Decreased activities of lipoprotein lipase and hepatic triglyceride lipase in patients with gout

Postheparin plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities were measured in 30 male primary gout patients as well as in control subjects. The activities of these lipolytic enzymes were significantly decreased in the patients as compared with the controls (gout v control; LPL, 5.4 +/- 0.4 v 7.9 +/- 0.9 U; HTGL, 14.6 +/- 2.0 v 17.9 +/- 3.4 U) when matched with serum triglyceride concentration. Further, LPL activity was negatively correlated with serum- and very-low-density lipoprotein (VLDL)-triglyceride in gout patients, while that of HTGL was negatively correlated with low-density lipoprotein (LDL)-triglyceride in both gout patients and control subjects. These results suggest that decreased activities of LPL and HTGL may contribute, in part, to the increased concentrations of serum-, VLDL-, and LDL-triglyceride seen in gout patients, leading to a higher risk for coronary atherosclerotic diseases in gout.     

The lipoprotein lipase gene HindIII polymorphism is associated with lipid levels in early-onset type 2 diabetic patients

Lipoprotein lipase (LPL) plays a central role in triglyceride metabolism, and the LPL gene T495G HindIII polymorphism has been associated with variations in lipid levels and heart disease in Caucasians with the more common H+ allele being associated with adverse lipid profiles and increased risk of CHD. We investigated this polymorphism in 785 Chinese subjects with varying components of the metabolic syndrome, including 61.4% with early-onset type 2 diabetes (age at diagnosis < or = 40 years), and 167 healthy control subjects using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. The allele and genotype frequencies were similar in the patients and control subjects. When grouped above or below standard cutoffs for triglyceride levels, the H+ allele was more frequent in hypertriglyceridemic than that in normotriglyceridemic subjects in the total population (81.5% v 76.1%) and early-onset type 2 diabetics (84.4% v 77.4%, both P <.05). Moreover, H+H+ carriers had significantly higher plasma triglyceride and lower high-density lipoprotein (HDL)-cholesterol levels when compared to subjects with the H- allele in the total population, and in patients with early-onset diabetics (both P <.05). In the total population and the early-onset diabetic patients, this relationship was confined to males when gender was considered. We conclude that the H+ allele of the LPL gene HindIII polymorphism is associated with higher plasma triglyceride and lower HDL-cholesterol levels in Chinese patients with early-onset diabetes.     

Atorvastatin improves diabetic dyslipidemia and increases lipoprotein lipase activity in vivo

A major factor contributing to cardiovascular mortality in type 2 diabetes is dyslipidemia, characterized by low HDL cholesterol and high triglycerides, rather than elevated LDL cholesterol. Lipoprotein lipase (LPL) is the rate-limiting enzyme of triglyceride removal from plasma and has been implicated in atherosclerosis. Since treatment with statins significantly reduces cardiovascular morbidity in diabetes, we analyzed the lipid profile and LPL activities in 61 patients with type 2 diabetes before and 8 weeks after initiation of atorvastatin (40 mg) or placebo treatment. Lipid parameters and LPL activity were unchanged under treatment with placebo. Atorvastatin treatment resulted in a 30% reduction of total and a 45% reduction of LDL cholesterol (6.06 +/- 1.39 mmol/L versus 4.14 +/- 1.27 mmol/L and 4.11 +/- 1.13 mmol/L versus 2.27 +/- 0.89 mmol/L, both P < 0.0001). Triglycerides and VLDL cholesterol were also significantly reduced by statin therapy (2.24 +/- 2.11 mmol/L versus 1.82 +/- 1.46 mmol/L and 1.08 +/- 1.56 mmol/L versus 0.67 +/- 0.66 mmol/L, both P < 0.05). HDL cholesterol was not different between the atorvastatin and the placebo group. Compared to baseline, LPL activity was increased by 25% after atorvastatin treatment (213.0 +/- 28.1 nmol/mL/min versus 171.9 +/- 17.7 nmol/mL/min, P < 0.01). Our data demonstrate that atorvastatin induces a significant improvement of diabetic dyslipidemia and a significant increase of LPL activity. Since low LPL activity indicates an increased cardiovascular risk, the statin-mediated increase in LPL activity may help to explain the reduction of CAD in diabetic patients treated with statins.     

高脂血症性急性胰腺炎脂蛋白脂酶基因多态性研究

目的 探讨三酰甘油分解代谢酶脂蛋白脂酶(LPL)的表达和基因多态性与高脂血症性急性胰腺炎(HLP)的相关性.方法 2005年5月至2006年12月HLP住院患者20例,急性胰腺炎患者50例,另选取血脂正常患其他疾病者50例为对照.测定血清三酰甘油(TG)、胆固醇(Ch)、游离脂肪酸(FFA)、脂蛋白数值、血清LPL/肝脂酶(HL)活性;RT-PCR检测LPL mRNA表达;聚合酶链-限制性酶切片段多态性分析(PCR-RFLP)法分析LPL基因内含子8 Hind Ⅲ基因多态性变化.结果 HLP组血清TG、胆固醇(Ch)和FFA测定值均显著高于AP组和对照组,差异均有统计学意义(P值均<0.05);HLP组ApoE值显著高于AP组和对照组(P<0.05);HLP组高密度脂蛋白(HDL)显著低于对照组(P<0.05).HLP组LPL值为(5.98±2.28)U/L,均显著高于AP组和对照组[(1.97±0.76)U/L和(1.04±0.53)U/L,P值分别=0.046和0.031];HLP组HL值为(8.15±2.86)U/L,均显著高于AP组和对照组(1.64±0.59)U/L和(0.86±0.39)U/L,P值分别=0.002和0.001].HLP组LPL mRNA表达高于AP组,差异有统计学意义(P=0.0325).LPL基因内含子8 Hind Ⅲ分析,H2等位基因频率HLP组显著高于对照组(0.90比0.72,P<0.05);H1等位基因频率在HLP和AP组均显著低于对照组(0.10比0.28和0.14比0.28,P<0.05).HLP组H2H2基因型患者TG和Apo E值均显著高于H2H1/H1H1基因型(P值分别=0.043和0.046);AP组H2H2基因型患者TG值显著高于H2H1/H1H1基因型(P=0.032).结论 HLP患者LPL Hind Ⅲ H2等位基因频率显著高于正常人群,主要与高三酰甘油血症(HTG)相关,而与胰腺炎无关;且H2H2基因型的HLP患者血清TG、ApoE值高于其他基因型者.HTG可引起LPL基因和蛋白表达活性增高,加速TG大量分解代谢和FFA等分解产物蓄积,是诱发和加重HLP的中心环节和重要病理生理机制.     

Glucose-stimulated insulin response in non-diabetic patients with lipoprotein lipase deficiency and hypertriglyceridemia

Elevations in plasma triglyceride (TG) and free fatty acid (FFA) concentrations are generally thought to play a role in the pathogenesis of insulin-resistant diabetes. The objective of this study was to investigate the relationship between hypertriglyceridemia and glucose-stimulated insulin responsiveness in non-diabetic patients. Forty subjects were divided into three BMI-matched groups as follows: one group consisted of 8 patients with a lipoprotein lipase (LPL) deficiency, another consisted of 12 patients with hypertriglyceridemia and a third consisted of 20 subjects with normal TG levels. In response to a 75 g oral glucose tolerance test, plasma insulin levels in the LPL-deficient subjects were higher (106+/-11 microU/ml) than those in the hypertriglyceridemic (69+/-16 microU/ml) and normolipidemic (29+/-3 microU/ml) subjects, at 30 min. On the other hand, their plasma glucose levels (127+/-6 mg/dl) were less than those seen in the normolipidemic group (165+/-9 mg/dl) after 90 min. Thus, LPL-deficient subjects with hypertriglyceridemia displayed an enhanced glucose-stimulated insulin response as well as lower blood glucose levels, the latter of which is not generally seen in those with hypertriglyceridemia and normolipidemia.     

Cardiac lipoprotein lipase: metabolic basis for diabetic heart disease

The heart has a limited potential to synthesize fatty acid (FA), and, therefore, FA is supplied from several sources: lipolysis of endogenous cardiac triglyceride (TG) stores or from exogenous sources in the blood. Lipoprotein lipase (LPL), synthesized in cardiomyocytes, catalyzes the breakdown of the TG component of lipoproteins to provide FA to the heart. It is the vascular endothelial-bound LPL that determines the rate of plasma TG clearance, and, hence, it is also called heparin-releasable (HR) "functional" LPL. Functional LPL is regulated by numerous dietary and hormonal factors and is sensitive to pathophysiological alterations like those observed during diabetes. In this condition, absolute or relative lack of insulin impairs cardiac glucose transport and oxidation, resulting in FA becoming the preferred means of energy supply. To make available this increased requirement of the heart for FA, the diabetic heart upregulates its luminal LPL activity by posttranslational mechanisms. Chronically elevated cardiac LPL can result in abnormal FA supply and utilization by the heart tissue that could potentially initiate and sustain cardiac dysfunction during diabetes. As effective blood glucose control is difficult during diabetes, it is conceivable that a parallel increase in functional cardiac LPL activity may predispose people with diabetes to premature death from cardiac disease. By gaining more insight into the initial metabolic processes in the diabetic heart, we can attempt to piece together a part of the cascade of events leading to diabetic heart disease.     

Insulin-induced upregulation of lipoprotein lipase in Schwann cells during diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is one of the major complications associated with diabetes. It is characterized by the degeneration of the myelin sheath around axons, referred to as demyelination. Such demyelinations are often caused by reduced lipid component of the myelin sheath. Since, lipoprotein lipase (LPL) provides the lipid for myelin sheath by hydrolysing the triglyceride rich lipoproteins, and also helps in the uptake of lipids by the Schwann cells (SCs) for its utilization, LPL is considered as the important factor in the regeneration of myelin sheath during diabetic neuropathy. Earlier reports from our laboratory have provided the insights of insulin and its receptor in SCs during diabetic neuropathy. In order to evaluate the long term effect of insulin on lipid metabolism during diabetic neuropathy, in this study, we analyzed the expression of LPL in SCs under normal, high glucose and insulin treated conditions. A decrease in the expression of LPL was observed in SCs of high glucose condition and it was reversed upon insulin treatment. Histochemical observations of sciatic nerve of insulin treated neuropathy subjects showed the improved nerve morphology, signifying the importance of insulin in restoring the pathophysiology of diabetic neuropathy.     

. Association of HindIII and PvuII genetic polymorphisms of lipoprotein lipase with lipid metabolism and macrovascular events in type 2 diabetic patients

AIM: Lipoprotein lipase (LPL) is a key enzyme of lipid metabolism, and its genetic polymorphism may be a candidate for modulating lipid parameters in type 2 diabetic subjects (D2). METHODS: In a group of 404 type 2 diabetic patients, aged 59.5+/-10.8y, BMI=28.9+/-5.3 kg/m2, HbA1c=8.2+/-1.9%, we studied the H and P polymorphisms at the LPL locus detectable with the restriction enzymes HindIII and PvuII. Patients were separated into 229 males (17H1H1, 84H1H2, 128H2H2 and 51P1P1, 110P1P2, 68P2P2) and 175 females (16H1H1, 69H1H2, 90H2H2 and 51P1P1, 85P1P2, 39P2P2), and compared on the basis of their lipid parameters and their macrovascular complications. RESULTS: Triglyceride (TG) and HDL-cholesterol(c) concentrations differed between patients with and without coronary heart disease (CHD) (3.44+/-2.09 and 1.96+/-1.40 mmol/l for TGs and 1.05+/-0.24 and 1.34+/-0.40 mmol/l for HDL-c, P<0.001). HDL-c concentrations were lower in male H2H2 and P2P2 subjects (P<0.001), and TG levels were higher in male H2H2 and P2P2 subjects (P<0.0001 for Hind III and P<0.05 for PvuII). Allele frequency of the HindIII and PvuII restriction site was similar to those reported in other Caucasian populations and the presence of the H2/P2 variants was significantly higher in CHD patients. The prevalence of CHD in this population was 18% but was 29% in H2H2 and 38% in P2P2 subjects (P<0.02). CONCLUSION: Thus, HindIII and PvuII polymorphisms seem to exert a modulating role on lipid profile particularly in male D2, contributing to increase the risk of macrovascular events.     

Decline of postheparin plasma lipoprotein lipase in acromegalic patients

Lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma were measured in seven patients with active acromegaly by an immunochemical method utilizing antiserum prepared against hepatic triglyceride lipase. A mild or moderate hypertriglyceridemia was shown, with plasma triglyceride concentrations between 156 and 544 mg/dl. Lipoprotein lipase was found to be decreased in all patients (p < 0.001). Hepatic triglyceride lipase was also low in these patients (p < 0.001). We speculate that acromegalic hypertriglyceridemia is mediated, at least in part, by the decline in lipoprotein lipase and possibly by the decline in hepatic triglyceride lipase activities.     

Lipoprotein pattern and plasma lipoprotein lipase activities in patients with primary biliary cirrhosis

Plasma lipids, apoprotein A-I and B in serum and in lipoprotein fractions (VLDL + LDL, HDL₂, and HDL₃) obtained by preparative ultracentrifugation, as well as postheparin lipoprotein lipase activity (H-TGL and LPL) were evaluated in 17 subjects with primary biliary cirrhosis (stage II and III) subdivided into two groups according to the presence or absence of lipoprotein X (Lp-X). A reduction in total lipoprotein lipase activity was observed in both patient groups, compared to controls (P<0.01); the hepatic lipoprotein lipase was significantly reduced (P<0.01) only in the Lp-X-positive group. The lipid (477.8+154.3 vs 239.6±51.1; P<0.01) and protein (147.4±37.1 vs 83.3±19.7; P< 0.01) masses in the VLDL + LDL fraction of the Lp-X-positive group were increased compared to controls. In the same group, the HDL₂ fraction also showed an increase in lipid (186.6±80.0 vs 77.9±21.6; P<0.01) and protein (133.9±60.0 vs 67.9±16.5; P <0.01) masses; in addition, the HDL₂ percent lipid composition was different in the two patient groups, showing a decrease in esterified cholesterol (20.4±3.6 vs 25.7±2.2; P <0.01) and an increase in phospholipids (59.2±2.9 vs 54.8±2.6; p<0.01) in the Lp-X-positive group. Apo B was also increased in Lp-X-positive patients both in the serum (134.0±27.6 vs 90.9±7.3; P<0.01) and in the VLDL + LDL fraction (134.0±22.2 vs 72.5±16.5; P<0.01). The differences seen in lipoprotein concentration and composition in the two patient groups seem related, in part, to the presence of Lp-X or, better, to the stage of the disease. The reduction in hepatic lipase may play an important role in determining the increase and altered composition of the HDL₂ subfraction.     

Human lipoprotein lipase HindIII polymorphism in young patients with myocardial infarction.

We investigated the possibility that the DNA HindIII polymorphism of human lipoprotein lipase (LPL) is associated with the severity of coronary artery disease (CAD) determined by angiography in young patients who survived a myocardial infarction (MI). Conflicting studies have explored the relationship linking CAD severity to the HindIII restriction site polymorphism at the LPL gene locus, and to our knowledge, no data are available from Italy. The patients were aged less than 45 years (mean age, 40.1 +/- 3.9 years); 83 were male and four were female. The 87 case-patients had a Q-wave or non-Q-wave infarction (67.3% and 32.7%, respectively); the MI was anterior (50.5%), lateral (41.7%), or inferior (7.8%). Analysis of coronary angiograms showed the absence of critical stenosis in 13.8% and the presence of monovessel disease in 50.6% and multivessel disease in 35.6% of the case-patients. The allelic frequency of the HindIII H(-) and H(+) allele was 0.37 and 0.63, respectively. There was a striking association between the HindIII polymorphism and the number of diseased vessels. The patients with HindIII(+/+) genotypes were significantly more likely to have double- or triple-vessel disease and less likely to have no significantly diseased vessels. In this study, we demonstrated that the homozygous form of the LPL HindIII(+) allele increases the risk of multivessel disease by a factor of 4 in an Italian group of young MI survivors. This association was independent from the smoking status and a positive family history for CAD and hypertension, which are known to predict CAD severity. The discrepancies in the results of these studies are difficult to explain. The lack of homogeneity in the study populations (age at which CAD occurred, number of enrolled patients, and geographical origin) and differences in the assessment of CAD severity may account for these conflicting results.     

Elevated adipose tissue lipoprotein lipase activity in craniopharyngioma patients

The activity of lipoprotein lipase (LPL) was measured in adipose tissue (AT-LPL) and postheparin plasma (PH-LPL) of 13 obese patients (aged 11 to 31 years) who had surgery for craniopharyngioma 1 to 13 years earlier. AT-LPL activity (mean +/- SEM) was higher in them than in subjects matched with respect to age, sex, and relative body weight (4.6 +/- 1.1 v 2.1 +/- 0.4 mumol free fatty acids (FFA).h-1.g-1, P less than .05). The activity was also higher when expressed per fat cell.     

Non-esterified fatty acids and lipoprotein lipase activity in patients with cirrhosis of the liver

After the intravenous injection of heparin the plasma concentration of non-esterified fatty acids rises in normal subjects and in patients with nephrosis or diabetes but not in patients with portal cirrhosis.     

Transient lipoprotein lipase deficiency with hyperchylomicronemia

Type I hyperlipoproteinemia is a rare disorder characterized by the presence of chylomicrons in fasting plasma and dysfunction of the lipoprotein lipase system. The disease may result from primary genetic defects leading to the lack of the enzyme lipoprotein lipase or to a deficiency in the CII apoprotein activator of that enzyme. It may also appear secondary to underlying systemic diseases. We now describe a case of hyperchylomicronemia and pancreatitis with a lack of lipoprotein lipase activity as assessed by three different methods. The patient had no evidence of a plasma inactivator of lipoprotein lipase, and his plasma was able to activate the enzyme in control postheparin plasma. The postheparin plasma hepatic triglyceride lipase was normal. Tests for associated systemic diseases were negative. Six weeks after presentation, that patient's lipoprotein levels and postheparin plasma lipase activities were normal. This was a unique case of hyperchylomicronemia which for a limited time was indistinguishable from primary lipoprotein lipase deficiency by current biochemical techniques.     

Lipid and lipoprotein abnormalities in diabetic patients with peripheral vascular disease

Coronary heart disease in insulin-dependent (IDDM) and in non-insulin-dependent diabetes (NIDDM) is associated with lipid and lipoprotein changes favouring atherosclerosis. Whether lipid and lipoprotein abnormalities are associated also with peripheral vascular disease in both types of diabetes is largely unknown. Therefore, we studied lipid and lipoprotein levels and their association with claudication in a representative sample of diabetic and non-diabetic subjects in East Finland. Altogether 87 subjects had IDDM (43 men, 44 women), 264 subjects NIDDM (126 men, 138 women) and 120 subjects were non-diabetic controls (63 men, 57 women). Patients with IDDM had an increased level of HDL and HDL2-cholesterol and patients with NIDDM a decreased level of HDL and HDL2-cholesterol and an increased level of total, LDL and VLDL triglycerides than did non-diabetic subjects. Analyses in both types of diabetes by claudication status revealed that total and LDL-cholesterol and total and VLDL triglycerides tended to be higher and HDL and HDL2-cholesterol lower in those having claudication as compared to those without a claudication symptom. Similarly, total cholesterol/HDL-cholesterol ratio and LDL-cholesterol/HDL-cholesterol ratio were also more atherogenic in patients with claudication than in those without claudication. In conclusion, our results indicate that in both types of diabetes peripheral vascular disease is associated with lipid and lipoprotein abnormalities favouring atherosclerosis.     

Serum high density lipoprotein in diabetic patients

Summary The purpose of the present investigation was the study of HDL lipoprotein changes in patients with diabetes mellitus. The comparison was made between 40 normal and 109 diabetic subjects and the following data was obtained: relative HDL concentration (polyacrylamide gel electrophoresis), HDL-cholesterol and apolipoprotein A concentrations. We found significant decreases in HDL (18–28%) and HDL-cholesterol (31–40 mg/ 100 ml) in most diabetics except in those with normalized serum levels of glucose and lipids (34% and 50 mg/100 ml respectively). There was a statistically significant difference in HDL and HDL-cholesterol concentrations between patients in the latter group and other diabetic patients. There was a negative correlation between HDL and HDL-cholesterol and serum glucose levels. No statistically significant difference was found when apolipoprotein A was compared in normal and diabetic subjects. Our results suggest that a deficient binding of cholesterol to apoprotein A might be present in diabetes.     

Role of macrophage-derived lipoprotein lipase in lipoprotein metabolism and atherosclerosis

Lipoprotein lipase (LPL) synthesis by macrophages is upregulated in early atherogenesis, implicating the possible involvement of LPL in plaque formation. However, it is still unclear whether macrophage-derived LPL displays a proatherosclerotic or an antiatherosclerotic role in atherosclerotic lesion development. In this study, the role of macrophage-derived LPL on lipid metabolism and atherosclerosis was assessed in vivo by transplantation of LPL-deficient (LPL-/-) and wild-type (LPL+/+) bone marrow into C57BL/6 mice. Eight weeks after bone marrow transplantation (BMT), serum cholesterol levels in LPL-/--->C57BL/6 mice were reduced by 8% compared with those in LPL+/+-->C57BL/6 mice (P:<0.05, n=16), whereas triglycerides were increased by 33% (P:<0.05, n=16). Feeding the mice a high-cholesterol diet increased serum cholesterol levels in LPL-/--->C57BL/6 and LPL+/+-->C57BL/6 mice 5-fold and 9-fold, respectively, resulting in a difference of approximately 50% (P:<0. 01) after 3 months on the diet. No effects on triglyceride levels were observed under these conditions. Furthermore, serum apolipoprotein E levels were reduced by 50% in the LPL-/--->C57BL/6 mice compared with controls under both dietary conditions. After 3 months on a high-cholesterol diet, the atherosclerotic lesion area in LPL-/--->C57BL/6 mice was reduced by 52% compared with controls. It can be concluded that macrophage-derived LPL plays a significant role in the regulation of serum cholesterol, apolipoprotein E, and atherogenesis, suggesting that specific blockade of macrophage LPL production may be beneficial for decreasing atherosclerotic lesion development.     

Detection of missense mutations in the genes for lipoprotein lipase and hepatic triglyceride lipase in patients with dyslipidemia undergoing coronary angiography

Coronary events have a close association with a low HDL/hypertriglyceridemia (LHDL/HTG) phenotype. As enzymes that hydrolyze triglyceride-rich lipoproteins are associated with a modulation of both HDL cholesterol and triglycerides, we have tested the hypothesis that mutations in the genes encoding lipoprotein lipase (LPL) or hepatic lipase (HTGL) may contribute to the formation of coronary atherosclerosis and, thus, of coronary heart disease (CHD). The entire coding and boundary regions of LPL and HTGL genes were analyzed by direct sequencing in 20 patients with both LHDL/HTG and diagnosed CHD. In the LPL gene six different polymorphisms were identified with same frequencies observed in the general population. In the HTGL gene, besides several polymorphisms, we identified three missense mutations: Asn37His, Val73Met, and Ser267Phe. Population screening using allele specific PCR identified Val73Met as a polymorphism while the two others were absent from 100 control individuals. One of the mutations (Ser267Phe) is known to cause HTGL deficiency and is associated with type III hyperlipoproteinemia. Since this dyslipoproteinemia meets the criteria of LHDL/HTG, it is intriguing to speculate that missense mutations in HTGL may play a role in the pathogenesis of this atherogenic phenotype.