Polymorphisms in the gene encoding lipoprotein lipase in men with low HDL-C and coronary heart disease: the Veterans Affairs HDL Intervention Trial

Our goal was to further define the role of LPL gene polymorphisms in coronary heart disease (CHD) risk. We determined the frequencies of three LPL polymorphisms (D9N, N291S, and S447X) in 899 men from the Veterans Affairs HDL Intervention Trial (VA-HIT), a study that examined the potential benefits of increasing HDL with gemfibrozil in men with established CHD and low high density lipoprotein cholesterol (HDL-C; < or =40 mg/dl), and compared them with those of men without CHD from the Framingham Offspring Study (FOS). In VA-HIT, genotype frequencies for LPL D9N, N291S, and S447X were 5.3, 4.5, and 13.0%, respectively. These values differed from those for men in FOS having an HDL-C of >40, who had corresponding values of 3.2% (P = 0.06), 1.5% (P < 0.01), and 18.2% (P < 0.01). On gemfibrozil, carriers of the LPL N9 allele in VA-HIT had lower levels of large LDL (-32%; P < 0.01) but higher levels of small, dense LDL (+59%; P < 0.003) than did noncarriers. Consequently, mean LDL particle diameter was smaller in LPL N9 carriers than in noncarriers (20.14 +/- 0.87 vs. 20.63 +/- 0.80 nm; P < 0.003). In men with low HDL-C and CHD: 1) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C, whereas the X447 allele is less frequent, and 2) the LPL N9 allele is associated with the LDL subclass response to gemfibrozil.     

Lipoprotein lipase and apoE polymorphisms: relationship to hypertriglyceridemia during pregnancy.

Pregnancy is associated with increases in plasma total cholesterol (TC) and triglycerides (TG). Individuals with decreased LPL activity have a mild form of hypertriglyceridemia. Variations in the apolipoprotein E (apoE) gene have been associated with increases in plasma TG in addition to differences in plasma TC, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C). Because of the overproduction of TG-rich VLDL, normal pregnancy challenges the lipolytic capacity of LPL and the clearance of remnants particles. During pregnancy, LPL and apoE polymorphisms may contribute to hypertriglyceridemia. This study investigated the impact of three LPL polymorphisms and the apoE genotypes on lipid levels during pregnancy. Fasting plasma lipids were measured and analyses of the LPL and apoE polymorphisms were performed in 250 women in the third trimester of pregnancy. S447X carriers had lower TG (P = 0.003), and N291S carriers had lower HDL-C (P < 0.02) and higher fractional esterification rate of HDL (FER(HDL)) (P = 0.007), a measure of HDL particle size, than the noncarriers. The E2 allele was associated with lower TC, LDL-C, and FER(HDL) (P < 0.05) compared to the E3/E3 genotype. These findings support that LPL and apoE polymorphisms play an important role in lipid metabolism in pregnancy. The relationship of these polymorphisms to risk of coronary heart disease in women requires further study.     

Novel mutations of the lipoprotein lipase gene associated with hypertriglyceridemia in members of type 2 diabetic pedigrees

Increased plasma triglyceride and free fatty acid levels are frequently associated with type 2 diabetes mellitus (T2DM). To test the hypothesis that LPL gene mutations contribute to the hypertriglyceridemia observed in members of T2DM pedigrees, we screened the LPL gene in 53 hypertriglyceridemic members of 26 families. Four known and three novel mutations were identified. All three novel mutations, Lys312insC, Thr361insA, and double mutation Lys312insC + Asn291Ser, are clinically associated with hypertriglyceridemia. In vitro mutagenesis and expression studies confirm that these variants are associated with a significant reduction in LPL activity. The modeled structures displaying the Lys312insC and Thr361insA mutations showed loss of the activity-related C-terminal domain in the LPL protein. Another novel double mutation, Lys312insC + Asn291Ser, resulted in the loss of the catalytic ability of LPL attributable to the complete loss of the C-terminal domain and alteration in the heparin association site. Thus, these novel mutations of the LPL gene contribute to the hypertriglyceridemia observed in members of type 2 diabetic pedigrees.     

Delayed clearance of postprandial large TG-rich particles in normolipidemic carriers of LPL Asn291Ser gene variant.

The carrier frequency of Asn291Ser polymorphism of the lipoprotein lipase (LPL) gene is 4;-6% in the Western population. Heterozygotes are prone to fasting hypertriglyceridemia and low high density lipoprotein (HDL) cholesterol concentrations especially when secondary factors are superimposed on the genetic defect. We studied the LPL Asn291Ser gene variant as a modulator of postprandial lipemia in heterozygote carriers. Ten normolipidemic carriers were compared to ten control subjects, who were selected to have similar age, sex, BMI, and apolipoprotein (apo)E-phenotype. The subjects were given a lipid-rich mixed meal and their insulin sensitivity was determined by euglycemic hyperinsulinemic clamp technique. The two groups had comparable fasting triglycerides and glucose utilization rate during insulin infusion, but fasting HDL cholesterol was lower in carriers (1.25 +/- 0.05 mmol/L) than in the control subjects (1. 53 +/- 0.06 mmol/L, P = 0.005). In the postprandial state the most pronounced differences were found in the very low density lipoprotein 1 (VLDL1) fraction, where the carriers displayed higher responses of apoB-48 area under the curve (AUC), apoB-100 AUC, triglyceride AUC, and retinyl ester AUC than the control subjects. The most marked differences in apoB-48 and apoB-100 concentrations were observed late in the postprandial period (9 and 12 h), demonstrating delayed clearance of triglyceride-rich particles of both hepatic and intestinal origin. Postprandially, the carriers exhibited enrichment of triglycerides in HDL fraction. Thus, in normolipidemic carriers the LPL Asn291Ser gene variant delays postprandial triglyceride, apoB-48, apoB-100, and retinyl ester metabolism in VLDL1 fraction and alters postprandial HDL composition compared to matched non-carriers.     

Atherogenic Dyslipidemia in Children: Evaluation of Clinical,Biochemical and Genetic Aspects

The precursors of atherogenic dyslipidemia (AD) are not well defined. Therefore, we investigated 62 non-obese, non-diabetic AD and 221 normolipemic children. Anthropometric parameters, blood pressure and biochemical measures were obtained in index children, their parents and all available siblings. The heritability (h²) of anthropometric and biochemical traits was estimated by SOLAR. Rare and common variants in APOA1 and LPL genes were screened by re-sequencing. Compared to normolipemic, AD children showed increased body mass index, waist circumference, plasma glucose, insulin, ApoB, HOMA-IR, hs-CRP and lower adiponectin (p<0.001 for all). Metabolic syndrome was present in 40% of AD while absent in controls. All traits (except adiponectin and hs-CRP) showed a strong familial aggregation, with plasma glucose having the highest heritability (89%). Overall, 4 LPL loss-of-function mutations were detected (p.Asp9Asn, p.Ser45Asn, p.Asn291Ser, p.Leu365Val) and their cumulative prevalence was higher in AD than in control children (0.073 vs. 0.026; P=0.038). The LPL p.S447* gain-of-function mutation, resulted to be less frequent in AD than in control children (0.064 vs. 0.126; P=0.082). No variant in the APOA1 gene was found. Our data indicate that AD is a rather common dyslipidemia in childhood; it associates with metabolic abnormalities typical of insulin resistant state and shows a strong familial aggregation. LPL variants may contribute to the development of AD phenotype.     

Hepatic lipase gene -514C>T variant is associated with exercise training-induced changes in VLDL and HDL by lipoprotein lipase

Our objective was to test the hypothesis that a common polymorphism in the hepatic lipase (HL) gene (LIPC -514C>T, rs1800588) influences aerobic exercise training-induced changes in TG, very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) through genotype-specific increases in lipoprotein lipase (LPL) activity and that sex may affect these responses. Seventy-six sedentary overweight to obese men and women aged 50-75 yr at risk for coronary heart disease (CHD) underwent a 24-wk prospective study of the LIPC -514 genotype-specific effects of exercise training on lipoproteins measured enzymatically and by nuclear magnetic resonance, postheparin LPL and HL activities, body composition by dual energy x-ray absorptiometry and computer tomography scan, and aerobic capacity. CT genotype subjects had higher baseline total cholesterol, HDL-C, HDL(2)-C, large HDL, HDL particle size, and large LDL than CC homozygotes. Exercise training elicited genotype-specific decreases in VLDL-TG (-22 vs. +7%; P < 0.05; CC vs. CT, respectively), total VLDL and medium VLDL, and increases in HDL-C (7 vs. 4%; P < 0.03) and HDL(3)-C with significant genotype×sex interactions for the changes in HDL-C and HDL(3)-C (P values = 0.01-0.02). There were also genotype-specific changes in LPL (+23 vs. -6%; P < 0.05) and HL (+7 vs. -24%; P < 0.01) activities, with LPL increasing only in CC subjects (P < 0.006) and HL decreasing only in CT subjects (P < 0.007). Reductions in TG, VLDL-TG, large VLDL, and medium VLDL and increases in HDL(3)-C and small HDL particles correlated significantly with changes in LPL, but not HL, activity only in CC subjects. This suggests that the LIPC -514C>T variant significantly affects training-induced anti-atherogenic changes in VLDL-TG, VLDL particles, and HDL through an association with increased LPL activity in CC subjects, which could guide therapeutic strategies to reduce CHD risk.     

Association of lipoprotein lipase and apolipoprotein C-III genes polymorphism with acute myocardial infarction in diabetic patients

Lipoprotein lipase (LPL) and Apolipoprotein C-III (APOC-III) play an important role in lipid metabolism. The aim of this study was to explore the possible associations of the gene polymorphisms (LPL HindIII, LPL Ser(447)-Ter and APOC3 SstI), diabetes mellitus, and plasma lipids with myocardial infarction. The polymorphisms were assessed by restriction assay in 200 Egyptian MI patients (100 diabetic and 100 non-diabetic) and 100 healthy controls. This study demonstrated that individuals with the H2H2 genotype or S2 allele have more than three times higher relative risk of suffering from MI than those carrying the H1H1 or S1S1. Type 2 DM mainly lowers HDL-C levels in MI patients who carry H2H2 or S2S2 genotype and increases TC, TG, and LDL levels in MI patients carrying H2H2 or S2S2 genotype compared with non-diabetic MI patients carrying the same genotypes. In S447X polymorphism, it was observed that DM led to loss of the protective lipid profile in MI patients carrying 447XX genotype. These findings suggest that H2H2 or S2S2 genotypes are associated with dyslipidemia and increased risk of myocardial infarction. The S447X polymorphism is associated with a favorable lipid profile. However, the association of diabetes mellitus with these polymorphisms leads to unfavorable lipid profile.     

Two novel mutations in the lipoprotein lipase gene in a family with marked hypertriglyceridemia in heterozygous carriers. Potential interaction with the polymorphic marker D1S104 on chromosome 1q21-q23

Two novel mutations in the lipoprotein lipase (LPL) gene are described in an Austrian family: a splice site mutation in intron 1 (3 bp deletion of nucleotides -2 to -4) which results in skipping of exon 2, and a missense mutation in exon 5 which causes an asparagine for histidine substitution in codon 183 and complete loss of enzyme activity. A 5-year-old boy who exhibited all the clinical features of primary hyperchylomicronemia was a compound heterozygote for these two mutations. Nine other family members were investigated: seven were heterozygotes for the splice site mutation, one was a heterozygote for the missense mutation, and one had two wild-type alleles of the LPL gene. LPL activity in the post-heparin plasma of the heterozygotes was reduced to 49;-79% of the mean observed in normal individuals. Two of the heterozygotes had extremely high plasma triglyceride levels; in three of the other heterozygotes the plasma triglycerides were also elevated. As plasma triglycerides in carriers of one defective LPL allele can be normal or elevated, the heterozygotes of this family have been studied for a possible additional cause of the expression of hypertriglyceridemia in these subjects. Body mass index, insulin resistance, mutations in other candidate genes (Asn291Ser and Asp9Asn in the LPL gene, apoE isoforms, polymorphisms in the apoA-II gene and in the apoAI-CIII-AIV gene cluster, and in the IRS-1 gene) could be ruled out as possible factors contributing to the expression of hypertriglyceridemia in this family. A linkage analysis using the allelic marker D1S104 on chromosome 1q21;-q23 suggested that a gene in this region could play a role in the expression of hypertriglyceridemia in the heterozygous carriers of this family, but the evidence was not sufficiently strong to prove this assumption. Nevertheless, this polymorphic marker seems to be a good candidate for further studies.     

中国人群脂蛋白脂肪酶基因突变与高脂血症的相关性研究

为进行脂蛋白脂肪酶基因突变与中国人群高脂血症的相关性研究,采用单链构象多态性分析结合DNA序列测定的方法,对386例(其中108例高脂血症患者,278例正常对照)中国人群进行突变筛查。结果发现1个新的沉默突变L103L,1个错义突变P207L,3个剪接突变Int3/3′-ass/C(-6)→T和普遍存在的S447X多态性,其中发生在高脂血症组的P207L杂合子为亚洲首报,并对先证者的家系进行了研究,认为P207L是家族性高脂血症的病因之一,而在正常对照组中也有发现的Int3/3′-ass/C(-6)→T,对以往研究认为其是高脂血症易患因素的观点提出了相反的报告,对于普遍认为有益的多态性位点S447X,进一步研究认为其对于正常人群,特别是健康男性的保护作用更强。结论:脂蛋白脂肪酶基因变异与高脂血症的相关性十分复杂多样,大规模的人群筛查具有重要意义。     

Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins

Lipoprotein lipase (LPL) is crucial in the hydrolysis of triglycerides (TG) in TG-rich lipoproteins in the formation of HDL particles. As both these lipoproteins play an important role in the pathogenesis of atherosclerotic vascular disease, we sought to assess the relationship between post-heparin LPL (PH-LPL) activity and lipids and lipoproteins in a large, well-defined cohort of Dutch males with coronary artery disease (CAD). These subjects were drawn from the REGRESS study, totaled 730 in number and were evaluated against 75 healthy, normolipidemic male controls. Fasting mean PH-LPL activity in the CAD subjects was 108 46 mU/ml, compared to 138 44 mU/ml in controls (P < 0.0001). When these patients were divided into activity quartiles, those in the lowest versus the highest quartile had higher levels of TG (P < 0.001), VLDLc and VLDL-TG (P = 0.001). Conversely, levels of TC, LDL, and HDLc were lower in these patients (P = 0.001, P = 0.02, and P = 0.001, respectively). Also, in this cohort PH-LPL relationships with lipids and lipoproteins were not altered by apoE genotypes. The frequency of common mutations in the LPL gene associated with partial LPL deficiency (N291S and D9N carriers) in the lowest quartile for LPL activity was more than double the frequency in the highest quartile (12.0% vs. 5.0%; P = 0.006). By contrast, the frequency of the S447X LPL variant rose from 11.5% in the lowest to 18.3% (P = 0.006) in the highest quartile. This study, in a large cohort of CAD patients, has shown that PH-LPL activity is decreased (22%; P = 0.001) when compared to controls; that the D9N and N291S, and S447X LPL variants are genetic determinants, respectively, in CAD patients of low and high LPL PH-LPL activities; and that PH-LPL activity is strongly associated with changes in lipids and lipoproteins.     

Lipoprotein lipase activity and common gene variants in severely hypertriglyceridemic patients with and without diabetes

OBJECTIVES: In severe type IV hypertriglyceridemia (triglyceride levels >10 g/l), it is yet unknown whether lipoprotein lipase (LPL) differs according to the presence or not of diabetes. METHODS: We compared LPL activity and the presence of four common variants in the LPL gene (Asp 9 Asn (exon 2), Gly 188 Glu (exon 5), Asn 291 Ser (exon 6) and Ser 447 Ter (exon 9)) in a group of 34 patients of whom 17 presented diabetes mellitus. RESULTS: Maximum triglyceride, cholesterol levels and distribution of apolipoprotein E phenotypes did not differ between the two subgroups. Mean post-heparin LPL activity was lower in non-diabetic compared to diabetic patients (9.74 vs. 12.98 micromol FFA/ml/h, p=0.033). Four patients were carrying a mutation in exon 9 (1 non-diabetic), 6 patients in exon 2 (4 non-diabetic) and 1 patient in the non-diabetic subgroup in exon 5. All mutations were at the heterozygous state. CONCLUSION: We found that LPL activity was lower in type IV hyperlipidemia in the absence of diabetes. Genetic defects in the LPL gene that could lead to this lower LPL tended to be more frequently observed in patients without diabetes. These data suggest that the pathomechanisms which contribute to severe type IV hyperlipidemia are different according to the presence or not of diabetes.     

Associations of LPL and APOC3 gene polymorphisms on plasma lipids in a Mediterranean population: interaction with tobacco smoking and the APOE locus

We conducted a cross-sectional study in a Spanish population (n = 1,029) to investigate associations between the LPL and APOC3 gene loci (LPL-HindIII, LPL-S447X, and APOC3-SstI) and plasma lipid levels and their interaction with APOE polymorphisms and smoking. Carriers of the H(-) or the X447 allele had higher levels of HDL cholesterol (HDL-C), and lower levels of TG, after adjustment for age, body mass index, alcohol, smoking, exercise, and education (P < 0.01). The APOC3 polymorphism presented additive effects to the LPL variants on TG and HDL-C levels in men, and on TG in women. The most and the least favorable haplotype combinations were H(-)/X447/S1 and H(+)/S447/S2, respectively. These combinations accounted for 7% and 5% of the variation in HDL-C and TG in men, and 3% and 4% in women. There was a significant interaction between APOE and LPL variants and HDL-C levels in both genders (P < 0.05). The increases in HDL-C observed for the rare alleles were higher in epsilon4 than in epsilon3 subjects, and absent in epsilon2 individuals. This effect was modulated by smoking (interaction HindIII-APOE-smoking, P = 0.019), indicating that smoking abolished the increase in HDL-C levels observed in epsilon4/H(-) subjects.Understanding this gene-gene-environmental interaction may facilitate preventive interventions to reduce coronary artery disease risk.     

Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student''s t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins     

Genetic variants of the lipoprotein lipase gene and myocardial infarction in the Central Valley of Costa Rica

To assess common variants of the LPL gene that could influence susceptibility to myocardial infarction (MI), we assessed three functional single-nucleotide polymorphisms (SNPs), D9N, N291S, and S447X, in 1,321 survivors of a first acute MI and 1,321 population-based controls, matched for age, gender, and area of residence, all living in the Central Valley of Costa Rica. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI). The frequency of the X447 mutant allele was significantly lower in cases than in controls (6.2% vs. 7.6%; P < 0.01), whereas no association with MI was found for D9N or N291S. The OR (95% CI) for carriers vs. noncarriers of the X447 allele was 0.80 (0.63-1.01); when considering the haplotype that contained X447 and normal alleles of D9N and N291S, the OR (95% CI) was 0.66 (0.48-0.91). Twelve other SNPs were assessed in a subgroup of the population, of which the four functional SNPs were found to be monomorphic, and no correlation with MI was observed for the other eight neutral SNPs. The X447 mutant allele of the LPL gene may protect from MI risk, although this effect is small.     

Genetic screening of the lipoprotein lipase gene for mutations associated with high triglyceride/low HDL-cholesterol levels

The lipoprotein lipase (LPL) enzyme plays a major role in lipid metabolism, primarily by regulating the catabolism of triglyceride (TG)-rich lipoprotein particles. The gene for LPL is an important candidate for affecting the risk of atherlosclerosis in the general population. Previously, we have shown that the HindIII polymorphism in intron 8 of the LPL gene is associated with plasma TG and HDL-cholesterol variation in Hispanics and non-Hispanic whites (NHWs). However, this polymorphism is located in an intron and hence may be in linkage disequilibrium with a functional mutation in the coding region or intron-exon junctions of the LPL gene. The aim of this study was to initially screen the LPL coding region and the intron-exon junctions by single-strand conformation polymorphism (SSCP) analysis for mutation detection in a group of 86 individuals expressing the phenotype of high TG/low HDL, followed by association studies in a population-based sample of 1,014 Hispanics and NHWs. Four sequence variations were identified by SSCP and DNA sequencing in the coding region of the gene, including two missense mutations (D9N in exon 2 and N291S in exon 6), one samesense mutation (V108V in exon 3), and one nonsense mutation (S447X in exon 9). Multiple regression analyses, including these four mutations and the HindIII polymorphic site, indicate that the association of the HindIII site with plasma TG (P=0.001 in NHWs and P=0.002 in Hispanics) and HDL-cholesterol (P=0.007 in NHWs and P=0.127 in Hispanics) is independent of all other LPL variable sites examined. These observations reinforce the concept that the intronic 8 HindIII site is functional by itself and provide a strong rationale for future comprehensive functional studies to delineate its biological significance.     

Interaction of PPARG Pro12Ala with dietary fat influences plasma lipids in subjects at cardiometabolic risk

The PPARγ2 gene single nucleotide polymorphism (SNP) Pro12Ala has shown variable association with metabolic syndrome traits in healthy subjects. The RISCK Study investigated the effect of interaction between genotype and the ratio of polyunsaturated:saturated (P:S) fatty acid intake on plasma lipids in 367 white subjects (ages 30-70 years) at increased cardiometabolic risk. Interaction was determined after habitual diet at recruitment, at baseline after a 4-week high-SFA (HS) diet, and after a 24-week reference (HS), high-MUFA (HM), or low-fat (LF) diet. At recruitment, there were no significant associations between genotype and plasma lipids; however, P:S × genotype interaction influenced plasma total cholesterol (TC) (P = 0.02), LDL-cholesterol (LDL-C) (P = 0.002), and triglyceride (TG) (P = 0.02) concentrations. At P:S ratio ≤ 0.33, mean TC and LDL-C concentrations in Ala12 allele carriers were significantly higher than in noncarriers (respectively, P = 0.003; P = 0.0001). Significant trends in reduction of plasma TC (P = 0.02) and TG (P = 0.002) concentrations occurred with increasing P:S (respectively, ≤0.33 to >0.65; 0.34 to >0.65) in Ala12 allele carriers. There were no significant differences between carriers and noncarriers after the 4-week HS diet or 24-week interventions. Plasma TC and TG concentrations in PPARG Ala12 allele carriers decrease as P:S increases, but they are not dependent on a reduction in SFA intake.     

Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins

Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg^-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice.     

Lipoprotein lipase activity determined in vivo is lower in carriers of apolipoprotein A-V gene variants 19W and -1131C

The apolipoprotein A-V (apo A-V) plays an important role in regulation of triglyceride (TG) concentration in serum. To better understand how apo A-V affects triglyceridemia and glucoregulation, the lipoprotein lipase (LPL) activity was determined using intravenous fat tolerance test (IVFTT) and oral glucose tolerance test (oGTT) was performed in carriers of apolipoprotein A-V gene (APOAV) variants known to be associated with increased triglyceridemia. Twelve carriers of 19W variant, 16 carriers of -1131C variant, 1 combined heterozygote and 16 control subjects homozygous for wild type variants (19S/-1131T) were selected from a population sample and matched with respect to body mass index and age. The APOAV variants carriers had increased TG, very low density lipoprotein-TG, and apo B concentrations (p < 0.05). The LPL activity evaluated as k(2) rate constant for clearance of Intralipid was 14 % lower in APOAV variants carriers. The depression of nonesterified fatty acids (NEFA) concentration after glucose load was delayed in APOAV variants carriers in spite of the same insulinemia and glycemia. Our results suggest that variants of APOAV combined with increased triglyceridemia are associated with lower LPL activity in vivo and with disturbances of regulation of NEFA concentration after glucose load.     

脂蛋白酯酶与动脉粥样硬化

脂蛋白酯酶(1ipopmtein lipase,LPL)是调节脂蛋白代谢的一种关键酶,如具有水解血浆脂蛋白中三酰甘油的作用等．体内LPL减少会导致血三酰甘油升高和高密度脂蛋白胆固醇降低,增加患动脉粥样硬化的危险．通过提高LPL的活性可以抑制动脉粥样硬化的发生发展．已有的研究说明NO-1886促进心肌和脂肪组织LPL mRNA表达,提高心肌、脂肪组织、骨骼肌和血液中LPL活性,因而改善脂蛋白代谢,抑制动脉粥样硬化．     

Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study.

Evidence of a gene-exercise interaction for traits related to body composition is limited. Here, the association between the lipoprotein lipase (LPL) S447X polymorphism and changes in body mass index, fat mass, percent body fat, abdominal visceral fat measured by computed tomography, and post-heparin plasma LPL activity in response to 20 wk of endurance training was investigated in 741 adult white and black subjects. Changes were compared between carriers and noncarriers of the X447 allele after adjustment for the effects of age and pretraining values. No evidence of association was observed in men. However, white women carrying the X447 allele exhibited greater reductions of body mass index (P = 0.01), fat mass (P = 0.01), and percent body fat (P = 0.03); in black women, the carriers exhibited a greater reduction of abdominal visceral fat (P = 0.05) and a greater increase in post-heparin LPL activity (P = 0.02). These results suggest that the LPL S447X polymorphism influences the training-induced changes in body fat and post-heparin LPL activity in women but not in men.