the expression. The total RNA was extracted from cultured monocytes, which were exposed to VLDL and OX-VLDL, and the media conditioned by monocytes were collected. MCP-1 mRNA expression was examined by Northern blot analysis. MCP-1 protein in conditioned media was determined by using sandwich ELISA. The results showed that monocytes can express MCP-1 after a 24 h incubation at 37℃，and the expression was markedly increased by a exposure to OX-VLDL, whereas the expression was slightly increased when exposed to VLDL. It suggests that the capacity of monocytes to produce MCP-1 that recruits and activates circulating monocytes may be of considerable importance in atherogenesis, and oxidation of VLDL enhances its potential to promote atherogenesis.
文摘Nonalcoholic fatty liver disease （NAFLD）, an pathologies characterized by fatty accumulation in escalating health problem worldwide, covers a spectrum of hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellu- lar role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metab- olism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11504287 and 11774279)
文摘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.
文摘报告一例常染色体隐性遗传发病的骨质疏松症-假性胶质瘤综合征。先证者女性,23岁,父母非近亲结婚,出生后发现双目失明,婴儿期因发现右眼视网膜母细胞瘤行右眼球摘除术,9岁开始反复发生轻微外力骨折,诊断为成骨不全。查体发现脊柱侧凸畸形、胸廓畸形、双上肢肘外翻、四肢关节韧带松弛。双能X线吸收检测仪(dual energy X-ray absorptiometry,DXA)骨密度明显低于同龄人,腰椎1-4骨密度Z值-5,左髋骨密度Z值-1.8。X线摄片示全身骨小梁稀疏。Sanger测序显示低密度脂蛋白受体相关蛋白-5(lowdensity lipoprotein receptor-related protein 5,LRP5)基因的6号外显子和23号外显子发生复合杂合突变,导致p.Pro382Leu+p.Cys1611LeufsX33。本文通过文献复习对该病的临床表现和诊疗特点进行讨论及总结,以期帮助临床医生提高对这一疾病的认识。
文摘目的分析低密度脂蛋白受体相关蛋白5(low density lipoprotein receptor related protein 5,LRP5)rs556442、rs312778位点基因多态性及突变在绝经后女性2型糖尿病(type 2 diabetes mellitus,T2DM)患者中骨量异常的意义。方法收集2021年5月至2023年5月新疆石河子地区的142例绝经后女性资料进行回顾性分析,分为正常对照组(A组,n=29)、T2DM组(B组,n=30)、骨量降低组(C组,n=28)、骨量降低+T2DM组(D组,n=55)。收集记录相关基线资料,运用全自动生化测定仪测定受试者血糖、血脂及骨代谢指标。通过双能X线骨密度仪测定骨密度(bone mineral density BMD),LRP5基因位点多态性采用飞行时间质谱法(MALDI-TOF-MS)测定,采用SNPscan技术对上述SNP位点进行基因分型。结果①四组基线资料比较,绝经年限、年龄及腰臀比(waist hip ratio,WHR)比较差异具有统计学意义(P<0.05);②与A组相比,B组的空腹血糖(FPG)、糖化血红蛋白(HbA1c)升高(P<0.05);D组的FPG、HbA1c的血清学水平升高,甘油三酯(TG)血清学水平降低(P<0.05);③rs556442位点:与A组相比,D组基因型分布(AA/AG/GG基因型)有统计学意义(P<0.05);rs312778位点组间基因型(CC/CT/TT基因型)及等位基因分布频率均无统计学意义(P>0.05);④rs556442位点:与AA基因型相比,B、C组AG/GG基因型的股骨颈BMD水平降低;D组AG/GG型的HDL血清学水平降低(P<0.05)。rs312778位点:与CC基因型相比,A组HbA1C、FPG血清学水平较CT/TT基因型低(P<0.05);D组CT/TT基因型的低密度脂蛋白(LDL)血清学水平升高(P<0.05);⑤多元线性回归分析:rs556442位点,TG增加是腰L_(1~4)BMD降低的危险因素(P<0.05);rs312778位点,体质量指数(body mass index,BMI)降低是腰L_(1~4)及股骨颈BMD降低的危险因素,TG增加是腰L_(1~4)BMD降低的危险因素(P<0.05);⑥在rs556442、rs312778位点骨量异常与基因型分布均无统计学意义(P>0.05)。结论新疆石河子地区绝经后T2DM女性患者LRP5基因rs556442、rs312778基因位点的突变可能与骨量降低有关。
文摘目的探讨微小RNA-370-3p(miR-370-3p)和低密度脂蛋白受体相关蛋白6(LRP6)对胎儿生长受限(FGR)孕妇的临床诊断价值。方法选取2020年6月—2022年6月期间产检并确诊为FGR的孕妇96例为观察组,另选取同期产检的健康孕妇96例作为对照组,记录两组分娩孕周、1 min Apgar评分、5 min Apgar评分、新生儿体重、胎盘质量,依据美国妇产科学院(ACOG)标准将观察组划分为FGR组、严重FGR组。qRT-PCR法检测血清miR-370-3p和LRP6 mRNA表达水平;血清miR-370-3p和LRP6 mRNA水平与分娩孕周、1 min Apgar评分、5 min Apgar评分、新生儿体重、胎盘质量的相关性采用Pearson法分析;miR-370-3p和LRP6 mRNA对FGR的诊断价值采用ROC曲线评估。结果两组孕妇年龄、分娩孕周、是否初产的比例差异有统计学意义(P<0.05);观察组miR-370-3p显著高于对照组,LRP6显著低于对照组(P<0.05);严重FGR组miR-370-3p显著高于FGR组,LRP6显著低于FGR组(P<0.05);对照组与观察组新生儿体重、1 min Apgar评分、5 min Apgar评分及胎盘质量之间差异有统计学意义(P<0.05);miR-370-3p与LRP6之间呈负相关(r=-0.692,P<0.05),miR-370-3p与分娩孕周、新生儿体重、1 min Apgar评分、5 min Apgar评分、胎盘质量均呈负相关(r=-0.401、-0.382、-0.425、-0.484、-0.504,均P<0.05),LRP6与分娩孕周、新生儿体重、1 min Apgar评分、5 min Apgar评分、胎盘质量均呈正相关(r=0.306、0.412、0.512、0.612、0.419,均P<0.05);ROC曲线显示,miR-370-3p对FGR诊断的AUC为0.877(95%CI:0.821~0.919),截断值为1.40,其敏感度、特异性分别为67.71%、93.75%;LRP6对FGR诊断的AUC为0.838(95%CI:0.778~0.887),截断值为0.83,其敏感度、特异性分别为84.37%、71.87%;二者联合对FGR诊断的AUC为0.923(95%CI:0.875~0.956),明显高于二者单独诊断(Z联合vs miR-370-3P=2.811、P=0.005;Z联合vs LRP6=3.372、P=0.001),其敏感度、特异性分别为85.42%、87.50%。结论FGR患者血清miR-370-3p高表达、LRP6低表达,二者联合对FGR具有一定诊断价值。
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.
