Plasma proprotein convertase subtilisin-kexin type 9 does not change during 24h insulin infusion in healthy subjects and type 2 diabetic patients

PurposeProprotein convertase subtilisin–kexin type 9 (PCSK9) promotes low density lipoprotein (LDL) receptor degradation, thereby providing a key pathway for LDL metabolism. PCSK9 mRNA expression may be upregulated by insulin in murine models. Here we examined effects of exogenous hyperinsulinemia on plasma PCSK9 levels in humans without and with type 2 diabetes mellitus.MethodsA 24 h moderately hyperinsulinemic glucose clamp (30 mU/kg/h) was performed in 8 healthy men and 8 male type 2 diabetic patients. Plasma PCSK9 was measured using a sandwich enzyme-linked immunosorbent assay.ResultsPlasma LDL cholesterol and apolipoprotein B were lowered by insulin in healthy subjects and diabetic patients (P < 0.01 for all), whereas triglycerides were also decreased in healthy subjects (P < 0.01). Plasma PCSK9 levels remained unchanged in healthy subjects (median (interquartile range) change, ?23 (?63 to 25) %, P = 0.50) and in diabetic patients (change, 4 (?17 to 44) %, P = 0.20). Individual absolute and relative changes in LDL cholesterol, apolipoprotein B and triglycerides after 24 h of insulin were unrelated to changes in PCSK9 (P > 0.15 for all).ConclusionPlasma PCSK9 levels are not increased by exposure to moderate 24 h hyperinsulinemia in healthy and type 2 diabetic individuals.     

ABO血型与血脂和PCSK9相关性研究

背景和目的：前蛋白转化酶枯草杆菌蛋白酶9(Proprotein convertase subtilisin/kexin type 9 ,PCSK9),是一个近期发现的在胆固醇平衡、高脂血症和冠心病治疗中起重要作用的新成员。但是决定PCSK9水平的因素尚不明确。已知ABO血型与胆固醇代谢相关。因此,本研究探讨了ABO血型和PCSK9水平之间的联系。     

Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia

Background and aimsTwo recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL.Methods and resultsMarkers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001).ConclusionsThe present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.     

冠心病患者体内前蛋白转化酶枯草溶菌素9水平与炎性因子的相关性分析

目的:探讨冠状动脉粥样硬化性心脏病(CAD)患者血浆前蛋白转化酶枯草溶菌素9(PCSK9)与血脂各指标及性因子的相关性。方法:入选210例未行降脂治疗的胸痛患者,入院后根据冠状动脉造影检查结果分为冠心病组120例和对照组(非冠心病)90例。收集临床资料,采集空腹静脉血检测血常规、血生化等各项指标。采用酶联免疫吸附实验(ELISA)检测患者血浆PCSK9、白介素10(IL-10)水平。结果:两组资料对比,CAD组吸烟及糖尿病史的比例高于对照组,空腹血糖、LDL-C、IL-10、PCSK9水平明显高于对照组,HDL-C水平低于对照组,差异有统计学意义。Logistic回归分析显示在调整了性别、高血压、TG、TC、载脂蛋白A1(Apo A1)、Apo B因素后,老年、吸烟、糖尿病史、LDL-C、脂蛋白(a)、HDL、PCSK9是CAD的独立危险因素。PCSK9与LDL-C、Apo B水平呈正相关;与炎性标志物hs-CRP、中性粒细胞和IL-10呈正相关。结论:PCSK9是CAD的独立危险因素,与动脉粥样硬化(As)的形成和发展有密切关系。PCSK9水平与抗炎细胞因子IL-10及hs-CRP正相关,提示IL-10和hs-CRP与PCSK9共同参与了AS的形成和发展。     

新型降胆固醇药物前蛋白转化酶枯草溶菌素9抑制剂的研究进展

动脉粥样硬化性心血管疾病已成为我国居民主要死亡原因之一,血脂异常是动脉粥样硬化发生、发展的重要因素。前蛋白转化酶枯草溶菌素9(PCSK9)是肝脏合成的分泌型丝氨酸蛋白酶,与低密度脂蛋白受体结合使其降解,减少低密度脂蛋白受体对血清低密度脂蛋白胆固醇的清除。而通过抑制PCSK9,可阻止低密度脂蛋白受体降解,促进低密度脂蛋白胆固醇的清除。近年来,以PCSK9抑制剂为代表的新型药物受到越来越多的关注,取得令人瞩目的进展。本文对PCSK9抑制剂的研究新进展进行综述。     

黑龙江省东部地区汉族人群PCSK9基因第1外显子多态性与脂代谢的相关性

目的 研究黑龙江省东部地区汉族人群前蛋白转化酶枯草溶菌素(PCSK)9基因第1外显子多态性与脂代谢的相关性.方法 因心绞痛和(或)运动试验阳性及有冠脉管腔狭窄证据而需入院行冠状动脉造影者220例中,110例冠心病(CHD)者为病例组,110例非CHD者为对照组,检测PCSK9基因第1外显子基因多态性及血脂水平,并对基因多态性与血脂水平进行相关性分析.结果 共发现c.121C>G、c.299C>T、c.427-428insGCT、A53V、P56S和c.556A>G 6个突变位点,其中在A53V突变位点上发现CC和TC两种基因型,但未发现TT基因型.病例组和对照组各基因型间血清三酰甘油(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)水平差异具有统计学意义(P<0.05).病例组中TC基因型血清TG、TC和LDL-C水平均显著高于CC基因型(P<0.05);对照组中TC基因型血清TC水平显著高于CC基因型(P<0.05).结论 PCSK9基因第1外显子在黑龙江省东部地区汉族人群中存在多态性,且与CHD患者脂代谢有关.     

前蛋白转化酶枯草溶菌素9抑制剂对血脂代谢作用的研究进展

家族性高胆固醇血症(FH)因其血脂水平明显增高,引发动脉粥样硬化及心血管事件。前蛋白转化酶枯草溶菌素9(PCSK9)可通过诱导低密度脂蛋白受体内化降解来调节低密度脂蛋白胆固醇(LDL-C)代谢。PCSK9抑制剂通过调节PCSK9水平使LDL-C显著降低,从而为FH患者带来获益。     

The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis

The LDL receptor (LDLR) plays an essential role in the regulation of plasma (LDL) cholesterol concentrations by virtue of its ability to clear plasma LDL. Down‐regulation of the LDLR by proprotein convertase subtilisin/kexin 9 (PCSK9) has recently emerged as a regulatory mechanism that controls plasma LDL cholesterol concentrations. Studies in which PCSK9 is over‐expressed in mice, have demonstrated that PCSK9, by enhancing hepatic LDLR degradation, decreases the availability of the LDLR for LDL uptake, resulting in increased plasma LDL cholesterol levels. However, PCSK9 has also recently been shown to mediate down‐regulation of surface receptors other than the LDLR, suggesting that it may have much broader roles than initially thought.     

Relationship between blood pressure and plasma insulin in non-obese and obese non-diabetic subjects

Summary In this study, we have measured plasma insulin at fasting and following an oral glucose load and blood pressure after glucose load in 367 (247 non-obese, 120 obese) normotensive and untreated mildly hypertensive subjects. Overall, there was no independent association between fasting plasma insulin levels and blood pressure values. After controlling for age and body weight, a significant relationship between postglucose plasma insulin levels and diastolic blood pressure was found. When non-obese and obese subjects were examined separately, significant relationships were identified between postglucose plasma insulin levels and both systolic and diastolic blood pressure values in the former but not in the latter. A comparison of sex-, age-, and weight-matched hyperinsulinaemic vs normoinsulinaemic subjects showed that the former had significantly higher values of blood pressure only if not obese. These results demonstrate that the plasma insulin response to glucose is independently correlated with blood pressure.     

The proprotein convertase subtilisin/kexin type 9 geneE670G polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was undertaken association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 649 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PCSK9 E670G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing. Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C) and apolipoprotein(Apo) AI were lower in Bai Ku Yao than in Han(P<0.01 for all).The frequency of A and G alleles was 98.00%and 2.00%in Bai Ku Yao,and 95.20%and 4.80%in Han(P<0.01);respectively. The frequency of AA,AG and GG genotypes was 95.99%,4.01%and 0%in Bai Ku Yao,and 91.02%, 8.36%and 0.62%in Han(P<0.01);respectively.There were also significant differences in the genotypic and allelic frequencies between n and the ratio of ApoAI to ApoB in Han Chinese but not in Bai Ku Yao were different between the AA and AG/GG genotypes(P<0.05 for all).The G allele carriers had higher serum HDL-C and higher ApoAI to ApoB ratio than the G allele noncarriers.When serum lipid parameters in Han were analyzed according to sex,the G allele carriers had higher serum HDL and ApoAI levels in males (P<0.05),and lower ApoB level and higher ApoAI to ApoB ratio in females(P<0.05 for all).Multiple linear regression analysis showed that serum HDL-C levels were correlated with genotypes in both ethnic groups(P<0.05 each).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consump