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Lysosomal Acid Lipase Deficiency

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https://www.readbyqxmd.com/read/28924047/endothelial-rab7-gtpase-mediates-tumor-growth-and-metastasis-in-lysosomal-acid-lipase-deficient-mice
#1
Ting Zhao, Xinchun Ding, Cong Yan, Hong Du
Tumors depend on their microenvironment for sustained growth, invasion and metastasis. In this environment, endothelial cells (ECs) are an important stromal cell type interacting with malignant cells to facilitate tumor angiogenesis and cancer cell extravasation. Of note, lysosomal acid lipase (LAL) deficiency facilitates melanoma growth and metastasis. ECs from LAL-deficient (lal-/-) mice possess enhanced proliferation, migration, and permeability of inflammatory cells by activating the mammalian target of rapamycin (mTOR) pathway...
September 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28900817/spleen-dimensions-are-inversely-associated-with-lysosomal-acid-lipase-activity-in-patients-with-non-alcoholic-fatty-liver-disease
#2
Licia Polimeni, Daniele Pastori, Francesco Baratta, Giulia Tozzi, Marta Novo, Roberto Vicinanza, Giovanni Troisi, Gaetano Pannitteri, Fabrizio Ceci, Laura Scardella, Francesco Violi, Francesco Angelico, Maria Del Ben
Fatty liver and splenomegaly are typical features of genetic lysosomal acid lipase (LAL) deficiency. No data in adult patients with non-genetic reduction of LAL activity are available. We investigate the association between spleen dimensions and LAL activity in non-alcoholic fatty liver disease (NAFLD) patients, in whom a reduced LAL activity has been reported. We include 425 consecutive patients who underwent abdominal ultrasound to evaluate hepatic steatosis and spleen dimensions. LAL activity was measured with dried blood spot method (Lalistat2)...
September 12, 2017: Internal and Emergency Medicine
https://www.readbyqxmd.com/read/28882870/crispr-cas9-mediated-gene-editing-in-human-ipsc-derived-macrophage-reveals-lysosomal-acid-lipase-function-in-human-macrophages
#3
Hanrui Zhang, Jianting Shi, Melanie A Hachet, Chenyi Xue, Robert C Bauer, Hongfeng Jiang, Wenjun Li, Junichiro Tohyama, John Millar, Jeffrey Billheimer, Michael C Phillips, Babak Razani, Daniel J Rader, Muredach P Reilly
OBJECTIVE: To gain mechanistic insights into the role of LIPA(lipase A), the gene encoding LAL (lysosomal acid lipase) protein, in human macrophages. APPROACH AND RESULTS: We used CRISPR (clustered regularly interspaced short palindromic repeats )/Cas9 (CRISPR-associated protein 9) technology to knock out LIPA in human induced pluripotent stem cells and then differentiate to macrophage (human-induced pluripotent stem cells-derived macrophage [IPSDM]) to explore the human macrophage LIPA loss-of-function phenotypes...
September 7, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28881270/molecular-and-clinical-characterization-of-a-series-of-patients-with-childhood-onset-lysosomal-acid-lipase-deficiency-retrospective-investigations-follow-up-and-detection-of-two-novel-lipa-pathogenic-variants
#4
Livia Pisciotta, Giulia Tozzi, Lorena Travaglini, Roberta Taurisano, Tiziano Lucchi, Giuseppe Indolfi, Francesco Papadia, Maja Di Rocco, Lorenzo D'Antiga, Patricia Crock, Komal Vora, Scott Nightingale, Helen Michelakakis, Anastasia Garoufi, Lilia Lykopoulou, Stefano Bertolini, Sebastiano Calandra
BACKGROUND AND AIMS: Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D...
August 26, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28804516/the-role-of-sebelipase-alfa-in-the-treatment-of-lysosomal-acid-lipase-deficiency
#5
REVIEW
Angelika L Erwin
Lysosomal acid lipase deficiency (LALD) is a lysosomal storage disorder (LSD) characterized either by infantile onset with fulminant clinical course and very poor prognosis or childhood/adult-onset disease with an attenuated phenotype. The disorder is often misdiagnosed or remains undiagnosed in children and adults due to a rather unspecific clinical presentation with dyslipidemia and steatohepatitis. Until recently, no good treatment options were available for LALD. Despite supportive and symptomatic therapies, death occurred before 1 year of age in patients with infantile-onset disease and patients with childhood/adult-onset LALD suffered from significant complications, such as liver cirrhosis, requiring liver transplantation and early-onset cardiovascular disease...
July 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/28659158/neural-stem-cells-for-disease-modeling-of-wolman-disease-and-evaluation-of-therapeutics
#6
Francis Aguisanda, Charles D Yeh, Catherine Z Chen, Rong Li, Jeanette Beers, Jizhong Zou, Natasha Thorne, Wei Zheng
BACKGROUND: Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. RESULTS: We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs)...
June 28, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28612634/lysosomal-acid-lipase-deficiency-a-form-of-non-obese-fatty-liver-disease-nofld
#7
Hassan H A-Kader
With the growing obesity epidemic, nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of the leading causes of liver disease worldwide. Although obesity is a main risk factor for the development of NAFLD, it can also develop in lean subjects and can be encountered in different clinical setting and in association with an array of genetic, metabolic, nutritional, infectious and drug-induced disorders. Areas covered: This article discusses causes of fatty liver in non-obese subjects focusing on Lysosomal acid lipase deficiency (LAL-D), a commonly overlooked disorder reviewing its prevalence, genetics, pathogenesis, clinical features, diagnosis and treatment...
June 26, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28587063/a-relative-deficiency-of-lysosomal-acid-lypase-activity-characterizes-non-alcoholic-fatty-liver-disease
#8
Francesco Tovoli, Lucia Napoli, Giulia Negrini, Sergio D'Addato, Giulia Tozzi, Jessica D'Amico, Fabio Piscaglia, Luigi Bolondi
Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)-however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to determine LAL activity in a cohort of NAFLD subjects and in a control group of hepatitis C virus (HCV)-infected patients, investigating the role of liver cirrhosis. A total of 81 patients with a diagnosis of NAFLD, and 78 matched controls with HCV-related liver disease were enrolled...
May 25, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28538091/wolman-disease-a-mimic-of-infant-leukemia
#9
Kaduveettil G Gopakumar, Priyakumari Thankamony, Sheela Nampoothiri, Deeksha Bali, Jubie Raj, Jayasudha A Vasudevan, Ramachandran K Nair
BACKGROUND: Infant leukemia most commonly present with pallor and hepatosplenomegaly. The possibility of other differential diagnosis also has to be kept in mind during evaluation, as identifying the precise etiology for this clinical presentation is crucial for management. OBSERVATION: An infant, was referred to us with suspected infant leukemia and was subsequently diagnosed to have lysosomal acid lipase deficiency/Wolman disease with a novel 5 bp deletion "c...
May 23, 2017: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/28537522/fast-progression-of-liver-damage-in-lysosomal-acid-lipase-deficiency
#10
Ralf Weiskirchen
No abstract text is available yet for this article.
June 7, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28532785/best-practice-in-the-measurement-and-interpretation-of-lysosomal-acid-lipase-in-dried-blood-spots-using-the-inhibitor-lalistat-2
#11
Zoltan Lukacs, Marianne Barr, John Hamilton
Lysosomal acid lipase deficiency (LAL-D) is an inherited, autosomal recessive lysosomal storage disorder characterized by progressive damage in multiple organ systems. Diagnosis is especially important in infants, in whom the course of disease is rapidly lethal without treatment. The recent regulatory approval of recombinant human lysosomal acid lipase (LAL), sebelipase alfa, merits rapid diagnosis in clinical routine, particularly in infants. A method for measuring LAL activity in dried blood spot (DBS) samples using the highly specific LAL inhibitor Lalistat 2 is available...
May 19, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28524215/-novel-therapies-in-neurometabolic-diseases-the-importance-of-early-intervention
#12
L G Gutierrez-Solana
INTRODUCTION: Individually, neurometabolic diseases are ultra rare, but for some of them there is an effective treatment. DEVELOPMENT: Several recent therapeutic advances are reviewed. Today, the possibilities of treatment for lysosomal diseases have improved. In recent years the use of enzyme replacement therapy has become more widely extended to treat mucopolysaccharidosis type IVA (Morquio A), mucopolysaccharidosis type VII (Sly syndrome), lysosomal acid lipase deficiency and alpha-mannosidosis...
May 17, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28504497/liver-disease-and-dyslipidemia-as-a-manifestation-of-lysosomal-acid-lipase-deficiency-lal-d-clinical-and-diagnostic-aspects-and-a-new-treatment-an-update
#13
Luisa Bay, Cristina Canero Velasco, Mirta Ciocca, Andrea Cotti, Miriam Cuarterolo, Alejandro Fainboim, Eduardo Fassio, Marcela Galoppo, Federico Pinero, Paula Rozenfeld
Lysosomal acid lipase deficiency (LAL-D) is still a little recognized genetic disease with significant morbidity and mortality in children and adults. This document provides guidance on when to suspect LAL-D and how to diagnose it. It is recommended to add lysosomal acid lipase deficiency to the List of differential diagnoses of sepsis, oncological diseases, storage diseases, persistent diarrhea, chronic malnutrition, and hemophagocytic lymphohistiocytosis. It should also be considered in young patients with dyslipidemia and atherosclerosis as well as diseases associated with fatty liver and/or hepatomegaly...
June 1, 2017: Archivos Argentinos de Pediatría
https://www.readbyqxmd.com/read/28502515/lysosomal-acid-lipase-deficiency-in-all-siblings-of-the-same-parents
#14
James J Maciejko, Premchand Anne, Saleem Raza, Hernando J Lyons
We present 4 normal-weight sibling children with lysosomal acid lipase deficiency (LAL-D). LAL-D was considered in the differential diagnosis based on the absence of secondary causes and primary inherited traits for their marked hyperlipidemia, together with unexplained hepatic transaminase elevation. Residual lysosomal acid lipase activity confirmed the diagnosis. DNA sequencing of LIPA indicated that the siblings were compound heterozygotes (c.894G>A and c.428+1G>A). This case describes the unusual occurrence of all offspring from the same nonconsanguineous mother and father inheriting compound heterozygosity of a recessive trait and the identification of an apparently unique LIPA mutation (c...
March 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28502505/lysosomal-acid-lipase-deficiency-a-hidden-disease-among-cohorts-of-familial-hypercholesterolemia
#15
Joana Rita Chora, Ana Catarina Alves, Ana Margarida Medeiros, Cibelle Mariano, Goreti Lobarinhas, António Guerra, Helena Mansilha, Helena Cortez-Pinto, Mafalda Bourbon
BACKGROUND: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder and an unrecognized cause of dyslipidemia. Patients usually present with dyslipidemia and altered liver function and mutations in LIPA gene are the underlying cause of LALD. OBJECTIVE: The aim of this study was to investigate LALD in individuals with severe dyslipidemia and/or liver steatosis. METHODS: Coding, splice regions, and promoter region of LIPA were sequenced by Sanger sequencing in a cohort of mutation-negative familial hypercholesterolemia (FH) patients (n = 492) and in a population sample comprising individuals with several types of dyslipidemia and/or liver steatosis (n = 258)...
March 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28420705/synthesis-of-neutral-ether-lipid-monoalkyl-diacylglycerol-by-lipid-acyltransferases
#16
Zhengping Ma, Joelle M Onorato, Luping Chen, David W Nelson, Chi-Liang Eric Yen, Dong Cheng
In mammals, ether lipids exert a wide spectrum of signaling and structural functions, such as stimulation of immune responses, anti-tumor activities, and enhancement of sperm functions. Abnormal accumulation of monoalkyl-diacylglycerol (MADAG) was found in Wolman's disease, a human genetic disorder defined by a deficiency in lysosomal acid lipase. In the current study, we found that among the nine recombinant human lipid acyltransferases examined, acyl-CoA:diacylglycerol acyltransferase (DGAT)1, DGAT2, acyl-CoA:monoacylglycerol acyltransferase (MGAT)2, MGAT3, acyl-CoA:wax-alcohol acyltransferase 2/MFAT, and DGAT candidate 3 were able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG)...
June 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28415797/rab7-gtpase-controls-lipid-metabolic-signaling-in-myeloid-derived-suppressor-cells
#17
Xinchun Ding, Wenjing Zhang, Ting Zhao, Cong Yan, Hong Du
Lysosomal acid lipase (LAL) is a critical neutral lipid metabolic enzyme that regulates metabolic reprogramming in myeloid-derived suppressor cells (MDSCs) through over-activation of mammalian target of rapamycin (mTOR). Affymetrix GeneChip microarray analysis of MDSCs from LAL deficient mouse (lal-/-) revealed upregulation of Rab7 GTPase protein, which belongs to a superfamily of small-molecular-weight GTPase known to regulate intracellular membrane trafficking from early to late endosomes and lysosomes. Here, the physical protein-protein interaction between Rab7 GTPase and mTOR has been detected by co-immunoprecipitation in the cell extract of wild type HD1A and lal-/- MDSC-like HD1B myeloid cell lines...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28402950/lysosomal-lipid-hydrolysis-provides-substrates-for-lipid-mediator-synthesis-in-murine-macrophages
#18
Stefanie Schlager, Nemanja Vujic, Melanie Korbelius, Madalina Duta-Mare, Juliane Dorow, Christina Leopold, Silvia Rainer, Martin Wegscheider, Helga Reicher, Uta Ceglarek, Wolfgang Sattler, Branislav Radovic, Dagmar Kratky
Degradation of lysosomal lipids requires lysosomal acid lipase (LAL), the only intracellular lipase known to be active at acidic pH. We found LAL to be expressed in murine immune cells with highest mRNA expression in macrophages and neutrophils. Furthermore, we observed that loss of LAL in mice caused lipid accumulation in white blood cells in the peripheral circulation, which increased in response to an acute inflammatory stimulus. Lal-deficient (-/-) macrophages accumulate neutral lipids, mainly cholesteryl esters, within lysosomes...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28401034/targeting-wolman-disease-and-cholesteryl-ester-storage-disease-disease-pathogenesis-and-therapeutic-development
#19
REVIEW
Francis Aguisanda, Natasha Thorne, Wei Zheng
Wolman disease (WD) and cholesteryl ester storage disease (CESD) are lysosomal storage diseases (LSDs) caused by a deficiency in lysosomal acid lipase (LAL) due to mutations in the LIPA gene. This enzyme is critical to the proper degradation of cholesterol in the lysosome. LAL function is completely lost in WD while some residual activity remains in CESD. Both are rare diseases with an incidence rate of less than 1/100,000 births for WD and approximate 2.5/100,000 births for CESD. Clinical manifestation of WD includes hepatosplenomegaly, calcified adrenal glands, severe malabsorption and a failure to thrive...
2017: Current Chemical Genomics and Translational Medicine
https://www.readbyqxmd.com/read/28391883/childhood-adult-onset-lysosomal-acid-lipase-deficiency-a-serious-metabolic-and-vascular-phenotype-beyond-liver-disease-four-new-pediatric-cases
#20
Pierre Poinsot, Sophie Collardeau Frachon, Lioara Restier, André Sérusclat, Mathilde Di Filippo, Sybil Charrière, Philippe Moulin, Alain Lachaux, Noel Peretti
BACKGROUND: The childhood/adult-onset lysosomal acid lipase deficiency (LALD; late-onset LALD) is a rare genetic disease. Children present severe fatty liver disease with early cirrhosis. Before enzyme replacement therapy, statins were the standard treatment to improve the severe dyslipidemia. However, late-onset LALD should be considered as a systemic metabolic disease: chronic hyper-low-density lipoprotein and hypo-high-density lipoprotein cholesterolemia induces early atherosclerosis in addition to the liver morbidity...
January 2017: Journal of Clinical Lipidology
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