Higher order lipase gene association with plasma triglycerides

Foulkes, Andrea S.; Wolfe, Megan L.; Rader, Daniel J.

doi:10.1194/jlr.m500042-jlr200

Cited by 9 publications

(9 citation statements)

References 41 publications

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“…Considering the redundant enzymatic activities and substrate specifi cities and the distinct, yet overlapping expression patterns of lipases, such interactions may have important contributions to dyslipidemia and atherosclerotic cardiovascular disease. For example, an association analysis of LPL, HL, and EL variants revealed genetic interaction in the determination of plasma TG levels in a normal population ( 47 ). To investigate the interaction between HL and EL directly, Brown et al ( 17 ) recently generated HL/EL double-knock-out mice representing the fi rst engineered mouse model of combined lipase defi ciency.…”

Section: Lmf1 Defi Ciency Diminishes Post-heparin Phospholipase Activitymentioning

confidence: 99%

Lipase maturation factor 1 is required for endothelial lipase activity

Ben-Zeev

Hosseini

Lai

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org hydrolyze two principal lipid substrates associated with lipoprotein particles, triglycerides (TGs), and phospholipids. The released fatty acids (FAs) resulting from lipase hydrolysis are taken up by subjacent tissue and used for energy storage (adipose), oxidation, and energy production (skeletal muscle and heart) and the synthesis of bioactive metabolites (variety of tissues).LPL is principally a TG lipase involved in the metabolism of TG-rich lipoproteins (chylomicrons and very-lowdensity lipoproteins) in adipose and muscle and heart tissues ( 1 ). Its defi ciency and overexpression have been linked to metabolic abnormalities such as hypertriglyceridemia, insulin resistance, and cardiomyopathy, indicating the critical role of this enzyme in TG metabolism ( 4-10 ). Unlike LPL, HL has comparable TG lipase and phospholipase activities and is involved in the hepatic metabolism of high-density lipoprotein (HDL) as well as apolipoprotein B (apoB)-containing lipoproteins (LpBs) ( 11,12 ). Overexpression of HL reduces plasma levels of HDL and LpBs, whereas HL defi ciency has the opposite effect ( 13-16 ). EL is predominantly a phospholipase affecting HDL metabolism, but it also shares a redundant role with HL in the metabolism of LpBs ( 11,17 ). Indeed, modulation of EL activity in mice leads to changes in plasma HDL levels similar to those of HL (18)(19)(20), refl ecting their related substrate specifi cities. Consistent with their multifaceted involvement in lipoprotein metabolism, LPL, HL, and EL are strongly associated with plasma lipid levels in the general population ( 21 ). Abstract Lipase maturation factor 1 (Lmf1) is an endoplasmic reticulum (ER) membrane protein involved in the posttranslational folding and/or assembly of lipoprotein lipase (LPL) and hepatic lipase (HL) into active enzymes.Mutations in Lmf1 are associated with diminished LPL and HL activities ("combined lipase defi ciency") and result in severe hypertriglyceridemia in mice as well as in human subjects. Here, we investigate whether endothelial lipase (EL) also requires Lmf1 to attain enzymatic activity. We demonstrate that cells harboring a ( cld ) loss-of-function mutation in the Lmf1 gene are unable to generate active EL, but they regain this capacity after reconstitution with the Lmf1 wild type. Furthermore, we show that cellular EL copurifi es with Lmf1, indicating their physical interaction in the ER. Finally , we determined that post-heparin phospholipase activity in a patient with the LMF1 W464X mutation is reduced by more than 95% compared with that in controls. Thus, our study indicates that EL is critically dependent on Lmf1 for its maturation in the ER and demonstrates that Lmf1 is a required factor for all three vascular lipases, LPL, HL, and EL. The vascular lipase family is composed of three evolutionarily related enzymes, lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL) ( 1-3 ). Localized to the luminal face of tissue capillaries, lipases

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Section: Lmf1 Defi Ciency Diminishes Post-heparin Phospholipase Activitymentioning

confidence: 99%

Lipase maturation factor 1 is required for endothelial lipase activity

Ben-Zeev

Hosseini

Lai

et al. 2011

Journal of Lipid Research

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“…For example, the combined effect of LPL, LIPE and LIPC accounted for 4.4% variation in HDL-C levels and had a better ability to predict the HDL-C levels than any single lipase gene. Similarly, the cumulative genetic effect of the lipase genes was previously reported [28]. Since we did not find any interactions between the lipase genes, the overall impact of multiple lipase genes is likely due to an additive rather than multiplicative effect.…”

Section: Discussionmentioning

confidence: 54%

Multiple genetic determinants of plasma lipid levels in Caribbean Hispanics

Liao

Lin

Rundek

et al. 2008

Clinical Biochemistry

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Objectives: To identify candidate genes in relation to plasma lipid levels in Caribbean Hispanics. Design and methods:A total of 114 single nucleotide polymorphisms (SNPs) at 17 lipid-related genes were genotyped in 477 Caribbean Hispanics from the Northern Manhattan Study (NOMAS). Analyses for each SNP and haplotype were performed to evaluate the associations with four lipid traits: high-and low-density lipoprotein cholesterol (HDL-C, LDL-C), triglyceride (TG) and total cholesterol (TC). Results:We identified 19 SNPs at 10 genes that were significantly related to lipids (p<0.01), including nine involved in the reverse cholesterol transport pathway, and one involved in bile acid synthesis. Three genes, namely the apolipoprotein A5, apolipoprotein B and cytochrome p450 polypeptide 7A1 genes, accounted for the largest proportion of variation in HDL-C/TG, TC and LDL-C respectively. Conclusions:The cumulative effects of multiple genetic variants led to a substantially better prediction of inter-individual variations in lipid levels.

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“…A recent study has observed that the apo CIII-SstI SNP increases fasting TG levels among carriers of the LPL P207L mutation. 30 Reilly et al 31 have also recently…”

Section: Discussionmentioning

confidence: 99%

Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects

et al. 2007

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Background: Abdominal obesity and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) increase cardiovascular risk. The very low-density lipoprotein (VLDL) is a triglyceride (TG)-rich particle. Frequent variations in the genes coding for enzymes and proteins involved in the VLDL catabolism have already been documented. The epistatic effect of such variants on the risk profile associated with abdominal obesity remains to be elucidated. Objective: This study aims to assess the effect of combinations of frequent single-nucleotide polymorphisms (SNPs) in the VLDL catabolic pathway on the relation between abdominal obesity and fasting TG. Method: Only gene variants in the lipoprotein lipase, apolipoprotein (apo) CIII, hepatic lipase and apo E genes known to be frequent in the general population (allele frequency45%) were included in this study. The presence of selected SNPs was detected by polymerase chain reaction-restriction fragment length polymorphisn in a sample of 640 non-diabetic French Canadians at high cardiovascular risk (405 obese, 235 non-obese). Results: Carrying more than two frequent gene variants involved in the VLDL catabolic pathway significantly increased the risk of hyperTG (odds ratio of TG41.7 mmol/l ¼ 4.15; P ¼ 0.001). This effect was proportional to the number of SNPs and genes involved and was significantly amplified by the presence of abdominal obesity defined on the basis of waist circumference. Conclusion: When combined with abdominal obesity, epistasis in the VLDL pathway has a deleterious effect on fasting TG and coronary artery disease risk profile according to the TG threshold (1.7 mmol/l) used in medical guidelines for the assessment of the metabolic syndrome and associated risk.

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Higher order lipase gene association with plasma triglycerides

Cited by 9 publications

References 41 publications

Lipase maturation factor 1 is required for endothelial lipase activity

Lipase maturation factor 1 is required for endothelial lipase activity

Multiple genetic determinants of plasma lipid levels in Caribbean Hispanics

Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects

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