Plasma lipoprotein distribution, faecal cholesterol excretion, and activities of lipoprotein lipase, hepatic lipase and lecithin:cholesterol acyltransferase in rats fed diets rich in sucrose or sunflower oil

Plasma HDL2 has been suggested to carry cholesterol to the liver for subsequent excretion in the bile and faeces. The enzymes lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin:cholesterol acyltransferase (LCAT) have been implicated in the centripetal cholesterol transport. Activities of these enzymes, the amount of faecal cholesterol excretion and the level of plasma lipoproteins were determined in male rats fed for 4 weeks on purified diets in which the sunflower oil:sucrose ratio was either 0.03 (group a) or 1.01 (group b). Whole plasma triacylglycerols (TG), unesterified cholesterol (UC) and phospholipids (PL) were highest in group (a). The concentration of cholesteryl esters (CE) was similar in the two groups. Protein, TG and UC of VLDL, and TG, UC, CE and PL of HDL2 were higher in group (a) than in group (b). The HDL3-protein and TG were lowest in group (a). Thus, total weight of VLDL and HDL2 were increased, and HDL3 reduced in group (a), which had also increased activities of HL and adipose tissue LPL. Activity of LCAT was lower, and faecal excretion of cholesterol was reduced by about 50% in group (a) compared to group (b). Accordingly, in the rat increased plasma levels of HDL2 are not necessarily indicative of increased faecal cholesterol excretion.     

血脂异常与冠心病研究进展

冠状动脉粥样硬化性心脏病成为导致我国人群死亡的主要疾病之一。血脂代谢异常是冠心病的主要发病机制,血脂异常引起动脉粥样硬化的机制是目前研究的热点。血脂异常通常是指血浆中胆固醇或（和）TG水平升高,近年研究认识到血浆中HDL-C降低也是一种血脂代谢异常。我国人群血脂代谢异常类型以高TG、低HDL血症为主。冠心病发病与血中LDL-C水平呈正相关,与HDL-C水平呈负相关。随着LDL-C水平的增加,缺血性心血管病发病的相对危险及绝对危险上升的趋势及程度与TC相似。血清TG水平轻至中度升高者患冠心病的危险性增加。血清HDL-C水平与冠心病发病成负相关。     

Lipoprotein lipase activity in patients with combined hyperlipidaemia

The aetiology of familial combined hyperlipidaemia remains obscure, with both genetic and environmental factors contributing to the phenotype, which is frequently associated with premature coronary heart disease. We have studied lipoprotein lipase (LPL) activity and hepatic lipase (HL) activity in patients with coronary heart disease to determine whether variation in lipase activities contributes to this phenotype. Forty-one patients (mean age 50 years; 30 male) were selected on the basis of cholesterol levels above 6.5 mmol/l and triglyceride levels above 2.2 mmol/1, with apoprotein B values over the 90th percentile. There was a family history of premature coronary heart disease in 78% and a personal history in 64%, at mean age 44, the patient group therefore predominantly corresponded to the common definition of familial combined hyperlipidaemia, appropriate in the absence of molecular markers. None of the patients was diabetic; hypertension and smoking were not over represented. Blood samples were taken following intravenous administration of heparin (100IU/kg body wt), and LPL and HL activities were measured. Mean post-heparin LPL was significantly lower in patients than controls 10 min after heparin administration (2.98 ± 1.04 and 3.86 ± 0.93 mol ml^-1 h^-1, respectively, P = 0.001), and 37% patients had values below the 10th percentile of controls. Both male and female patients had significantly higher HL activities than their respective controls at 5, 10, 20 and 30 minutes postheparin. As expected, both female patients and controls had lower HL activities than males, although this sex difference did not reach statistical significance in the patient group. Mean lipid and lipoprotein results were: cholesterol 8.2 mmol/1; triglycerides 4.2 mmol/l; high-density lipoprotein cholesterol 0.90 mmol/1; apoprotein Al 122 mg/dl; apoprotein B 171 mg/dl; lipoprotein (a) 23 mg/dl (median 10 mg/dl). High-density lipoprotein cholesterol and triglycerides were negatively correlated (r = -0.26, P = 0.05). HL was significantly related to body mass index at all time points whereas the negative correlation between post-heparin LPL and body mass index was significant only 30 min after heparin administration. Post-heparin LPL was only weakly correlated with triglycerides 10 and 20 min after heparin administration. These lipid and lipoprotein results are clearly potentially atherogenic as indicated by the extent of premature coronary heart disease in the group described. A decrease in LPL activity may contribute to this pattern.Abbreviations FCHL familial combined hyperlipidaemia - CHD coronary heart disease - LPL lipoprotein lipase - HL hepatic lipase - HDL high-density lipoprotein - VLDL very low density lipoprotein; - apo apoprotein - TG triglyceride - BMI body mass index Correspondence to: M. Seed     

Plasma high-density lipoproteins and liver lipids and proteins in man. Relation to hepatic histology and microsomal enzyme induction

The association of high-density lipoproteins (HDL) in plasma with liver lipids and proteins was investigated in 28 subjects with diagnostic liver biopsy. Lipids and proteins were evaluated in relation to hepatic histology and microsomal enzyme induction, assessed by liver cytochrome P-450. Moderate-severe hepatic parenchymal changes were associated with low liver phospholipids, protein and cytochrome P-450, low plasma HDL cholesterol (HDL-C), and high hepatic triglycerides. Liver microsomal induction accompanying anticonvulsant therapy was associated with high liver phospholipids and protein, high plasma HDL-C, apoproteins A-I and A-II, and high HDL-C/total cholesterol (T-C) ratio. HDL-C, A-I and the HDL-C/T-C ratio were directly proportional to liver phospholipids, protein and cytochrome P-450, inversely related to hepatic triglycerides. Increases in hepatic phospholipids and protein, characteristic of microsomal induction, may lead to the elevation of plasma HDL apoprotein and HDL-C levels and HDL-C/T-C ratios, and thus reduce the risk of coronary heart disease.     

内皮脂酶在动脉粥样硬化及冠心病中的研究进展

内皮脂酶(endothelial lipase,EL)是近年来发现的三酰甘油脂肪酶基因家族的新成员,它是HDL代谢的关键酶。EL通过降解HDL而在冠心病发病过程中起着重要作用。近年来的基础研究发现:EL参与了脂质代谢、内皮损伤、炎症反应这三个动脉粥样硬化(atherosclerosis,AS)形成的关键过程,因此EL可能是AS形成的枢纽及媒介。临床研究也表明EL可能是冠心病的重要危险因素。但目前EL与冠心病关系的研究多为基础研究,临床研究尚刚刚起步。     

Cholesterol and heart disease: current concepts in pathogenesis and treatment

One of the modifiable risk factors associated with coronary heart disease (CHD) is hypercholesterolemia. This paper reviews the major plasma lipids and how they relate to coronary heart disease. Among blacks, CHD is the leading cause of death and disability. Blacks, in general, have been found to have lower low density lipoprotein (LDL), lower very low density lipoprotein (VLDL), and higher high density lipoprotein (HDL) levels than whites, but there is some evidence to suggest that lipid and lipoprotein profiles may differ in middle and upper socioeconomic subgroups of the black population from those reported for lower socioeconomic groups.     

Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states

Our purpose is to provide a framework for diagnosing the inherited causes of marked high-density lipoprotein (HDL) deficiency (HDL cholesterol levels <10 mg/dL in the absence of severe hypertriglyceridemia or liver disease) and to provide information about coronary heart disease (CHD) risk for such cases. Published articles in the literature on severe HDL deficiencies were used as sources. If apolipoprotein (Apo) A-I is not present in plasma, then three forms of ApoA-I deficiency, all with premature CHD,and normal low-density lipoprotein (LDL) cholesterol levels have been described: ApoA-I/C-III/A-IV deficiency with fat malabsorption, ApoA-I/C-III deficiency with planar xanthomas, and ApoA-I deficiency with planar and tubero-eruptive xanthomas (pictured in this review for the first time). If ApoA-I is present in plasma at a concentration <10 mg/dL, with LDL cholesterol that is about 50% of normal and mild hypertriglyceridemia, a possible diagnosis is Tangier disease due to mutations at the adenosine triphosphate binding cassette protein A1 (ABCA1) gene locus. These patients may develop premature CHD and peripheral neuropathy, and have evidence of cholesteryl ester-laden macrophages in their liver, spleen, tonsils, and Schwann cells, as well as other tissues. The third form of severe HDL deficiency is characterized by plasma ApoA-I levels <40 mg/dL, moderate hypertriglyceridemia, and decreased LDL cholesterol, and the finding that most of the cholesterol in plasma is in the free rather than the esterified form, due to a deficiency in lecithin:cholesterol acyltransferase activity. These patients have marked corneal opacification and splenomegaly, and are at increased risk of developing renal failure, but have no clear evidence of premature CHD. Marked HDL deficiency has different etiologies and is generally associated with early CHD risk.     

HDL-ApoE Content Regulates the Displacement of Hepatic Lipase from Cell Surface Proteoglycans

Human hepatic lipase (HL) is an interfacial enzyme that must be liberated from cell surface proteoglycans to hydrolyze lipoprotein triglyceride. Both high-density lipoprotein (HDL) and apolipoprotein (apo)A-I can displace HL from cell surface proteoglycans, much like heparin. HL displacement is inhibited by HDL-apoE content. Postprandial HDL is approximately twofold better at displacing HL than is fasting HDL, but only has approximately one-half the apoE content. Enriching native HDL with triglyceride decreases HDL-apoE content and increases HL displacement. Incubation of HDL with the anti-apoE antibody, 6C5, also increases HL displacement. In contrast, enrichment of synthetic HDL with apoE significantly inhibits HL displacement. HDL from fasted female normolipidemic subjects displaces HL approximately twofold better than HDL from male subjects. HDL from female subjects also has significantly less apoE than HDL from males. Normolipidemic females have increased circulating HDL-bound HL. Hyperlipidemia has little effect on the HL displacement ability of HDL from men, whereas HDL from hypercholesterolemic females exhibits impaired HL displacement. HL displacement from liver heparan sulfate proteoglycans therefore appears to be linked to interlipoprotein apoE exchange. Decreased HL displacement is associated with higher HDL-apoE levels and may therefore affect vascular triglyceride hydrolysis.Hepatic lipase (HL) is an interfacial enzyme that is bound to the surface of hepatocytes by heparan sulfate proteoglycans (HSPG).¹ HL hydrolyzes both triglycerides (TG) and phospholipids in plasma lipoproteins. HL activity is undetectable in fasted plasma and can only be measured after HL is released from the liver with an injection of heparin. Elevated postheparin HL activities are considered to be a risk factor of heart disease and correspond to a pro-atherogenic lipid profile. Patients with familial hyperlipidemia² and type 2 diabetes patients,³ who are at a higher risk for heart disease, also have elevated postheparin HL activity. Other heart disease risk factors have also been linked to a higher postheparin HL activity including smoking,⁴ visceral obesity,⁵ and sedentary lifestyle.⁶ An increase in androgenous hormones, such as testosterone, leads to an increase in postheparin HL activity^7,8 and an increase in estrogen can lower postheparin HL activity.^9,10 Women consequently tend to have a lower postheparin activity than men.¹¹HL must be liberated from cell surface HSPG to hydrolyze lipoprotein TG.¹² A higher postheparin activity therefore appears to be a marker for a larger liver depot of inactive HSPG-bound HL. High-density lipoprotein (HDL) has been shown to displace HL from the cell surface much like heparin^12,13,14; however, the composition of the HDL can affect its ability to displace HL. While apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II) and apolipoprotein C-I (apoC-I) appear to stimulate HL displacement, other apoproteins had the opposite effect and blocked HDL from displacing cell surface HL.^12,13,14 Apolipoprotein E (apoE) is an exchangeable apolipoprotein present on both HDL- and TG-rich lipoproteins. Plasma apoE levels appear to correlate to postheparin HL activity.^15,16 It has been shown that women have lower plasma apoE levels than men^15,16 and that hyperlipidemic patients have higher amounts of plasma apoE than normolipidemic subjects.^17,18,19 Subjects with very high levels of plasma apoE have also been shown to be hypertriglyceridemic¹⁷ and high levels of apoE can increase cardiovascular disease mortality, specifically in the older population.²⁰In this study, we show that increasing apoE content of synthetic HDL directly inhibits HL displacement. Conversely, HDL isolated at the peak of a postprandial response contains less apoE and is more effective at displacing HL, than HDL isolated from fasted plasma. HDL isolated from females contains lower levels of apoE and displaces more HL from cell-surface HSPG, than HDL isolated from males. Women were also shown to have significantly more HDL-bound HL circulating in their bloodstream. Interlipoprotein apoE movement therefore plays central role in regulating the displacement and hydrolytic activity of HL.     

Fenofibrate improves postprandial chylomicron clearance in II B hyperlipoproteinemia

In 11 patients with 1113 hyperlipoproteinemia we studied fasting lipids, lipoproteins, lipoprotein-modifying enzymes, and postprandial lipid metabolism after a standardized oral fat load supplemented with vitamin A before and 12 weeks after treatment with fenofibrate, a third-generation fibric acid derivative. Fasting plasma cholesterol, triglycerides, low-density lipoprotein cholesterol decreased significantly (P < 0.05, P < 0.01, P < 0.01), high-density lipoprotein subfraction 3 cholesterol increased significantly (P < 0.05), and high-density lipoprotein subfraction 2 cholesterol remained unchanged. Postprandial lipemia, i.e., the integrated postprandial triglyceride concentrations corrected for the fasting triglyceride level, and postprandial chylomicron concentrations, as assessed by biosynthetic labeling of chylomicrons with retinyl palmitate, decreased by 40.6% and 60.1% (P < 0.05; P < 0.05), respectively. The activity of lipoprotein lipase (LPL) increased by 33.6% (P < 0.05); the increase in LPL during fenofibrate treatment was positively correlated with the increase in high-density lipoprotein cholesterol (r = 0.84; P < 0.005). Hepatic lipase and cholesteryl ester transfer protein mass and activity remained unchanged. We conclude that lipid-lowering therapy with fenofibrate ameliorates fasting and, more profoundly, postprandial lipoprotein transport in hypertriglyceridemia by curbing postprandial triglyceride and chylomicron accumulation, at least in part, through an increase in LPL activity.Abbreviations LDL low-density lipoproteins - HDL high-density lipoproteins - LPL lipoprotein lipase - HL hepatic lipase - CETP cholesteryl ester transfer protein - CHD coronary heart disease - VLDL very low density lipoproteins - TG triglycerides - apo apolipoprotein Correspondence to: J.R. Patsch     

Effects of ethanol on lipids and atherosclerosis.

Moderate alcohol consumption is associated with an increase in plasma high density lipoprotein (HDL) cholesterol concentration and a decrease in low density lipoprotein (LDL) cholesterol concentration. Changes in the concentration and composition of lipoproteins are estimated to account for more than half of alcohol's protective effect for coronary heart disease. Alcohol intake also affects plasma proteins involved in lipoprotein metabolism: cholesteryl ester transfer protein, phospholipid transfer protein, lecithin:cholesterol acyltransferase, lipoprotein lipase, hepatic lipase, and phospholipases. In addition, alcohol intake may result in acetaldehyde modification of apolipoproteins. Furthermore, "abnormal" lipids, phosphatidylethanol and fatty acid ethyl esters are formed in the presence of ethanol and are associated with lipoproteins in plasma. Ethanol and ethanol-induced modifications of lipids may modulate the effects of lipoproteins on the cells in the arterial wall. The molecular mechanisms involved in these processes are complex, requiring further study to better understand the specific effects of ethanol in the pathogenesis of atherosclerosis. This review discusses the effects of ethanol on lipoproteins and lipoprotein metabolism, as well as the novel effects of lipoproteins on vascular wall cells.     

小而密低密度脂蛋白及常见血脂指标与冠心病的相关性研究

目的 探讨血清小而密低密度脂蛋白(small dense low-density lipoprotein, sd-LDL)水平与血清胆固醇(cholesterol,CHO)、甘油三酯(triglyceride, TG)、低密度脂蛋白(low density lipoprotein,LDL)指标与冠心病(coronary heart disease, CHD)的发生发展及各指标之间的相互关系.方法 选取CHD患者87例作为病例组,其中男48例,女39例.纳入109例健康体检者作为对照组,男52例,女57例.采用全自动日立7600仪器,日本积水相关检测试剂测定各组血清CHO、TG、LDL水平,血清sd-LDL水平采用九强小而密低密度脂蛋白测定试剂于雅培C16000仪器上进行测定.采用SPSS 22.0软件进行相关数据分析.结果 病例组血清CHO水平、LDL水平及sd-LDL水平高于正常对照组,差异具有统计学意义(P<0.01).女性病例组TG水平高于对照组,男性及总体病例组与对照组TG水平差异无统计学意义.年龄和sd-LDL水平为冠心病相关的独立危险因素.冠心病患者血清sd-LDL与CHO、TG及LDL水平均呈显著正相关,血清LDL与CHO呈显著正相关(P<0.01).结论 血清sd-LDL是独立的冠心病危险因素,血脂常规项目联合sd-LDL对于冠心病的早期预测可能具有更好的提示和诊断作用.     

老年冠心病患者血浆HCY、CRP和血脂水平变化及其与冠脉病变程度的关系

目的:探讨冠心病(CHD)患者血浆同型半胱氨酸(HCY)水平与冠脉病变程度及C-反应蛋白(CRP)、血脂水平的关系。方法:检测102例CHD患者和27例正常对照人群的血浆HCY和CRP、甘油三酯(TG)、总胆固醇(TC)和脂蛋白(a)[LP(a)]水平,并进行比较及相关性分析。结果:CHD组血浆HCY以及CRP、TG、TC、LP(a)水平显著高于正常对照组;CHD组血浆HCY水平与CRP、TG、TC、LP(a)无明显相关性(P>0.05),血浆HCY、CRP、TG、TC、LP(a)水平随着冠脉病变支数增加而增高,呈显著正相关。结论:高血浆HCY是CHD的独立危险因素,对CHD的预防和诊断具有一定的临床意义。     

氧化型高密度脂蛋白与冠状动脉粥样硬化性心脏病的 相关性分析

目的 研究冠状动脉粥样硬化性心脏病（CHD）患者血浆中氧化型高密度脂蛋白（ox-HDL）水平与冠状动脉病变程度（Gensini评分）之间的相关性,ox-HDL与高密度脂蛋白胆固醇（HDL-C）的比值（ox-HDL/HDL-C）相较HDL-C对血浆HDL真实水平的代表性。方法 选取2018年7月~2019年2月于新乡医学院第一附属医院心内科二病区住院行冠状动脉造影被确诊为冠心病的患者84例为实验组,另选取冠状动脉造影正常者44例为对照组,通过酶联免疫吸附剂（ELISA）检测所有研究对象血浆中ox-HDL水平,应用Pearson相关性分析实验组内ox-HDL、ox-HDL/HDL-C分别与Hcy、冠状动脉粥样硬化病变程度（采用Gensini评分评价）的相关性。结果 实验组ox-HDL水平高于对照组,差异具有统计学意义（P＜0.05）;ox-HDL与Gensini评分呈现明显的正相关（r=0.335,P＜0.01）;oxHDL/HDL-C与Gensini评分之间呈显著正相关（r=0.819,P＜0.01）;多因素Logistic回归分析结果表明ox-HDL水平与冠心病的病变程度相关。结论 ox-HDL是冠心病的危险因素,应用ox-HDL及ox-HDL/HDL-C可以更好的评价冠状动脉病变程度以及冠心病患者血浆HDL-C的真实水平,ox-HDL可能会成为动脉粥样硬化的新的危险因素和治疗的新靶点。     

Association between -250G/A polymorphism of the hepatic lipase gene promoter and coronary artery disease and HDL-C levels in a Southern Brazilian population

Hepatic lipase (HL) is a glycoprotein that plays a major role in remodeling high-density lipoprotein (HDL). The effect of the -250G/A promoter polymorphism on coronary artery disease (CAD) and lipid levels was studied in 231 male CAD patients and in a population-based sample of men and women (n = 514). A sample of 140 men was chosen among those included in the population-based sample as controls for the CAD sample. In the total group of CAD patients, the frequency of the -250A allele was somewhat lower (25% in CAD patients and 32% in controls; p = 0.06), but when the control samples were compared only with the CAD(+) sample (more than 60% of luminal stenosis in at least one coronary artery or major branch segment) the -250A allele was significantly less frequent (23% in the patients vs 32% in controls; p = 0.02). A multiple logistic regression analysis showed that this association was independent of classical CAD risk factors [odds ratio (OR) = 1.79, p = 0.025]. Using multiple linear regression analyses, it has been shown that this polymorphism was a significant factor affecting HDL-C levels in men from the population-based sample (p = 0.001), an interaction between -250G/A variant and wine consumption was also detected (p = 0.001). Thus, our results show that the -250G/A polymorphism in the HL gene is associated with significant variations in HDL-C levels and CAD risk in males.     

Higher values of hepatic lipase activity in postmenopause: relationship with atherogenic intermediate density and low density lipoproteins

OBJECTIVE: To investigate the enzymatic activity of hepatic lipase (HL) in postmenopausal women (PMW) and reproductive age women (RAW); and to evaluate the relationship between this enzyme and the atherogenic intermediate density lipoproteins (IDL) and low density lipoproteins (LDL), and antiatherogenic high density lipoproteins (HDL) and its subfractions (HDL2 and HDL3). DESIGN: We studied 55 PMW receiving no hormonal treatment in a cross-sectional study in comparison with a control group of 55 RAW, matched by body mass index. Follicle-stimulating hormone was > 40 mUI/ml in PMW and 3-12 mUI/ml in RAW. PMW presented at least 1 year of natural menopause and no more than 10 years of amenorrhea with E2 serum concentration < 15 pg/ml. RESULTS: HL activity was significantly higher in PMW versus RAW (14.0 +/- 1.4 vs. 10.9 +/- 0.4 micromol of fatty acids/ml of postheparin plasma, respectively, mean +/- SEM, p < 0.001). In PMW, IDL cholesterol showed a positive correlation with LDL cholesterol (r = 0.28, p < 0.05), and HDL2 cholesterol was inversely correlated with HL activity (r = 0.31, p < 0.05). HL was positively correlated with plasma concentration of LDL cholesterol in both groups (r = 0.27, p < 0.05). The higher values of HL activity and IDL cholesterol were independent of age. CONCLUSIONS: Higher HL activity is associated with a more atherogenic profile in PMW.     

Glucose tolerance,plasma lipoproteins and tissue lipoprotein lipase activities in body builders

Summary Oral glucose tolerance, insulin binding to erythrocyte receptors, serum lipids, and lipoproteins, and lipoprotein lipase activities of adipose tissue and skeletal muscle were measured in nine body builders (relative body weight (RBW) 118±4%), eight weight-matched (RBW 120±5%) and seven normal-weight controls (RBW 111±3%). The body builders had 50% higher relative muscle mass of body weight (% muscle) and 50% smaller relative body fat content (% fat) than the two other groups (P<0.005). Maximal aerobic power was comparable in the three groups. In the oral glucose tolerance test (OGTT), blood glucose levels, and plasma insulin levels were lower (P<0.05) in the body builders than in weight-matched controls. Insulin binding to erythrocytes was similar in each group. On the basis of multiple linear regression analysis, 87% of the variation in plasma insulin response could be explained by body composition (% muscle and % fat) and .Plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL) triglyceride concentrations were significantly lower in the body builders than in weight-matched controls. In comparison with the normal-weight group, the body builders had a lower total cholesterol level. High density lipoprotein (HDL) cholesterol, its subfractions (HDL₂ and HDL₃ cholesterol) and lipoprotein lipase (LPL) activities of adipose tissue and skeletal muscle were comparable in all three groups. Partial correlation analysis showed a positive relationship between plasma total triglyceride, total cholesterol and LDL cholesterol on the other hand and the % fat on the other.The results indicate that a shift in body composition from the adipose to the muscular type is associated with 1) lower glucose and insulin levels during the OGTT and 2) decrease in total and VLDL triglyceride and in total and LDL cholesterol levels but unchanged HDL cholesterol level. Thus, body builders are characterized by some metabolic features which decrease the risk of coronary heart disease. In contrast to aerobic training, body building does not influence HDL or its subfractions.     

The LPL S447X cSNP is associated with decreased blood pressure and plasma triglycerides, and reduced risk of coronary artery disease

Linkage of the lipoprotein lipase (LPL) gene to blood pressure levels has been reported. The LPL S447X single nucleotide polymorphism (cSNP) has been associated with decreased triglycerides (TG), increased high density lipoprotein cholesterol, and a decreased risk of coronary artery disease (CAD), which may occur independently of its beneficial lipid changes. To investigate the relationship between LPL S447X cSNP and these parameters, we studied a cohort of individuals with familial hypercholesterolemia in whom blood pressures and information regarding the use of blood pressure lowering medications were available. Carriers of the S447X variant had decreased TG (1.21+/-0.47 vs. 1.52+/-0.67, p<0.001) and a trend towards decreased vascular disease (12.7 vs. 19.5%) compared to non-carriers. More interestingly, however, carriers of this cSNP had decreased diastolic blood pressure compared to non-carriers (78+/-10 vs. 82+/-11, p=0.002), evident in both men and women, youths and adults, with similar trends for systolic blood pressure. Furthermore, the decrease in blood pressure appeared independent of the decrease in TG (p=0.02), suggesting that the LPL protein may have a direct influence on the vascular wall. This suggests an additional mechanism whereby this variant may have protective effects, independent of changes in plasma lipid levels.     

C-514T polymorphism in hepatic lipase gene promoter is associated with elevated triglyceride levels and decreasing insulin sensitivity in nondiabetic Japanese subjects

Hepatic lipase (HL) is synthesized in the liver and hydrolyses triglyceride and phospholipids. C-514T polymorphism in HL gene promoter was reported to associate with hepatic lipase activity and plasma lipid levels. We examined whether C-514T polymorphism affects glucose metabolism beyond its effect on plasma lipid levels in nondiabetic Japanese subjects. Gene frequencies of C/C homozygote, C/T heterozygote and T/T homozygote were 18, 51 and 31%, respectively. The allelic frequencies of C and T were 44 and 56%, respectively. T allele frequency was much higher than in Caucasian subjects. Moreover, -514T allele carriers had higher levels of triglyceride (P=0.027), fasting insulin (P=0.016) and HOMA-IR (P=0.033) than non-carriers. In contrast to some former studies, -514T allele affected triglyceride levels and insulin sensitivity. Taken together, HL gene might be one of the important susceptibility genes of type 2 diabetes and the high incidence of type 2 diabetes could be explained by high frequency of -514T allele in the Japanese population. Moreover, since HL and adiponectin showed an additive effect on insulin sensitivity, these genetic variations can be independently associated with insulin sensitivity.     

Identification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans

Triglyceride (TG) metabolism is crucial for whole body and local energy homeostasis and accumulating evidence suggests an independent association between plasma TG concentration and increased atherosclerosis risk. We previously generated a mouse insertional mutation lpd (lipid defect) whose phenotype included elevated plasma TG and hepatic steatosis. Using shotgun sequencing (approximately 500 kb) and bioinformatics, we have now identified a novel lipase gene lpdl (lpd lipase) within the lpd locus, and demonstrate the genetic disruption of exon 10 of lpdl in the lpd mutant locus. lpdl is highly expressed in the testis and weakly expressed in the liver of 2-week old mice. Human LPDL cDNA was subsequently cloned, and was found to encode a 460AA protein with 71% protein sequence identity to mouse lpdl and approximately 35% identity to other known lipases. We next sequenced the human LPDL gene exons in hypertriglyceridemic subjects and normal controls, and identified seven SNPs within the gene exons and six SNPs in the adjacent introns. Two hypertriglyceridemic subjects were heterozygous for a rare DNA variant, namely 164G>A (C55Y), which was absent from 600 normal chromosomes. Two other coding SNPs were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. Using bioinformatics, we identified another novel lipase designated LPDLR (for 'LPDL related lipase'), which had 44% protein sequence identity with LPDL. Together with the phospholipase gene PSPLA1, LPDL and LPDLR form a new lipase gene subfamily, which is characterized by shortened lid motif. Study of this lipase subfamily may identify novel molecular mechanisms for plasma and/or tissue TG metabolism.     

Reduced plasma concentrations of total, low density lipoprotein and high density lipoprotein cholesterol in patients with Gaucher type I disease

Plasma lipid and serum apoprotein concentrations were determined in twenty-nine individuals with Gaucher type I disease. Plasma total cholesterol, low density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol were all significantly reduced in the patients with Gaucher disease compared to a group of matched control subjects. Total, LDL and HDL cholesterol were lower in males than in females with Gaucher disease. These sex differences appeared to be inversely correlated with the severity of disease manifestations which were greater in the males. Serum levels of apoprotein-B and apoprotein-AI, the major structural apoproteins of LDL and HDL, respectively, were decreased in the subjects with Gaucher disease. Thus, the reductions in LDL and HDL cholesterol were associated with reduced numbers of lipoprotein particles in plasma. In contrast, apoprotein-E, a protein which is secreted by several tissues, including activated macrophages and which may mediate hepatic catabolism of lipoproteins, was elevated in the patients. Since macrophages may also catabolize lipoproteins, Gaucher disease may serve as a model for the effect of activated macrophages upon human lipoprotein metabolism.
This work was supported by the following grants: USPHS HL 23077, HD 07105, HL 25752, CA 31656 and RR-71 from the National Institutes of Health; 1–273 and 1–578 from the March of Dimes Birth Defects Foundation; grant from the New York Heart Assocation. Dr. Ginsberg is a recipient of a Research Career Development Award HL 00949 and is an Irma T. Hirschl Career Scientist. Dr. Grabowski is a recipient of a Clinical Investigator Award HD 00386.