脂蛋白脂酶基因的研究进展

脂蛋白脂酶(lipoprotein lipase, LPL)是脂质代谢的关键酶, 主要催化乳糜微粒和极低密度脂蛋白中的甘油三酯水解, 产生供组织利用的脂肪酸和单酰甘油。LPL基因突变影响LPL活性, 导致脂质代谢紊乱, 与2型糖尿病、高血压、动脉硬化、肥胖、冠心病的发病风险相关联。文章综述了LPL基因的结构、功能、表达调控以及与复杂疾病的关联研究进展。     

脂蛋白酯酶在动脉粥样硬化发生发展中的作用

脂蛋白酯酶(lipoprotein lipase,LPL)是调节甘油三酯代谢的关键酶,在动脉粥样硬化(atherosclerosis,As)的发生发展中起重要作用.LPL产生部位的差异决定了其具有促As作用还是抗As作用.其次,不同因素对LPL的调控也会使LPL对As产生相反的作用效果.本文综述了LPL在As发生发展中...     

miRNAs与脂蛋白酯酶

miRNAs是一类具有调控基因功能的非编码RNAs,它在细胞核中合成,可转运至细胞质,调控脂质代谢相关性疾病的发生发展。脂蛋白酯酶(lipoprotein lipase,LPL)作为甘油三酯水解的限速酶,由心肌、脂肪、骨骼肌、乳腺及巨噬细胞等实质细胞合成和分泌,在脂蛋白转运和脂质代谢过程中发挥重要作用。近期研究证实多种miRNAs,包括miR-29、miR-467b、miR-590、miR-27、miR-134和miR-186,可通过调控脂蛋白酯酶LPL的表达,进而影响脂质代谢。为了深入探讨miRNAs对LPL的影响,本文以miRNAs对LPL的调控作用进行综述,期望以miRNAs为靶点,为脂质代谢相关性疾病的防治提供治疗方案。     

脂蛋白脂酶基因与代谢综合征关系的研究进展

脂蛋白脂酶是脂质代谢的关键酶之一,是血浆中清除甘油三酯的限速酶,主要催化乳糜微粒和极低密度脂蛋白核心中的甘油三酯水解,使得机体能够利用由食物摄取和肝脏合成的脂肪,同时释放出脂肪酸和单酰甘油.脂蛋白脂酶基因突变可以影响脂蛋白脂酶的活性,从而导致脂代谢紊乱,与肥胖、胰岛素抵抗、2型糖尿痛和高血压的发病风险相关.本文综述了脂蛋白脂酶的结构、功能、基因结构及其多态性与血脂和代谢综合征关系的研究进展.     

海水鱼真鲷脂蛋白脂肪酶基因cDNA序列与组织表达

为研究脊椎动物真鲷脂蛋白脂肪酶 (LPL)结构与功能关系以及探讨动脉粥样硬化形成机理 ,通过构建cDNA文库 ,克隆对动脉粥样硬化表现抗性的海水鱼真鲷LPL基因cDNA全序列 .再通过PCR方法扩增基因组DNA ,获取内含子 9及其两侧序列以确定外显子 10的大小 ,最后通过RT PCR ,以 β肌动蛋白为外参照 ,比较真鲷在食用两种脂肪含量不同饲料和摄食状态不同的处理条件下 ,肝脏和腹腔肠系膜脂肪组织LPLmRNA的相对水平 .从腹腔肠系膜脂肪组织cDNA文库中克隆出LPLcDNA序列 ,其完整的开放阅读框架由 15 36bp组成 ,编码 5 11个氨基酸残基 .与哺乳类不同 ,真鲷LPL基因外显子 10的开始部分是翻译的 .LPL的催化位点、二硫键位点、N 糖基化位点、肝素结合区、脂质结合位点、介导脂蛋白与低密度脂蛋白受体结合位点、二聚体形成位点等主要功能域在真骨鱼类真鲷与其它脊椎动物间基本保守 ,但肝素结合区的碱性氨基酸残基含量较人类减少 ,并在结合脂质底物的疏水环套中出现插入片段 .与哺乳类不同 ,真鲷LPL基因在成体肝脏存在诱导性表达 ,而在其腹腔肠系膜脂肪组织则存在与哺乳类相似的组成性表达 .当真鲷喂食高脂饲料时 ,其饱食状态下肝脏LPLmRNA水平升高 ,但对其腹腔肠系膜脂肪组织LPL表达没有影响 .当真鲷喂食标准商业饲料时 ,     

脂蛋白脂酶调控因子研究进展

脂蛋白脂酶(Lipoprotein lipase, LPL)是脂质代谢的关键酶, 其正常调控对于机体向组织提供脂质营养至关重要。作为LPL重要的调控因子, 糖基化磷脂酰肌醇锚定高密度脂蛋白结合蛋白1(Glycosylphosphatidylinositol- anchored high density lipoprotein-binding protein 1, GPIHBP1)能与LPL结合起脂解平台的作用, 并作为载体参与LPL向毛细血管内皮细胞的转运。另外, 近年来也鉴定出其他几个LPL活性调控因子, 包括microRNAs、A型重复排序蛋白相关受体(Sortilin-related receptor with A-type repeats, SorLA)和载脂蛋白(Apolipoproteins, apo)。这些LPL调控因子的成功鉴定, 有助于人们深入认识机体脂解代谢和乳糜微粒血症发生的内在机制。文章重点综述了LPL的调控因子GPIHBP1的研究进展, 同时也对其他几个调控因子的研究进展进行了讨论。     

糖基化磷脂酰肌醇锚定高密度脂蛋白结合蛋白1——影响血浆甘油三酯代谢的新基因

近年研究发现,脂蛋白脂酶(lipoprotein lipase,LPL)水解血浆富含甘油三酯的脂蛋白这一脂解过程中,糖基化磷脂酰肌醇锚定高密度脂蛋白结合蛋白1(glycosylphosphatidylinositol-anchoredhigh density lipoprotein-binding protein 1,GPIHBP1)起到了非常重要的作用。它能够结合LPL和乳糜微粒,发挥脂解平台的作用;同时它也参与LPL向毛细血管内皮细胞的转运。GPIHBP1基因敲除小鼠和GPIHBP1基因突变的病人发生严重高乳糜微粒血症。GPIHBP1的发现丰富了人们对于血浆脂蛋白代谢的认识,并为治疗高乳糜微粒血症提供了新的途径。     

脂蛋白脂酶与疾病的关系及中药对脂蛋白脂酶的作用

脂蛋白脂酶(lipoprotcin lipase,LPL)是脂质代谢的关键酶,主要水解甘油三酯,在乳糜微粒及极低密度脂蛋白的代谢中发挥重要作用.该酶的缺乏或活力异常,与血脂异常、代谢综合症、动脉粥样硬化、糖尿病、子痫前期等疾病有一定关系.一些具有调脂作用的中药能够影响脂蛋白脂酶的活力或表达.     

脂蛋白脂酶的调控及在动脉粥样硬化中的作用

脂蛋白脂酶(lipoprotein lipase,LPL,EC 3.1.1.34)是降解甘油三酯(triglyceride,TG)的限速酶,其活性降低是引起高甘油三酯血症的主要原因。LPL受到众多因素调控,包括血管生成素样蛋白、载脂蛋白、miRNAs和lncRNAs等。LPL是影响动脉粥样硬化(atherosclerosis,AS)发生发展的重要因素,其分布位置不同决定了LPL具有促AS或抗AS作用。该文重点阐述了LPL调控机制对AS的影响,有助于进一步揭示LPL在脂质代谢及AS发生发展中的作用。     

脂蛋白脂酶与糖尿病心肌病

脂蛋白脂酶(lipoprotein lipase,LPL)通过水解血浆中富含甘油三酯(triglyceride,TG)的脂蛋白,为心肌组织提供游离脂肪酸(free fatty acid,FFA)供能。糖尿病期间,由于心肌组织减弱对葡萄糖的利用能力,导致心脏供能不足。此时,机体通过一系列机制上调心肌LPL活性,促进血浆极低密度脂蛋白(very low density lipoprotein,VLDL)和乳糜微粒(chylomicrons,CM)的水解,以增强FFA为心肌组织代偿性供能。糖尿病患者通过上调心肌LPL活性,进而促使血浆FFA浓度显著升高,导致大量活性氧、脂质等在心肌细胞内蓄积,并潜在地诱发糖尿病心肌病(diabetic cardiomyopathy,DCM)。因此,本文主要针对糖尿病对心肌LPL的调控机制及LPL如何潜在地诱发DCM做一综述,以期为DCM提供新的治疗靶点和途径。     

Overexpression of lipoprotein lipase in transgenic rabbits inhibits diet-induced hypercholesterolemia and atherosclerosis

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of TG-rich lipoproteins. To elucidate the physiological roles of LPL in lipid and lipoprotein metabolism, we generated transgenic rabbits expressing human LPL. In postheparinized plasma of transgenic rabbits, the human LPL protein levels were about 650 ng/ml, and LPL enzymatic activity was found at levels up to 4-fold greater than that in nontransgenic littermates. Increased LPL activity in transgenic rabbits was associated with as much as an 80% decrease in plasma triglycerides and a 59% decrease in high density lipoprotein-cholesterol. Analysis of the lipoprotein density fractions revealed that increased expression of the LPL transgene resulted in a remarkable reduction in the level of very low density lipoproteins as well as in the level of intermediate density lipoproteins. In addition, LDL cholesterol levels in transgenic rabbits were significantly increased. When transgenic rabbits were fed a cholesterol-rich diet, the development of hypercholesterolemia and aortic atherosclerosis was dramatically suppressed in transgenic rabbits. These results demonstrate that systemically increased LPL activity functions in the metabolism of all classes of lipoproteins, thereby playing a crucial role in plasma triglyceride hydrolysis and lipoprotein conversion, and that overexpression of LPL protects against diet-induced hypercholesterolemia and atherosclerosis.     

Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle.

Hormone-sensitive lipase (HSL) is believed to play an important role in the mobilization of fatty acids from triglycerides (TG), diglycerides, and cholesteryl esters in various tissues. Because HSL-mediated lipolysis of TG in adipose tissue (AT) directly feeds non-esterified fatty acids (NEFA) into the vascular system, the enzyme is expected to affect many metabolic processes including the metabolism of plasma lipids and lipoproteins. In the present study we examined these metabolic changes in induced mutant mouse lines that lack HSL expression (HSL-ko mice). During fasting, when HSL is normally strongly induced in AT, HSL-ko animals exhibited markedly decreased plasma concentrations of NEFA (-40%) and TG (-63%), whereas total cholesterol and HDL cholesterol levels were increased (+34%). Except for the increased HDL cholesterol concentrations, these differences were not observed in fed animals, in which HSL activity is generally low. Decreased plasma TG levels in fasted HSL-ko mice were mainly caused by decreased hepatic very low density lipid lipoprotein (VLDL) synthesis as a result of decreased NEFA transport from the periphery to the liver. Reduced NEFA transport was also indicated by a depletion of hepatic TG stores (-90%) and strongly decreased ketone body concentrations in plasma (-80%). Decreased plasma NEFA and TG levels in fasted HSL-ko mice were associated with increased fractional catabolic rates of VLDL-TG and an induction of the tissue-specific lipoprotein lipase (LPL) activity in cardiac muscle, skeletal muscle, and white AT. In brown AT, LPL activity was decreased. Both increased VLDL fractional catabolic rates and increased LPL activity in muscle were unable to provide the heart with sufficient NEFA, which led to decreased tissue TG levels in cardiac muscle. Our results demonstrate that HSL deficiency markedly affects the metabolism of TG-rich lipoproteins by the coordinate down-regulation of VLDL synthesis and up-regulation of LPL in muscle and white adipose tissue. These changes result in an "anti-atherogenic" lipoprotein profile.     

Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV

Lipoprotein lipase (LPL)-mediated hydrolysis of triglycerides (TG) contained in chylomicrons requires the presence of a cofactor, apolipoprotein (apo) C-II. The physiological mechanism by which chylomicrons gain apoC-II necessary for LPL activation in whole plasma is not known. Using a gum arabic stabilized TG emulsion, activation of LPL by lipoprotein apoC-II was studied. Hydrolysis of TG by LPL was greater in the presence of serum than with addition of either high density lipoproteins (HDL) or very low density lipoproteins (VLDL). LPL activation by either VLDL or HDL increased with addition of the lipoprotein-free fraction of plasma. A similar increase in LPL activity by addition of the lipoprotein-free fraction together with HDL or VLDL was observed when another TG emulsion (Intralipid) or TG-rich lipoproteins from an apoC-II deficient subject were used as a substrate. Human apoA-IV, apoA-I, apoE, and cholesteryl ester transfer protein were assessed for their ability to increase LPL activity in the presence of VLDL. At and below physiological concentrations, only apoA-IV increased LPL activity. One hundred percent of LPL activity measured in the presence of serum was achieved using VLDL plus apoA-IV. In the absence of an apoC-II source, apoA-IV had no effect on LPL activity. Removal of greater than 80% of the apoA-IV from the nonlipoprotein-containing fraction of plasma by incubation with Intralipid markedly reduced its ability to activate LPL in the presence of VLDL or HDL. Gel filtration chromatography demonstrated that incubation of the nonlipoprotein-containing fraction of plasma with HDL and the TG emulsion caused increased transfer of apoC-II to the emulsion and association of apoA-IV with HDL. Our studies demonstrate that apoA-IV increases LPL activation in the presence of lipoproteins. We hypothesize that apoA-IV is required for efficient release of apoC-II from either HDL or VLDL, which then allows for LPL-mediated hydrolysis of TG in nascent chylomicrons.     

Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depending on its localization. Decreased plasma LPL activity is associated with the high triglyceride (TG);-low HDL phenotype that is often observed in patients with premature vascular disease. In contrast, in the vessel wall, decreased LPL may be associated with less lipoprotein retention due to many potential mechanisms and, therefore, decreased foam cell formation. To directly assess this hypothesis, we have distinguished between the effects of variations in plasma and/or vessel wall LPL on atherosclerosis susceptibility in apoE-deficient mice. Reduced LPL in both plasma and vessel wall (LPL(+/-)E(-/-)) was associated with increased TG and increased total cholesterol (TC) compared with LPL(+/+)E(-/-) sibs. However despite their dyslipidemia, LPL(+/-)E(-/-) mice had significantly reduced lesion areas compared to the LPL(+/+)E(-/-) mice. Thus, decreased vessel wall LPL was associated with decreased lesion formation even in the presence of reduced plasma LPL activity. In contrast, transgenic mice with increased plasma LPL but with no increase in LPL expression in macrophages, and thus the vessel wall, had decreased TG and TC and significantly decreased lesion areas compared with LPL(+/+)E(-/-) mice. This demonstrates that increased plasma LPL activity alone, in the absence of an increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis.Taken together, these results provide in vivo evidence that the contribution of LPL to atherogenesis is significantly influenced by the balance between vessel wall protein (pro-atherogenic) and plasma activity (anti-atherogenic).     

Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4

Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate.     

A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoE-deficient mice

KK/Snk mice (previously KK/San) possessing a recessive mutation (hypl) of the angiopoietin-like 3 (Angptl3) gene homozygously exhibit a marked reduction of VLDL due to the decreased Angptl3 expression. Recently, we proposed that Angptl3 is a new class of lipid metabolism modulator regulating VLDL triglyceride (TG) levels through the inhibition of lipoprotein lipase (LPL) activity. In this study, to elucidate the role of Angptl3 in atherogenesis, we investigated the effects of hypl mutation against hyperlipidemia and atherosclerosis in apolipoprotein E knockout (apoEKO) mice. ApoEKO mice with hypl mutation (apoEKO-hypl) exhibited a significant reduction of VLDL TG, VLDL cholesterol, and plasma apoB levels compared with apoEKO mice. Hepatic VLDL TG secretion was comparable between both apoE-deficient mice. Turnover studies revealed that the clearance of both [3H]TG-labeled and 125I-labeled VLDL was significantly enhanced in apoEKO-hypl mice. Postprandial plasma TG levels also decreased in apoEKO-hypl mice. Both LPL and hepatic lipase activities in the postheparin plasma increased significantly in apoEKO-hypl mice, explaining the enhanced lipid metabolism. Furthermore, apoEKO-hypl mice developed 3-fold smaller atherogenic lesions in the aortic sinus compared with apoEKO mice. Taken together, the reduction of Angptl3 expression is protective against hyperlipidemia and atherosclerosis, even in the absence of apoE, owing to the enhanced catabolism and clearance of TG-rich lipoproteins.     

Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice.

Lipoprotein lipase (LPL) is known to play a crucial role in lipoprotein metabolism by hydrolyzing triglycerides; however its role in atherogenesis has yet to be determined. We have previously shown that low density lipoprotein receptor knockout mice overexpressing LPL are resistant to diet-induced atherosclerosis due to the suppression of remnant lipoproteins. Plasma lipoproteins and atherosclerosis of apolipoprotein (apo) E knockout mice which overexpress the human LPL transgene (LPL/APOEKO) were compared with those of control apoE knockout mice (APOEKO). On a normal chow diet, LPL/APOEKO mice showed marked suppression of the plasma triglyceride levels compared with APOEKO mice (54 vs. 182 mg/dl), but no significant changes in plasma cholesterol and apoB levels. Non-high density lipoproteins (HDL) from LPL/APOEKO mice had lower triglyceride content, a smaller size, and a more positive charge compared with those from APOEKO mice. Cholesterol, apoA-I, and apoA-IV were increased in HDL. Although both groups developed hypercholesterolemia to a comparable degree in response to an atherogenic diet, the LPL/APOEKO mice developed 2-fold smaller fatty streak lesions in the aortic sinus compared to the APOEKO mice. In conclusion, overproduction of LPL is protective against atherosclerosis even in the absence of apoE.     

Activation of human post heparin lipoprotein lipase by apolipoprotein H (β2-glycoprotein I)

Lipoprotein lipase (LPL) is the major enzyme involved in triglyceride hydrolysis of lymph chylomicrons and plasma very low density lipoproteins. LPL can be isolated from human post heparin plasma by heparin-Sepharose 4B affinity chromatography. In the present study the effects of apolipoproteins (apo) C-II, C-III, and H on the enzymic activity of LPL were investigated. ApoH is a recently described protein (β₂-glycoprotein I) constituent of triglyceride rich lipoproteins in human lymph and plasma. Human LPL was activated by apoC-II, and the apoC-II activation of LPL was inhibited by apoC-III. ApoH increased the enzymic activity of LPL in the presence of apoC-II by 45±17 percent. ApoC-III decreased the apoH + apoC-II enhanced activity of LPL by 77 percent. These results provide evidence for the concept that the enzymic activity of LPL in triglyceride metabolism is modulated by apoH. The relative proportion of apoH, apoC-II, and apoC-III in triglyceride rich lipoprotein particles may determine the ultimate rate of LPL catalyzed triglyceride hydrolysis.     

Lipoprotein lipase activation by red ginseng saponins in hyperlipidemia model animals.

The effect of ginseng saponins isolated from red ginseng (a steamed and dried root of Panax ginseng) has been studied in a cyclophosphamide (CPM)-induced hyperlipidemia model in fasted rabbits. In this model, chylomicrons and very low density lipoprotein (VLDL) accumulation was known to occur as a result of reduction in lipoprotein lipase (LPL) activity in the heart and heparin-releasable heart LPL. Oral administration of ginseng saponins at a dose of 0.01 g/kg for 4 weeks was found to reverse the increase in serum triglycerides (TG) and concomitant increase in cholesterol produced by CPM treatment, especially in chylomicrons and VLDL. In addition, ginseng saponins treatment led to a recovery in postheparin plasma LPL activity and heparin-releasable heart LPL activity, which were markedly reduced by CPM treatment. In rats given 15% glycerol/15% fructose solution, postheparin plasma LPL activity declined to two third of normal rats, whereas ginseng saponins reversed it to normal levels. In the present study we first demonstrated that ginseng saponins sustained LPL activity at a normal level or protected LPL activity from being decreased by several factors, resulting in the decrease of serum TG and cholesterol.     

Determining hepatic triglyceride production in mice: comparison of poloxamer 407 with Triton WR-1339

Triglyceride (TG), a water-insoluble energy-rich lipid, is secreted by the liver as part of very low density lipoproteins (VLDLs) to supply energy to extrahepatic tissues. Overproduction of VLDL is associated with increased risk of cardiovascular heart disease; this has renewed an interest in factors that affect hepatic TG production. The TG production rate is determined by measuring temporal increases in plasma TG under conditions in which TG hydrolysis by lipoprotein lipase (LPL) is inhibited. The nonionic detergent, Triton WR-1339 (Triton), has commonly been used to inhibit LPL for this purpose. Triton, in addition to inhibition of TG hydrolysis, has properties that have the potential to adversely influence lipoprotein metabolism. Another nonionic detergent, poloxamer 407 (P-407), also inhibits LPL. In these studies, we demonstrate that P-407 is comparable to Triton in the determination of TG production but without the unwanted side effects of Triton.