Lipoprotein Lipase Deficiency Research Articles

Familial Chylomicronemia Syndrome (FCS) Patients Recruited to the APPROACH Trial of Volanesorsen Therapy are Representative of Subjects with FCS

Familial Chylomicronemia Syndrome (FCS) Patients Recruited to the APPROACH Trial of Volanesorsen Therapy are Representative of Subjects with FCS

Gene Expression Signature of Platelet Count in Lipoprotein Lipase Deficiency

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Natural History (up to 15 years) of Platelet Count in 84 Patients with Familial Hyperchylomicronemia Due to Lipoprotein Lipase Deficiency

Natural History (up to 15 years) of Platelet Count in 84 Patients with Familial Hyperchylomicronemia Due to Lipoprotein Lipase Deficiency

The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study

ABSTRACTBackground: Familial Chylomicronemia Syndrome (FCS) is a rare genetic disorder that is caused by a decrease or an absence of lipoprotein lipase activity. FCS is characterized by marked accumulation of chylomicrons and extreme hypertriglyceridemia, which have major effects on both physical and mental health. To date, there have been no systematic efforts to characterize the impact of chylomicronemia on FCS patients’ lives. In particular, the impact of FCS on the burden of illness (BoI) and quality of life (QoL) has not been fully described in the literature.Methods: IN-FOCUS was a comprehensive web-based research survey of patients with FCS focused on capturing the BoI and impact on QoL associated with FCS. Sixty patients from the US diagnosed with FCS participated. Patients described multiple symptoms spanning across physical, emotional and cognitive domains.Results: Patients on average cycled through 5 physicians of varying specialty before being diagnosed with FCS, reflecting a lengthy journey to diagnosis Nearly all respondents indicated that FCS had a major impact on BoI and QoL and significantly influenced their career choice and employment status, and caused significant work loss due to their disease.Conclusion: FCS imparts a considerable burden across multiple domains with reported impairment on activities of daily living and QoL.

Extreme hypertriglyceridemia, pseudohyponatremia, and pseudoacidosis in a neonate with lipoprotein lipase deficiency due to segmental uniparental disomy

Extreme hypertriglyceridemia is rare in the neonatal period. We report a neonate with lipoprotein lipase (LPL) deficiency who presented with diagnostic and management conundrum. A full-term 36-day-old female was noted to have “Pepto-Bismol like” blood when repeating a newborn screening. The initial plasma triglyceride level was 24,318 mg/dL. The laboratory tests revealed serum bicarbonate level of <5 mmol/L, sodium of 127 mmol/L, and severe anemia. There were no signs of acute distress. The point of care capillary blood testing, however, demonstrated normal serum pH (7.2), bicarbonate (25.4 mmol/L), and sodium (139 mmol/L). The patient had mild elevation of serum lactic acid and no ketonuria. A diagnosis of type I hyperlipoproteinemia was made. Oral feeding was stopped, and the infant received intravenous fluids for the next 7 days resulting in lowering of serum triglyceride levels to 1016 mg/dL. Oral feeding was initiated with an amino acid–rich formula to which medium chain triglycerides were slowly added, while maintaining the total fat content to <15% of total daily energy. Sequencing of the LPL gene revealed a homozygous c.644G>A, p.(Gly215Glu) mutation. Subsequent analysis of the parental samples revealed that only the father, but not the mother, was a heterozygous carrier of the same mutation. Analysis of 18 informative microsatellite markers on chromosome 8 revealed paternal segmental uniparental disomy with partial absence of the maternal chromosome 8p, confirmed by single-nucleotide polymorphism microarray. We conclude that besides pseudohyponatremia, extreme hypertriglyceridemia can rarely present as pseudoacidosis and uniparental disomy can be an underlying mechanism for autosomal recessive diseases such as LPL deficiency.

Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease

The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Circulating lipid levels and CAD. Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.

Early Insights from Commercialization of Gene Therapies in Europe.

After years of research and development, gene therapies are now becoming a commercial reality with several products approved by European regulatory authorities [...].

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.

Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients.

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency.

Biochemical Analysis of the Lipoprotein Lipase Truncation Variant, LPLS447X, Reveals Increased Lipoprotein Uptake.

Lipoprotein lipase (LPL) is responsible for the hydrolysis of triglycerides from circulating lipoproteins. Whereas most identified mutations in the LPL gene are deleterious, one mutation, LPLS447X, causes a gain of function. This mutation truncates two amino acids from LPL's C-terminus. Carriers of LPLS447X have decreased VLDL levels and increased HDL levels, a cardioprotective phenotype. LPLS447X is used in Alipogene tiparvovec, the gene therapy product for individuals with familial LPL deficiency. It is unclear why LPLS447X results in a serum lipid profile more favorable than that of LPL. In vitro reports vary as to whether LPLS447X is more active than LPL. We report a comprehensive, biochemical comparison of purified LPLS447X and LPL dimers. We found no difference in specific activity on synthetic and natural substrates. We also did not observe a difference in the Ki for ANGPTL4 inhibition of LPLS447X relative to that of LPL. Finally, we analyzed LPL-mediated uptake of fluorescently labeled lipoprotein particles and found that LPLS447X enhanced lipoprotein uptake to a greater degree than LPL did. An LPL structural model suggests that the LPLS447X truncation exposes residues implicated in LPL binding to uptake receptors.

Lipoprotein Lipase Deficiency in an Infant With Chylomicronemia, Hepatomegaly, and Lipemia Retinalis.

Lipoprotein lipase (LPL; EC 3.1.1.1.34) is a key enzyme needed for the hydrolysis of triacylglycerol in chylomicrons and very low density lipoproteins.1 LPL deficiency is a rare autosomal recessive disorder with a prevalence of ~1 in 1 000 000 in the United States and higher in other regions of the world.2 LPL deficiency is characterized biochemically by severe hypertriglyceridemia and clinically by features including failure to thrive, eruptive xanthomas, hepatosplenomegaly, recurrent pancreatitis, and lipemia retinalis.2Over 100 mutations in the LPL gene have been found in LPL deficiency. Dietary fat restriction is the mainstay of treatment.3 We report an infant with one novel and one reported mutation within exon 6 of the LPL gene who presented with chylomicronemia, hepatomegaly, and lipemia retinalis.

Heterozygous familial hypercholesterolemia presenting as chylomicronemia syndrome

Heterozygous familial hypercholesterolemia (HeFH) is characterized by a twofold elevation in low-density lipoprotein cholesterol. Severe elevations in triglycerides are an uncommon manifestation. In this case report, we discuss an atypical presentation of the chylomicronemia syndrome in a patient with HeFH. Genetic analyses of the low-density lipoprotein receptor mutation and single nucleotide polymorphisms that elevate triglycerides provide confirmation for this atypical presentation of HeFH.

Diagnostic algorithm for familial chylomicronemia syndrome

BackgroundFamilial chylomicronemia syndrome (FCS) is a rare genetic disease that leads to severe hypertriglyceridemia often associated with recurrent episodes of pancreatitis. The recognition and correct diagnosis of the disease is challenging due to its rarity, and to the lack of specificity of signs and symptoms. Lipid experts, endocrinologists, gastroenterologists, pancreatologists, and general practitioners may encounter patients who potentially have FCS. Therefore, cooperation between experts and improved knowledge of FCS is essential in improving the diagnosis. Currently, a consensus on best practice for the diagnosis of FCS is lacking. MethodsAiming to define a diagnostic algorithm for FCS, a board of European experts was instituted. Such an algorithm for FCS is important to guide practitioners in the diagnosis of suspected FCS and to optimize therapeutic strategies. ResultsThe multidisciplinary views were merged, leading to a diagnostic algorithm, proposed here. ConclusionThis diagnostic algorithm represents a potentially useful tool to support primary and secondary care practitioners in the recognition of signs and clinical manifestations in individuals potentially affected by FCS.

Pradigastat disposition in humans: in vivo and in vitro investigations

1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients.2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans.3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma.4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed.5. Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.

New oral agents for treating dyslipidemia.

We provide an overview of orally administered lipid-lowering therapies under development. Recent data support statins for intermediate risk primary prevention, and ezetimibe for high-risk secondary prevention. Novel agents in development include bempedoic acid and gemcabene, and work continues on one remaining cholesteryl ester transfer protein inhibitor, anacetrapib, to determine whether this class can reduce cardiovascular risk. Selective peroxisome proliferator-activated receptor modulators such as K-877 are under study to determine whether they have an advantage over older fibrates. Diacylglycerol transferase inhibitors such as pradigastat appear to have potent triglyceride-lowering effects, even for patients with familial chylomicronemia syndrome. Finally, novel ω-3 preparations are available with significant triglyceride lowering, although their role in therapy remains unclear. Statins will remain the backbone of lipid-lowering therapy, although several novel oral agents are promising. The common theme across drugs in development is the demonstration of good lipid-lowering effect, although lacking cardiovascular outcomes data, which will likely be necessary before any of them, can be recommended or approved for widespread use.

Abstract 11169: Whole Exome Sequencing in Subjects With Mendelian Form of Primary Severe Hypertriglyceridemia

Background: Few data exist regarding clinical application of whole exome sequencing (WES) for the molecular diagnosis of the subjects with Mendelian form of primary severe hypertriglyceridemia (HTG). Methods: WES was performed on 28 individuals exhibiting severe HTG (≥ 1,000 mg/dl) without any transient causes (15 men, mean age 42 ± 20 yr, median triglyceride 1,756 mg/dl [interquartile range 1,288-2,443]) followed by recessive and dominant inheritance modeling in known monogenic HTG genes and disease-network candidate analysis gene ranking to identify a causative mutation(s), including novel underlying genetic mechanism for severe HTG. Results: Using our schema, we identified possible causative mutation(s) in 14 individuals (50%). Among them, we identified 2 individuals with lipoprotein lipase (LPL) deficiency with double mutations in LPL gene, and 2 individuals with a heterozygous mutation carrier in LPL gene. Moreover, we identified one individual harboring a double mutations in LPL gene and APOA5 gene. Also we identified one individual with a heterozygous mutation in lipase maturation factor 1 (LMF1) gene, which is rarer form of familial hyperchylomicronemia, and 2 individuals with type 3 hyperlipidemia harboring mutations in APOE gene, including novel ones. Interestingly, we also identified 6 other individuals harboring a deleterious mutation in cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3), MLX Interacting Protein-Like (MLXIPL), SLC25A40 genes, glucokinase regulatory protein (GCKR), possibly associated with this extreme phenotype. Conclusion: We identified potential causative mutations in 14 among 28 individuals (50%) with severe HTG within the coding region of the genes known to cause rare Mendelian dyslipidemias. Clinical WES is now feasible where molecular diagnoses could be made in such extreme cases, which could potentially provide appropriate therapies.

Investigation of LPL independent pathways of TG-rich lipoprotein metabolism in LPL deficiency

Objectives: Lipoprotein lipase (LPL) is a key enzyme of TG-rich lipoproteins metabolism. LPL deficiency (LPLD) is a rare mendelian cause of severe hypertriglyceridemia and chylomicronemia (CM). Recent data obtained with an ApoC-III ASO in LPLD support APOC3 as a key regulator of LPL-independent pathways of TG-rich lipoproteins metabolism. The aim of this study was to investigate gene expression profiles and lipoprotein characteristics in CM and a wide spectrum of LPL activity (0%, 50% and 100%).

Molecular analysis of genes involved in lipoprotein lipase deficiency in Slovak patients with familial chylomicronemia

Molecular analysis of genes involved in lipoprotein lipase deficiency in Slovak patients with familial chylomicronemia

Gene therapy: Case study on the first lipoprotein lipase deficiency patient treated with Alipogene Tiparvovec in Germany

Gene therapy: Case study on the first lipoprotein lipase deficiency patient treated with Alipogene Tiparvovec in Germany

A case of severe chylomicronaemia syndrome, in a patient with normal lipoprotein lipase activity, due to a previously unidentified mutation in the GPIHBP1 gene

A case of severe chylomicronaemia syndrome, in a patient with normal lipoprotein lipase activity, due to a previously unidentified mutation in the GPIHBP1 gene