RESUMEN
Introduction: Hypertriglyceridemia (HTG) is a complex disorder caused by genetic and environmental factors that frequently results from loss-of-function variants in the gene encoding lipoprotein lipase (LPL). Heterozygous patients have a range of symptoms, while homozygous LPL deficiency presents with severe symptoms including acute pancreatitis, xanthomas, and lipemia retinalis. Methods: We described the clinical characteristics of three Slovenian patients (an 8-year-old female, an 18-year-old man, and a 57-year-old female) and one Pakistani patient (a 59-year-old male) with LPL deficiency. We performed next-generation sequencing (NGS) targeting all coding exons and intron-exon boundaries of the LPL gene, and Sanger sequencing for variant confirmation. In addition, we performed a systematic literature review of all cases with three identified variants and described their clinical characteristics. Results: Two Slovenian patients with a heterozygous pathogenic variant NM_000237.3:c.984G>T (p.Met328Ile) were diagnosed within the first three years of life and had triglyceride (TG) values of 16 and 20 mmol/L. An asymptomatic Pakistani patient with TG values of 36.8 mmol/L until the age of 44 years, was identified as heterozygous for a pathogenic variant NM_000237.3:c.724G>A (p.Asp242Asn). His TG levels dropped to 12.7 mmol/L on dietary modifications and by using fibrates. A Slovenian patient who first suffered from pancreatitis at the age of 18 years with a TG value of 34 mmol/L was found to be homozygous for NM_000237.3:c.337T>C (p.Trp113Arg). Conclusions: Patients with LPL deficiency had high TG levels at diagnosis. Homozygous patients had worse outcomes. Good diet and medication compliance can reduce severity.
Asunto(s)
Lipoproteína Lipasa , Humanos , Masculino , Femenino , Eslovenia/epidemiología , Adolescente , Persona de Mediana Edad , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/deficiencia , Niño , Pakistán/epidemiología , Hiperlipoproteinemia Tipo I/genética , MutaciónRESUMEN
RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.
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Hiperlipoproteinemia Tipo I , Oligonucleótidos , Pancreatitis , Triglicéridos , Humanos , Femenino , Adolescente , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Hiperlipoproteinemia Tipo I/genética , Pancreatitis/tratamiento farmacológico , Triglicéridos/sangre , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/deficiencia , Resultado del Tratamiento , Apolipoproteína C-IIIRESUMEN
Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas.
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Aorta/metabolismo , Quilomicrones/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Gotas Lipídicas/metabolismo , Triglicéridos/metabolismo , Xantomatosis/metabolismo , Animales , Aorta/patología , Quilomicrones/genética , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Gotas Lipídicas/patología , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Triglicéridos/genética , Xantomatosis/genética , Xantomatosis/patologíaRESUMEN
Microglia become increasingly dysfunctional with aging and contribute to the onset of neurodegenerative disease (NDs) through defective phagocytosis, attenuated cholesterol efflux, and excessive secretion of pro-inflammatory cytokines. Dysfunctional microglia also accumulate lipid droplets (LDs); however, the mechanism underlying increased LD load is unknown. We have previously shown that microglia lacking lipoprotein lipase (LPL KD) are polarized to a pro-inflammatory state and have impaired lipid uptake and reduced fatty acid oxidation (FAO). Here, we also show that LPL KD microglia show excessive accumulation of LD-like structures. Moreover, LPL KD microglia display a pro-inflammatory lipidomic profile, increased cholesterol ester (CE) content, and reduced cholesterol efflux at baseline. We also show reduced expression of genes within the canonical cholesterol efflux pathway. Importantly, PPAR agonists (rosiglitazone and bezafibrate) rescued the LD-associated phenotype in LPL KD microglia. These data suggest that microglial-LPL is associated with lipid uptake, which may drive PPAR signaling and cholesterol efflux to prevent inflammatory lipid distribution and LD accumulation. Moreover, PPAR agonists can reverse LD accumulation, and therefore may be beneficial in aging and in the treatment of NDs.
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Gotas Lipídicas/metabolismo , Lipoproteína Lipasa/metabolismo , Microglía/metabolismo , Animales , Línea Celular , Colesterol/metabolismo , Ácidos Grasos/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Inflamación/patología , Metabolismo de los Lípidos/genética , Lipidómica , Lipoproteína Lipasa/deficiencia , Ratones , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Fenotipo , Fosfolípidos/metabolismoRESUMEN
Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p < 0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p < 0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients.
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Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Eliminación de Gen , Leucemia Linfocítica Crónica de Células B/genética , Lipoproteína Lipasa/deficiencia , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Femenino , Genes p53 , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/fisiología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Piperidinas , Modelos de Riesgos Proporcionales , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Medición de Riesgo , Rituximab/administración & dosificación , Sulfonamidas/administración & dosificación , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/deficiencia , Proteína Tirosina Quinasa ZAP-70/biosíntesis , Proteína Tirosina Quinasa ZAP-70/genéticaRESUMEN
Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5' untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5'UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.
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Variaciones en el Número de Copia de ADN , Eliminación de Gen , Hipertrigliceridemia/genética , Lipoproteína Lipasa/genética , Biología Computacional , Análisis Mutacional de ADN , Exones , Humanos , Hipertrigliceridemia/metabolismo , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/metabolismoRESUMEN
A 44-year-old woman was admitted with pancreatitis caused by hypertriglyceridaemia (fasting triglycerides 28 mmol/L). She used oral contraceptives and ezetimibe 10 mg. She was overweight (body mass index 29.7 kg/m2). Diabetes mellitus was ruled out, as were nephrotic syndrome, alcohol abuse, hypothyroidism and dysbetalipoproteinaemia. Genetic analysis revealed mutations in two genes involved in triglyceride metabolism (apolipoprotein A5 and lipoprotein lipase [LPL]). The LPL activity was 45% compared with pooled healthy controls. The post-heparin triglyceride reduction was 6%, compared with a normal reduction of >20%. The patient was initially treated with gemfibrozil, but this was discontinued due to side effects. Dietary triglyceride restriction and discontinuation of the oral contraceptives lowered the plasma triglycerides within 2 weeks to 3.4 mmol/L. Hypertriglyceridaemia is a risk factor for pancreatitis and cardiovascular disease, and has a broad differential diagnosis including genetic causes. Patients can achieve near-normal triglyceride values with a low-fat diet only.
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Apolipoproteína A-V/genética , Hiperlipoproteinemia Tipo I/genética , Hipertrigliceridemia/genética , Lipoproteína Lipasa/genética , Pancreatitis/genética , Adulto , Femenino , Humanos , Lipoproteína Lipasa/deficiencia , MutaciónRESUMEN
BACKGROUND AND AIMS: Type I hyperlipoproteinemia is an autosomal recessive disorder of lipoprotein metabolism caused by mutations in the LPL gene, with an estimated prevalence in the general population of 1 in a million. In this work, we studied the molecular mechanism of two known mutations in the LPL gene in ex vivo and in vitro experiments and also the effect of two splice site mutations in ex vivo experiments. METHODS: Two patients with hypertriglyceridemia were selected from the Lipid Clinic in Vienna. The first patient was compound heterozygote for c.680T > C (exon 5; p.V200A) and c.1139+1G > A (intron 7 splice site). The second patient was compound heterozygote for c.953A > G (exon 6; p.N291S) and c.1019-3C > A (intron 6 splice site). The LPL gene was sequenced and post-heparin plasma samples (ex vivo) were used to test LPL activity. In vitro experiments were performed in HEK 293T/17â¯cells transiently transfected with wild type or mutant LPL plasmids. Cell lysate and media were used to evaluate LPL production, secretion, activity and dimerization by Western blot analysis and LPL enzymatic assay, respectively. RESULTS: Our data show that in both patients, LPL activity is absent. V200A is a mutation that alters LPL secretion and activity whereas the N291S mutation affects LPL activity, but both mutations do not affect dimerization. The effect of these mutations in patients is more severe since they have splice site mutations on the other allele. CONCLUSIONS: We characterized these LPL mutations at the molecular level showing that are pathogenic.
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Hiperlipoproteinemia Tipo I/enzimología , Hiperlipoproteinemia Tipo I/genética , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/genética , Mutación Missense , Adulto , Células HEK293 , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo I/sangre , Hipertrigliceridemia , Masculino , Mutagénesis Sitio-Dirigida , Linaje , Fenotipo , Multimerización de Proteína , Análisis de Secuencia de ADNRESUMEN
One-year results are reported of the first lipoprotein lipase deficiency (LPLD) patient treated with alipogene tiparvovec, which is indicated for the treatment of patients with genetically confirmed LPLD suffering from acute and recurrent pancreatitis attacks (PAs) despite dietary restrictions and expressing >5% of lipoprotein lipase (LPL) mass compared to a healthy control. During clinical development, alipogene tiparvovec has shown improvement of chylomicron metabolism and reduction of pancreatitis incidence up to 5.8 years post treatment. A 43-year-old female presented with severe hypertriglyceridemia (median triglyceride [TG] value of 3,465 mg/dL) and a history of 37 PAs within the last 25 years, despite treatment with fibrates, omega 3 fatty acids, and-since 2012-twice-weekly lipid apheresis. LPLD was confirmed by identification of two different pathogenic variants in the LPL gene located on separate alleles and therefore constituting a compound heterozygous state. With a detectable LPL mass level of 55.1 ng/mL, the patient was eligible for alipogene tiparvovec treatment, and in September 2015, she receved 40 injections (1 × 1012 genome copies/kg) in the muscles of her upper legs under epidural anesthesia and immunosuppressive therapy. Alipogene tiparvovec was well tolerated: no injection site or systemic reactions were observed. Median TG values decreased by 52%, dropping to 997 mg/dL at month 3 and increasing thereafter. Within the first 18 months post treatment, the patient discontinued plasmapheresis and had no abdominal pain or PAs. In March 2017, the patient suffered from a PA due to diet violation. Within the first 12 months post treatment, overall quality of life improved, and no change in humoral or cellular immune response against LPL or AAV-1 was observed. In conclusion, alipogene tiparvovec was well tolerated, with a satisfactory response to treatment. Long-term effects on the recurrence of pancreatitis continue to be monitored.
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Terapia Genética , Vectores Genéticos/uso terapéutico , Hiperlipoproteinemia Tipo I/terapia , Pancreatitis/terapia , Adulto , Dependovirus/genética , Femenino , Humanos , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/fisiopatología , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/genética , Pancreatitis/genética , Pancreatitis/fisiopatología , Calidad de VidaRESUMEN
OBJECTIVE: Tissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride catabolism, is expressed by macrophages in atherosclerotic plaques. We questioned whether LpL, which is also expressed in the bone marrow (BM), affects circulating white blood cells and BM proliferation and modulates macrophage retention within the artery. APPROACH AND RESULTS: We characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/Ghi). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, which are required for monocyte and monocyte precursor proliferation and differentiation. As a result, differentiation of macrophages from BM-derived monocyte progenitors and monocytes was decreased in MCKL0 mice. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF-macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor in BM-derived macrophage precursor cells. Arterial macrophage numbers decreased after heparin-mediated LpL cell dissociation and by genetic knockout of arterial LpL. Reconstitution of LpL-expressing BM replenished aortic macrophage density. CONCLUSIONS: LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation.
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Aorta/enzimología , Enfermedades de la Aorta/enzimología , Aterosclerosis/enzimología , Hiperlipoproteinemia Tipo I/enzimología , Lipoproteína Lipasa/deficiencia , Macrófagos/enzimología , Monocitos/enzimología , Células Progenitoras Mieloides/enzimología , Mielopoyesis , Animales , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Proliferación Celular , Citocinas/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/patología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lipoproteína Lipasa/genética , Macrófagos/patología , Ratones Noqueados , Monocitos/patología , Células Progenitoras Mieloides/patología , Transducción de Señal , Triglicéridos/metabolismoRESUMEN
2-Arachidonoylglycerol (2-AG) is an important endogenous signaling lipid that activates the cannabinoid receptors (CB1 R and CB2 R), thereby regulating a diverse range of physiological processes including anxiety, appetite, inflammation, memory, pain sensation, and nociception. Diacylglycerol lipases (DAGLs) are the principle enzymes responsible for 2-AG biosynthesis. Recently, the (patho)physiological functions of DAGLs have been explored by both genetic methods and chemical tools. This review will focus on the recent efforts to develop highly selective and in vivo active DAGLs inhibitors using activity-based protein profiling.
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Ácidos Araquidónicos/biosíntesis , Endocannabinoides/biosíntesis , Glicéridos/biosíntesis , Lipoproteína Lipasa/metabolismo , Animales , Ácidos Araquidónicos/química , Endocannabinoides/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glicéridos/química , Humanos , Lipoproteína Lipasa/antagonistas & inhibidores , Lipoproteína Lipasa/deficiencia , Estructura MolecularAsunto(s)
Enfermedades Carenciales/complicaciones , Enfermedades Carenciales/dietoterapia , Dermatosis de la Mano/etiología , Lipoproteína Lipasa/deficiencia , Xantomatosis/etiología , Niño , Enfermedades Carenciales/tratamiento farmacológico , Dieta Reductora , Dermatosis de la Mano/fisiopatología , Humanos , Hipolipemiantes/uso terapéutico , Masculino , Pronóstico , Enfermedades Raras , Medición de Riesgo , Índice de Severidad de la Enfermedad , Xantomatosis/fisiopatologíaRESUMEN
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.
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Hipertrigliceridemia/enzimología , Hipertrigliceridemia/genética , Lipoproteína Lipasa/deficiencia , Sodio/sangre , Disomía Uniparental , Ácidos/sangre , Femenino , Humanos , Hipertrigliceridemia/sangre , Recién NacidoRESUMEN
Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.
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Terapia Genética , Vectores Genéticos/administración & dosificación , Hiperlipoproteinemia Tipo I/complicaciones , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/genética , Pancreatitis/terapia , Adulto , Dependovirus/genética , Europa (Continente) , Femenino , Humanos , Hiperlipoproteinemia Tipo I/genética , Masculino , Persona de Mediana Edad , Pancreatitis/etiología , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
Spontaneous hyperlipidemia in rats causes glomerular disease. Idiopathic hypertriglyceridemia (HTG) is prevalent in Miniature Schnauzers, but its relationship with proteinuria is unknown. Decreased activity of major lipid metabolism enzymes, lipoprotein lipase (LPL) and hepatic lipase (HL), may play a role in the cyclic relationship between hyperlipidemia and proteinuria. These enzymes have also not been previously investigated in Miniature Schnauzers. The aims of this study were to determine the relationship between HTG and proteinuria in Miniature Schnauzers and to measure LPL and HL activities in a subset of dogs. Fifty-seven Miniature Schnauzers were recruited (34 with and 23 without HTG). Fasting serum triglyceride concentrations and urine protein-to-creatinine ratios (UPC) were measured in all dogs, and LPL and HL activities were determined in 17 dogs (8 with and 9 without HTG). There was a strong positive correlation between triglyceride concentration and UPC (r = 0.77-0.83, P < 0.001). Proteinuria (UPC ≥ 0.5) was present in 60% of dogs with HTG and absent from all dogs without HTG (P < 0.001). Proteinuric dogs were not azotemic or hypoalbuminemic. Dogs with HTG had a 65% reduction in LPL activity relative to dogs without HTG (P < 0.001); HL activity did not differ. Proteinuria occurs with HTG in Miniature Schnauzers and could be due to lipid-induced glomerular injury. Reduced LPL activity may contribute to the severity of HTG, but further assay validation is required.
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Hipertrigliceridemia/veterinaria , Lipoproteína Lipasa/metabolismo , Proteinuria/veterinaria , Triglicéridos/sangre , Animales , Creatinina/sangre , Enfermedades de los Perros , Perros , Femenino , Hipertrigliceridemia/metabolismo , Lipoproteína Lipasa/deficiencia , Masculino , Minnesota , Ohio , Proteinuria/metabolismo , Especificidad de la EspecieAsunto(s)
Dieta con Restricción de Grasas , Hiperlipoproteinemia Tipo I/dietoterapia , Hipertrigliceridemia/dietoterapia , Apolipoproteínas C/deficiencia , Apolipoproteínas C/genética , Quilomicrones/sangre , Quilomicrones/genética , Humanos , Hipertrigliceridemia/genética , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/genética , MutaciónRESUMEN
BACKGROUND AND PURPOSE: Inhibition of diacylglycerol lipase (DGL)ß prevents LPS-induced pro-inflammatory responses in mouse peritoneal macrophages. Thus, the present study tested whether DGLß inhibition reverses allodynic responses of mice in the LPS model of inflammatory pain, as well as in neuropathic pain models. EXPERIMENTAL APPROACH: Initial experiments examined the cellular expression of DGLß and inflammatory mediators within the LPS-injected paw pad. DAGL-ß (-/-) mice or wild-type mice treated with the DGLß inhibitor KT109 were assessed in the LPS model of inflammatory pain. Additional studies examined the locus of action for KT109-induced antinociception, its efficacy in chronic constrictive injury (CCI) of sciatic nerve and chemotherapy-induced neuropathic pain (CINP) models. KEY RESULTS: Intraplantar LPS evoked mechanical allodynia that was associated with increased expression of DGLß, which was co-localized with increased TNF-α and prostaglandins in paws. DAGL-ß (-/-) mice or KT109-treated wild-type mice displayed reductions in LPS-induced allodynia. Repeated KT109 administration prevented the expression of LPS-induced allodynia, without evidence of tolerance. Intraplantar injection of KT109 into the LPS-treated paw, but not the contralateral paw, reversed the allodynic responses. However, i.c.v. or i.t. administration of KT109 did not alter LPS-induced allodynia. Finally, KT109 also reversed allodynia in the CCI and CINP models and lacked discernible side effects (e.g. gross motor deficits, anxiogenic behaviour or gastric ulcers). CONCLUSIONS AND IMPLICATIONS: These findings suggest that local inhibition of DGLß at the site of inflammation represents a novel avenue to treat pathological pain, with no apparent untoward side effects.
Asunto(s)
Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Lipoproteína Lipasa/antagonistas & inhibidores , Neuralgia/tratamiento farmacológico , Nocicepción/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inflamación/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuralgia/metabolismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB1 receptors has been linked to depression in humans and depression-like behaviors in mice. The two main endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), are produced on demand from phospholipids. The pathways and enzymes involved in endocannabinoid biosynthesis thus play a major role in regulating the activity of this system. This study investigates the role of the main 2-AG producing enzyme diacylglycerol lipase α (DAGL-α). METHODS: We generated and used knockout mice lacking DAGL-α (Dagla(-/-)) to assess the behavioral consequences of reduced endocannabinoid levels in the brain. We performed different behavior tests to determine anxiety- and depression-related behavioral changes in Dagla(-/-) mice. We also analyzed expression of genes related to the endocannabinoid system via real-time polymerase chain reaction and used the mitotic marker 5-bromo-2'-deoxyuridine to analyze adult neurogenesis. RESULTS: Dagla(-/-) animals show an 80% reduction of brain 2-AG levels but also a reduction in cortical and amygdalar anandamide. The behavioral changes induced by Dagla deletion include a reduced exploration of the central area of the open field, a maternal neglect behavior, a fear extinction deficit, increased behavioral despair, increased anxiety-related behaviors in the light/dark box, and reduced hippocampal neurogenesis. Some of these behavioral changes resemble those observed in animals lacking the CB1 receptor. CONCLUSIONS: Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses.
Asunto(s)
Ansiedad/metabolismo , Endocannabinoides/metabolismo , Miedo/fisiología , Lipoproteína Lipasa/deficiencia , Estrés Psicológico/metabolismo , Animales , Encéfalo/metabolismo , Estudios de Cohortes , Conducta Exploratoria/fisiología , Extinción Psicológica/fisiología , Femenino , Lipoproteína Lipasa/genética , Masculino , Conducta Materna/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/fisiología , Neurogénesis/fisiología , Conducta SocialRESUMEN
BACKGROUND: Lipoprotein Lipase (LPL) deficiency is a rare autosomal recessive disorder with a heterogeneous clinical presentation. Several mutations in the LPL gene have been identified to cause decreased activity of the enzyme. FINDINGS: An 11-week-old, exclusively breastfed male presented with coffee-ground emesis, melena, xanthomas, lipemia retinalis and chylomicronemia. Genomic DNA analysis identified lipoprotein lipase deficiency due to compound heterozygosity including a novel p.Q240H mutation in exon 5 of the lipoprotein lipase (LPL) gene. His severe hypertriglyceridemia, including xanthomas, resolved with dietary long-chain fat restriction. CONCLUSIONS: We describe a novel mutation of the LPL gene causing severe hypertriglyceridemia and report the response to treatment. A review of the current literature regarding LPL deficiency syndrome reveals a few potential new therapies under investigation.