Role Of Lipoprotein Lipase Research Articles

Leptin-mediated suppression of lipoprotein lipase cleavage enhances lipid uptake and facilitates lymph node metastasis in gastric cancer.

Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation. We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.

Correction to: Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo.

Correction to: Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo.

Genetic Parameters for Yolk Cholesterol and Transcriptional Evidence Indicate a Role of Lipoprotein Lipase in the Cholesterol Metabolism of the Chinese Wenchang Chicken.

The yolk cholesterol has been reported to affect egg quality and breeding performance in chickens. However, the genetic parameters and molecular mechanisms regulating yolk cholesterol remain largely unknown. Here, we used the Wenchang chicken, a Chinese indigenous breed with a complete pedigree, as an experimental model, and we examined 24 sire families (24 males and 240 females) and their 362 daughters. First, egg quality and yolk cholesterol content were determined in 40-week-old chickens of two consecutive generations, and the heritability of these parameters was analyzed using the half-sib correlation method. Among first-generation individuals, the egg weight, egg shape index, shell strength, shell thickness, yolk weight, egg white height, Haugh unit, and cholesterol content were 45.36 ± 4.44 g, 0.81 ± 0.12, 3.07 ± 0.92 kg/cm2, 0.340 ± 0.032 mm, 15.57 ± 1.64 g, 3.36 ± 1.15 mm, 58.70 ± 12.33, and 274.3 ± 36.73 mg/egg, respectively. When these indexes were compared to those of the following generation, no statistically significant difference was detected. Although yolk cholesterol content was not associated with egg quality in females, an increase in yolk cholesterol content was correlated with increased yolk weight and albumin height in sire families (p < 0.05). Moreover, the heritability estimates for the yolk cholesterol content were 0.328 and 0.530 in female and sire families, respectively. Therefore, the yolk cholesterol content was more strongly associated with the sire family. Next, chickens with low and high yolk cholesterol contents were selected for follicular membrane collection. Total RNA was extracted from these samples and used as a template for transcriptional sequencing. In total, 375 down- and 578 upregulated genes were identified by comparing the RNA sequencing data of chickens with high and low yolk cholesterol contents. Furthermore, Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated the involvement of energy metabolism and immune-related pathways in yolk cholesterol deposition. Several genes participating in the regulation of the yolk cholesterol content were located on the sex chromosome Z, among which lipoprotein lipase (LPL) was associated with the peroxisome proliferator-activated receptor signaling pathway and the Gene Ontology term cellular component. Collectively, our data suggested that the ovarian steroidogenesis pathway and the downregulation of LPL played critical roles in the regulation of yolk cholesterol content.

Lipoprotein lipase: new roles for an 'old' enzyme.

Lipoprotein lipase (LpL) is well known for its lipolytic action in blood lipoprotein triglyceride catabolism. This article summarizes the recent mechanistic and molecular studies on elucidating the 'unconventional' roles of LpL in mediating biological events related to immune cell response and lipid transport in the pathogenesis of cardiovascular disease (CVD) and tissue degenerative disorders. Several approaches to inactivate the inhibitors that block LpL enzymatic activity have reestablished the importance of systemic LpL activity in reducing CVD risk. On the other hand, increasing evidence suggests that focal arterial expression of LpL relates to aortic macrophage levels and inflammatory processes. In the hematopoietic origin, LpL also plays a role in modulating hematopoietic stem cell proliferation and circulating blood cell levels and phenotypes. Finally, building upon the strong genetic evidence on the association with assorted brain disorders, a new era in exploring the mechanistic insights into the functions and activity of LpL in brain that impacts central nerve systems has begun. A better understanding of the molecular action of LpL will help to devise novel strategies for intervention of a number of diseases, including blood cell or metabolic disorders, as well to inhibit pathways related to CVD and tissue degenerative processes.

Stephen G. Young

Stephen G. Young

Chylomicrons stimulate incretin secretion in mouse and human cells

Aims/hypothesisLipids are a potent stimulus for the secretion of glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Traditionally, this effect was thought to involve the sensing of lipid digestion products by free fatty acid receptor 1 (FFA1) and G-protein coupled receptor 119 (GPR119) on the apical surface of enteroendocrine cells. However, recent evidence suggests that lipids may in fact be sensed basolaterally, and that fatty acid absorption and chylomicron synthesis may be a prerequisite for their stimulatory effect on gut peptide release. Therefore, we investigated the effect of chylomicrons on GLP-1 and GIP secretion in vitro.MethodsThe effect of chylomicrons on incretin secretion was investigated using GLUTag cells and duodenal cultures of both murine and human origin. The role of lipoprotein lipase (LPL) and FFA1 in GLUTag cells was assessed by pharmacological inhibition and small (short) interfering RNA (siRNA)-mediated knockdown. The effect of chylomicrons on intracellular calcium concentration ([Ca2+]i) was determined by imaging GLUTag cells loaded with Fura-2. In the primary setting, the contributions of FFA1 and GPR119 were investigated using L cell-specific Gpr119 knockout cultures treated with the FFA1 antagonist GW1100.ResultsChylomicrons stimulated GLP-1 release from GLUTag cells, and both GLP-1 and GIP secretion from human and murine duodenal cultures. Chylomicron-triggered GLP-1 secretion from GLUTag cells was largely abolished following lipase inhibition with orlistat or siRNA-mediated knockdown of Lpl. In GLUTag cells, both GW1100 and siRNA-mediated Ffar1 knockdown reduced GLP-1 secretion in response to chylomicrons, and, consistent with FFA1 Gq-coupling, chylomicrons triggered an increase in [Ca2+]i. However, LPL and FFA1 inhibition had no significant effect on chylomicron-mediated incretin secretion in murine cultures. Furthermore, the loss of GPR119 had no impact on GLP-1 secretion in response to chylomicrons, even in the presence of GW1100.Conclusions/interpretationChylomicrons stimulate incretin hormone secretion from GLUTag cells as well as from human and murine duodenal cultures. In GLUTag cells, the molecular pathway was found to involve LPL-mediated lipolysis, leading to the release of lipid species that activated FFA1 and elevated intracellular calcium.

Regulation of the human lipoprotein lipase gene by the forkhead box transcription factor FOXA2/HNF-3β in hepatic cells

Lipoprotein lipase (LPL) plays a major role in the hydrolysis of triglycerides (TG) from circulating TG-rich lipoproteins. The role of LPL in the liver has been controversial but recent studies in mice with liver LPL overexpression or deficiency have revealed important new roles of the enzyme in glucose and lipid metabolism. The objective of this study was to identify regulatory elements and factors that control the transcription of the human LPL gene in hepatocytes. Deletion analysis of the human LPL promoter revealed that the proximal region which harbors a binding site for the forkhead box transcription factor FOXA2/HNF-3β at position −47/−40 is important for its hepatic cell activity. Silencing of FOXA2 in HepG2 cells reduced the LPL mRNA and protein levels. Direct binding of FOXA2 to the novel binding site was established in vitro and ex vivo. Mutagenesis of the FOXA2 site reduced the basal activity and abolished the FOXA2-mediated transactivation of the LPL promoter. Ιnsulin decreased LPL mRNA levels in HepG2 cells and this was associated with phosphorylation of AKT and nuclear export of FOXA2. In summary, the data of the present study combined with previous findings on the role of FOXA2 in HDL metabolism and gluconeogenesis, suggest that FOXA2 is a key regulator of lipid and glucose homeostasis in the adult liver. Understanding the mechanisms by which FOXA2 exerts its functions in hepatocytes may open the way to novel therapeutic strategies for patients with metabolic diseases such as dyslipidemia, diabetes and the metabolic syndrome.

A Proposal of The New Mechanism on Remnant Lipoprotein Formation and Clearance after Food Intake

To understand the mechanism of plasma TG increase after food intake, the characteristics of remnant lipoproteins in postprandial plasma and the role of lipoprotein lipase (LPL) were investigated. The accumulation of TG in remnant lipoproteins (RLP-TG) is caused by the unchanged levels of LPL activity for hydrolysis of chylomicrons and VLDL when overloaded at endothelium after food intake. This review proposed a new hypothesis on the metabolism of plasma TG-rich lipoprotein based on the no-change of LPL activity at endothelium after food intake and the discovery of RLP-LPL complex in postprandial plasma.

Role of lipoprotein lipase in lipid metabolism.

A major step in energy metabolism is hydrolysis of triacylglycerol-rich lipoproteins (TRLs) to release fatty acids that can be used or stored. This is accomplished by lipoprotein lipase (LPL) at 'binding lipolysis sites' at the vascular endothelium. A multitude of interactions are involved in this seemingly simple reaction. Recent advances in the understanding of some of these factors will be discussed in an attempt to build a comprehensive picture. The first event in catabolism of TRLs is that they dock at the vascular endothelium. This requires LPL and GPIHBP1, the endothelial transporter of LPL.Kinetic studies in rats with labeled chylomicrons showed that once a chylomicron has docked in the heart it stays for minutes and a large number of triacylglycerol molecules are split. The distribution of binding between tissues reflects the amount of LPL, as evident from studies with mutant mice.Clearance of TRLs is often slowed down in metabolic disease, as was demonstrated both in mice and men. In mice, this was directly connected to decreased amounts of endothelial LPL. The LPL system is central in energy metabolism and results from interplay between several factors. Rapid and exciting progress is being made.

Role of fatty acids in the nervous control of energy balance

Fatty acid (FA)-sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy and glucose homeostasis including feeding behavior, insulin secretion and action. Subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Molecular effectors of these FA effects include ion channels such as chloride, potassium or calcium. In addition at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, a FA translocator/receptor that does not require intracellular metabolism to activate downstream signaling. Recently, an important role of lipoprotein lipase in FA sensing has also been demonstrated not only in hypothalamus, but also in the hippocampus and striatum. Finally, FA overload might impair neural control of energy homeostasis through enhanced ceramide synthesis and may contribute to obesity and/or type 2 diabetes pathogenesis in predisposed subjects.

Physiological and pathophysiological implications of lipid sensing in the brain.

Fatty acid (FA)-sensitive neurons are present in the brain, especially the hypothalamus, and play a key role in the neural control of energy homeostasis. Through neuronal output, FA may modulate feeding behaviour as well as insulin secretion and action. Subpopulations of neurons in the ventromedial and arcuate hypothalamic nuclei are selectively either inhibited or activated by FA. Molecular effectors of these FA effects probably include chloride or potassium ion channels. While intracellular metabolism and activation of the ATP-sensitive K⁺ channel appear to be necessary for some of the signalling effects of FA, at least half of the FA responses in ventromedial hypothalamic neurons are mediated by interaction with FAT/CD36, an FA transporter/receptor that does not require intracellular metabolism to activate downstream signalling. Thus, FA or their metabolites can modulate neuronal activity as a means of directly monitoring ongoing fuel availability by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. Recently, the role of lipoprotein lipase in FA sensing has also been shown in animal models not only in hypothalamus, but also in hippocampus and striatum. Finally, FA overload might impair neural control of energy homeostasis through enhanced ceramide synthesis and may contribute to obesity and/or type 2 diabetes pathogenesis in predisposed subjects.

Lipoprotein Lipase in the Brain and Nervous System

Lipoprotein lipase (LPL) is rate limiting in the provision of triglyceride-rich lipoprotein-derived lipids into tissues. LPL is also present in the brain, where its function has remained elusive. Recent evidence implicates a role of LPL in the brain in two processes: (a) the regulation of energy balance and body weight and (b) cognition. Mice with neuron-specific deletion of LPL have increases in food intake that lead to obesity, and then reductions in energy expenditure that further contribute to and sustain the phenotype. In other mice with LPL deficiency rescued from neonatal lethality by somatic gene transfer wherein LPL in the brain remains absent, altered cognition ensues. Taking into consideration data that associate LPL mutations with Alzheimer's disease, a role for LPL in learning and memory seems likely. Overall, the time is ripe for new insights into how LPL-mediated lipoprotein metabolism in the brain impacts CNS processes and systems biology.

Chylomicronemia mutations yield new insights into interactions between lipoprotein lipase and GPIHBP1

Lipoprotein lipase (LPL) is a 448-amino-acid head-to-tail dimeric enzyme that hydrolyzes triglycerides within capillaries. LPL is secreted by parenchymal cells into the interstitial spaces; it then binds to GPIHBP1 (glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1) on the basolateral face of endothelial cells and is transported to the capillary lumen. A pair of amino acid substitutions, C418Y and E421K, abolish LPL binding to GPIHBP1, suggesting that the C-terminal portion of LPL is important for GPIHBP1 binding. However, a role for LPL's N terminus has not been excluded, and published evidence has suggested that only full-length homodimers are capable of binding GPIHBP1. Here, we show that LPL's C-terminal domain is sufficient for GPIHBP1 binding. We found, serendipitously, that two LPL missense mutations, G409R and E410V, render LPL susceptible to cleavage at residue 297 (a known furin cleavage site). The C terminus of these mutants (residues 298-448), bound to GPIHBP1 avidly, independent of the N-terminal fragment. We also generated an LPL construct with an in-frame deletion of the N-terminal catalytic domain (residues 50-289); this mutant was secreted but also was cleaved at residue 297. Once again, the C-terminal domain (residues 298-448) bound GPIHBP1 avidly. The binding of the C-terminal fragment to GPIHBP1 was eliminated by C418Y or E421K mutations. After exposure to denaturing conditions, the C-terminal fragment of LPL refolds and binds GPIHBP1 avidly. Thus, the binding of LPL to GPIHBP1 requires only the C-terminal portion of LPL and does not depend on full-length LPL homodimers.

Abstract 1256: A role for lipoprotein lipase in fatty acid acquisition by breast, prostate and liposarcoma tumors

Abstract The importance of de novo fatty acid (FA) synthesis for tumor cell growth is well established, and we have now examined the hypothesis that the uptake of exogenous FA provides an alternative FA fuel source for tumors. Background: Many tumor cells utilize FA as a major energy source, and they do not survive if the supply is interrupted. In order to obtain lipids, tumors can synthesize fatty acids from glucose-derived precursors using fatty acid synthase (FASN), or they could potentially hydrolyze diet-derived triglycerides from circulating lipoproteins using the enzyme lipoprotein lipase (LPL), and take up the free fatty acids using the cell surface channel CD36. It is also conceivable that they could obtain lipids by receptor-mediated endocytosis, using syndecan (Sdc1) and LPL. The latter two of these three mechanisms have not been examined. Methods: We employed cDNA microarray and quantitative RT-PCR to study mRNA expression, measured secreted LPL enzyme activity, and produced a monoclonal antibody for LPL protein analysis and immunohistochemistry (IHC). We also assessed cellular uptake of fluorescently labeled very low density lipoproteins (VLDL). We studied cell lines and/or tumor tissues for expression of FASN, Spot 14 (a nuclear protein that drives FASN expression), LPL, CD36, and Sdc1. Results: 1. By RT-PCR, FASN and Spot14, a driver of FASN gene expression, are expressed in all cell lines (45 breast cancer, 1 liposarcoma, 1 cervical carcinoma, 3 prostate cancer) and tumor tissues (160 breast cancer, 24 liposarcoma, 10 prostate cancer) examined. 2. By RT-PCR and enzyme activity assays, LPL is expressed only in liposarcoma and triple-negative breast cancer cell lines. Prostate cancer cells secrete negligible LPL. 3. Addition of exogenous LPL and triglyceride substrate to culture media enhanced the growth of breast cancer and liposarcoma cell lines, but not prostate cancer cell lines. 4. Provision of exogenous LPL, however, rescued prostate cancer cell lines from the cytotoxicity of FASN inhibition. 5. siRNA-mediated knockdown of LPL impaired the growth of HeLa cells, 6. In contradistinction to observations in cell lines, IHC demonstrated brisk expression of LPL in all liposarcomas, prostate tumors, and breast cancer tumors examined, irrespective of ER/PR or HER2/neu status. 7. CD36 is expressed in the majority of tumors examined by IHC, including 98% of breast cancers. 8. Sdc1 and CD36 are expressed in triple-negative DU4475 breast cancer cells, but they did not endocytose labeled VLDL particles. Conclusions: These data demonstrate that, in addition to de novo FA synthesis, tumors can utilize diet-derived fat, and that this can fuel their growth. Our findings provide a mechanism, namely lipolysis by LPL and uptake by CD36, for the link between dietary fat intake and tumor progression. Inhibition of lipolysis, as well as lipogenesis, may be a necessary strategy to target the FA requirement of aggressive tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1256. doi:10.1158/1538-7445.AM2011-1256

Detection of lipoprotein lipase mRNA by real-time quantitative reverse transcriptase polymerase chain reaction in chronic lymphocytic leukemia

Objective To investigate the expression level of lipoprotein lipase (LPL) mRNA in chronic lymphocytic leukemia (CLL) patients and evaluate the prognostic value of LPL in CLL Methods Quantitative real-time RT-PCR (qRT-PCR) was performed in 62 CLL patients, 10 normal controls using Taqman probe system. Association between LPL and other known prognostic factors, such as IgVH mutation status, ZAP-70 and CD38 expression, was determined using the Spearman correlation analysis. ROC curve was used to determine the cut-off value of LPL expression level, the positive and negative predictive value of IgVH mutation status. Results The correlation coefficients of the standard curves in qRT-PCR were not less than 0.990. The coefficients of variation (CV) of interrun assay and intramn assay were < 5%, and the sensitivity can reached 102 copies/μg RNA. The median LPL mRNA expression level was 0.006 0 (0-0.737 0) in 62 CLL patients, whereas in 10 normal controls LPL mRNA expression level was extremely low with the median level of 0 (0-0.000 4). The expression levels of LPL in three CLL samples after miniMACS-sorted CD19 positive B cells were 0.036 0, 0.075 0 and 0.197 0, which were similar to the levels before miniMACS-sorted (0.024 0, 0.074 0 and 0.225 0). LFL expression was significantly associated with IgVH mutation status (r=0.45, P<0.05) . LPL expression level in IgVH unmutated patients [0.006 0 (0.000 7-0.110 0)] was significantly higher than the level in IgVH mutated patients [0.002 0(0.000 2-0.027 0)] (U=96.5, P<0.05). LPL expression was also significantly associated with ZAP-70 (r=0.38, P<0.05), CD38 expressions (r=0.43, P<0.05). According to ROC curve, the cut-off of LPL mRNA expression level was 0.036, with a 66.7% specificity, a 72.4% sensitivity, a 51.8% positive predictive value (IgVH unmutated), and a 83.3% negative predictive value (IgVH mutated) for IgVH mutation status. Conclusions The qRT-PCR assay is reliable and sensitive. LPL mRNA expression significantly correlates with IgVH mutation status, ZAP-70 and CD38 expression, and could be a predictive marker of IgVH mutation status. Our data confirms a role for LPL as a novel prognostic indicator in CLL. Key words: Leukemia, lymphocytic, chronic, B-cell; Lipoprotein lipase; Reverse transcriptase polymerase chain reaction; Prognosis

Presynaptic Defects Underlying Impaired Learning and Memory Function in Lipoprotein Lipase-Deficient Mice

Lipoprotein lipase (LPL) is predominantly expressed in adipose and muscle where it plays a crucial role in the metabolism of triglyceride-rich plasma lipoproteins. LPL is also expressed in the brain with highest levels found in the pyramidal cells of the hippocampus, suggesting a possible role for LPL in the regulation of cognitive function. However, very little is currently known about the specific role of LPL in the brain. We have generated a mouse model of LPL deficiency which was rescued from neonatal lethality by somatic gene transfer. These mice show no exogenous and endogenous LPL expression in the brain. To study the role of LPL in learning and memory, the performance of LPL-deficient mice was tested in two cognitive tests. In a water maze test, LPL-deficient mice exhibited increased latency to escape platform and increased mistake frequency. Decreased latency to platform in the step-down inhibitory avoidance test was observed, consistent with impaired learning and memory in these mice. Transmission electron microscopy revealed a significant decrease in the number of presynaptic vesicles in the hippocampus of LPL-deficient mice. The levels of the presynaptic marker synaptophysin were also reduced in the hippocampus, whereas postsynaptic marker postsynaptic density protein 95 levels remained unchanged in LPL-deficient mice. Theses findings indicate that LPL plays an important role in learning and memory function possibly by influencing presynaptic function.

Association of lipoprotein lipase (LPL) single nucleotide polymorphisms with type 2 diabetes mellitus

The etiology and pathogenesis of type 2 diabetes mellitus (T2DM) are not completely understood although it is often associated with other conditions such as obesity, hypertension, and dyslipidemia. Lipoprotein lipase (LPL) is a key enzyme in human lipid metabolism that facilitates the removal of triglyceride-rich lipoproteins from the bloodstream. LPL hydrolyzes the core of triglyceride-rich lipoproteins (chylomicrons and very low density lipoprotein) into free fatty acids and monoacylglycerol. To gain insight into the possible role of LPL in T2DM, nine single nucleotide polymorphisms (SNPs) of LPL were analyzed for the association with T2DM using 944 unrelated Koreans, including 474 T2DM subjects and 470 normal healthy controls. Of the nine LPL SNPs we analyzed, a significant association with multiple tests by the false discovery rate (FDR) was observed between T2DM and SNP rs343 (+13836C>A in intron 3). SNP rs343 was also marginally associated with some of T2DM-related phenotypes including total cholesterol, high density lipoprotein cholesterol (HDLc), and log transformed glycosylated hemoglobin in 470 normal controls, although no significant association was detected by multiple tests. In total, our results suggest that the control of lipid level by LPL in the bloodstream might be an important factor in T2DM pathogenesis in the Korean population.

A polymorphism in lipoprotein lipase affects the severity of Alzheimer's disease pathophysiology

Emerging evidences indicate a role for lipoprotein lipase (LPL) in degenerative states. Genetic variations in the LPL gene were previously associated to lipid imbalance and coronary artery disease (CAD) risk and severity, a condition that shares pathological features with common Alzheimer's disease (AD). To evaluate whether these genetic variations associate with the risk and pathophysiology of common AD, autopsy-confirmed patients (242 controls, 153 AD) were genotyped for a PvuII single nucleotide polymorphism (SNP; rs285; referred to as the P+ allele) of LPL. Brain LPL mRNA levels, cholesterol levels, amyloid concentration, senile plaques and neurofibrillary tangles density counts were measured and contrasted with specific LPL genotypes. When adjusted for age and sex, homozygosity for the P+ allele resulted in an odds ratio of 2.3 for the risk of developing AD. More importantly, we report that the presence of the P+ allele of LPL significantly affects its mRNA expression level (n = 51; P = 0.026), brain tissue cholesterol levels (n = 55; P = 0.0013), neurofibrillary tangles (n = 52; P = 0.025) and senile plaque (n = 52; P = 0.022) densities. These results indicate that a common polymorphism in the lipoprotein lipase gene modulates the risk level for sporadic AD in the eastern Canadian population but more importantly, indirectly modulates the pathophysiology of the brain in autopsy-confirmed cases.

Lipoprotein lipase expression is a novel prognostic factor in B-cell chronic lymphocytic leukemia

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course. Recent studies have shown that expression of lipoprotein lipase (LPL) and ADAM29 may serve as novel prognostic markers in B-CLL. To investigate the prognostic value of these genes, we quantified their expression in peripheral blood mononuclear cells using quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) in a cohort of 133 B-CLL patients and correlated the results with clinical outcome, and other known prognostic factors. LPL, ADAM29, LPL and ADAM29 ratios, as well as CD38 and ZAP-70 protein expression determined by multiparameter flow cytometry, were predictive of treatment-free survival. Multivariate Cox regression analysis identified LPL, ADAM29 and CD38 as independent prognostic markers. Evaluation of several disease characteristics in association with the LPL expression status of the patients' B-CLL cells showed highly significant differences for CD38 and ZAP-70 expression, suggesting a correlation of LPL expression with these established adverse prognostic factors. Sequential RQ-PCR analyses in a subset of 22 patients revealed that LPL mRNA expression was relatively stable in the majority of patients, whereas ADAM29 expression levels varied substantially over time. Furthermore, in a subgroup analysis, LPL provided prognostic information in both early stage (Binet A) and patients with more advanced disease (Binet B and C). Conversely, high ADAM29 expression was predictive of a long treatment-free interval in Binet stage A but did not retain its prognostic significance in Binet B and C patients. The LPL/ADAM29 expression ratio was not found to be an independent prognostic factor and did not offer any advantages over the use of LPL alone. Collectively, our data confirm a role for LPL as a novel prognostic indicator in B-CLL.

Lipoprotein Lipase Gene Polymorphisms and the Risk of Target Vessel Revascularization After Percutaneous Coronary Intervention

We sought to identify polymorphisms in genes that predispose to restenosis. Variations in the lipoprotein lipase (LPL) gene have been implicated in a number of pathophysiologic conditions associated with coronary heart disease. The present study examines the impact of polymorphisms in the LPL gene on restenosis (defined by target vessel revascularization [TVR]) in a large patient population undergoing percutaneous coronary intervention (PCI). A mouse model for restenosis was used to further investigate LPL's role in restenosis. The GENetic DEterminants of Restenosis (GENDER) project is a multicenter, prospective study design that enrolled 3,104 consecutive patients after successful PCI. These patients were genotyped for four different LPL gene polymorphisms. In apolipoprotein E (ApoE)*3-Leiden transgenic mice, arterial messenger ribonucleic acid (mRNA) was used to assess LPL expression during a cuff-induced restenotic process. Using multivariable analysis, carriers of the 447Ter allele of the LPL enzyme showed a lower risk of TVR compared with 447Ser homozygotes (p = 0.005). In the mouse model, LPL mRNA levels were increased 40-fold compared with control arteries at 6 h after cuff placement. The LPL C/G polymorphism (Ser447Ter), resulting in a truncation of the two C-terminal amino acids of the mature LPL protein, appears to be an important protective factor for TVR in humans. The role of LPL in this process was further established in a mouse model, where LPL expression was very strongly up-regulated in the target arterial wall, suggesting a contribution of this lipolytic enzyme to restenosis. Possibly, LPL Ser447Ter genotyping may lead to better risk stratification and tailored therapy in the prevention of restenosis after PCI.