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Lysosomal Acid Lipase Deficiency

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2016: Medical Letter on Drugs and Therapeutics
Ryan W Himes, Sarah E Barlow, Kevin Bove, Norma M Quintanilla, Rachel Sheridan, Rohit Kohli
Lysosomal acid lipase deficiency (LAL-D) is a classic lysosomal storage disorder characterized by accumulation of cholesteryl ester and triglyceride. Although it is associated with progressive liver injury, fibrosis, and end-stage liver disease in children and adolescents, LAL-D frequently presents with nonspecific signs that overlap substantially with other, more common, chronic conditions like nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, and certain inherited dyslipidemias. We present 2 children with NAFLD who achieved clinically significant weight reduction through healthy eating and exercise, but who failed to have the anticipated improvements in aminotransferases and γ-glutamyl transferase...
September 13, 2016: Pediatrics
Ting Zhao, Cong Yan, Hong Du
Bone marrow mesenchymal stem cells (MSCs) are an important participant in the tumor microenvironment, in which they promote tumor growth and progression. Here we report for the first time that depletion of lysosomal acid lipase (LAL) in MSCs impairs their abilities to stimulate tumor growth and metastasis both in allogeneic and syngeneic mouse models. Reduced cell viability was observed in LAL-deficient (lal-/-) MSCs, which was a result of both increased apoptosis and decreased proliferation due to cell cycle arrest...
August 12, 2016: Oncotarget
Stephen A Harrison
No abstract text is available yet for this article.
May 2016: Gastroenterology & Hepatology
Ting Zhao, Xinchun Ding, Hong Du, Cong Yan
Lysosomal acid lipase (LAL), a key enzyme in the metabolic pathway of neutral lipids, has a close connection with inflammation and tumor progression. One major manifestation in LAL-deficient (Lipa(-/-)) mice is an increase of tumor growth and metastasis associated with expansion of myeloid-derived suppressor cells. In the lung, LAL is highly expressed in alveolar type II epithelial cells. To assess how LAL in lung epithelial cells plays a role in this inflammation-related pathogenic process, lung alveolar type II epithelial cell-specific expression of human LAL (hLAL) in Lipa(-/-) mice was established by crossbreeding of CCSP-driven rtTA transgene and (TetO)7-CMV-hLAL transgene into Lipa(-/-) mice (CCSP-Tg/KO)...
August 2016: American Journal of Pathology
Barbara Sjouke, Joep C Defesche, Janine S E de Randamie, Albert Wiegman, Sigrid W Fouchier, G Kees Hovingh
BACKGROUND AND AIMS: We recently identified lysosomal acid lipase (LAL) deficiency, a recessive disease caused by mutations in LIPA, in 3 patients with a clinical diagnosis of familial hypercholesterolemia (FH). We aimed to determine the prevalence of LIPA mutations among individuals with a clinical FH diagnosis. METHODS: In 276 patients with phenotypic FH, in whom no genetic basis for their phenotype was found, LIPA was sequenced. All variants were assessed for pathogenicity using a literature search and in silico prediction models...
August 2016: Atherosclerosis
S Sreekantam, I Nicklaus-Wollenteit, J Orr, K Sharif, S Vijay, P J McKiernan, S Santra
Late-onset LAL deficiency, previously referred to as cholesteryl ester storage disorder, is a rare lysosomal storage disorder characterized by accumulation of cholesteryl esters. It has a heterogeneous clinical phenotype including abdominal pain, poor growth, hyperlipidemia with vascular complications and hepatosplenomegaly. End-stage liver disease may occur, but there are few reports of successful LT. There are also concerns that systemic manifestations of the disease might persist post-LT. We report a case with excellent outcome eight yr following LT...
September 2016: Pediatric Transplantation
D M Paton
Sebelipase alfa was approved for use in 2015 for patients suffering from lysosomal acid lipase deficiency in either of its two forms. The more severe, early-onset form, Wolman disease, occurs in young infants in whom it is normally fatal within the first year of life. Sebelipase alfa has allowed a small number of such infants to achieve a relatively normal growth rate and to survive for 2 or more years. In older children and adults, the enzyme has corrected their dyslipidemia and produced significant improvement in markers of hepatic function...
May 2016: Drugs of Today
Lukas Grumet, Thomas O Eichmann, Ulrike Taschler, Kathrin A Zierler, Christina Leopold, Tarek Moustafa, Branislav Radovic, Matthias Romauch, Cong Yan, Hong Du, Guenter Haemmerle, Rudolf Zechner, Peter Fickert, Dagmar Kratky, Robert Zimmermann, Achim Lass
Lysosomal acid lipase (LAL) is essential for the clearance of endocytosed cholesteryl ester and triglyceride-rich chylomicron remnants. Humans and mice with defective or absent LAL activity accumulate large amounts of cholesteryl esters and triglycerides in multiple tissues. Although chylomicrons also contain retinyl esters (REs), a role of LAL in the clearance of endocytosed REs has not been reported. In this study, we found that murine LAL exhibits RE hydrolase activity. Pharmacological inhibition of LAL in the human hepatocyte cell line HepG2, incubated with chylomicrons, led to increased accumulation of REs in endosomal/lysosomal fractions...
August 19, 2016: Journal of Biological Chemistry
Branislav Radović, Nemanja Vujić, Christina Leopold, Stefanie Schlager, Madeleine Goeritzer, Jay V Patankar, Melanie Korbelius, Dagmar Kolb, Julia Reindl, Martin Wegscheider, Tamara Tomin, Ruth Birner-Gruenberger, Matthias Schittmayer, Lukas Groschner, Christoph Magnes, Clemens Diwoky, Saša Frank, Ernst Steyrer, Hong Du, Wolfgang F Graier, Tobias Madl, Dagmar Kratky
AIMS/HYPOTHESIS: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s). METHODS: We studied metabolic adaptations in Lal (-/-) mice. RESULTS: Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice...
August 2016: Diabetologia
Barbara K Burton
No abstract text is available yet for this article.
September 2016: Journal of Pediatric Gastroenterology and Nutrition
Eyal Shteyer, Rivka Villenchik, Mahmud Mahamid, Nidaa Nator, Rifaat Safadi
Fatty liver has become the most common liver disorder and is recognized as a major health burden in the Western world. The causes for disease progression are not fully elucidated but lysosomal impairment is suggested. Here we evaluate a possible role for lysosomal acid lipase (LAL) activity in liver disease. To study LAL levels in patients with microvesicular, idiopathic cirrhosis and nonalcoholic fatty liver disease (NAFLD). Medical records of patients with microvesicular steatosis, cryptogenic cirrhosis and NAFLD, diagnosed on the basis of liver biopsies, were included in the study...
2016: International Journal of Molecular Sciences
Ambar Grijalva, Xiaoyuan Xu, Anthony W Ferrante
Adipose tissue (AT) macrophages (ATMs) contribute to obesity-induced inflammation and metabolic dysfunction, but also play critical roles in maintaining tissue homeostasis. ATMs catabolize lipid in a lysosomal-dependent manner required for the maintenance of AT; deficiency in lysosomal acid lipase (Lipa), the enzyme required for lysosome lipid catabolism, leads to AT atrophy and severe hepatic steatosis, phenotypes rescued by macrophage-specific expression of Lipa Autophagy delivers cellular products, including lipid droplets, to lysosomes...
April 2016: Diabetes
Daniel Gaudet
PURPOSE OF REVIEW: Novel therapies for severe dyslipidemia target a wide range of unmet medical needs: severe familial hypercholesterolemia, severe hypertriglyceridemia and chylomicronemia, elevated lipoprotein (a), lipodystrophies, high-density lipoprotein particle diseases, lysosomal acid lipase deficiency and storage diseases, nonalcoholic fatty liver disease and others. The purpose of this review is to describe the contribution of human genetics to the development of therapeutic approaches targeting severe dyslipidemia...
April 2016: Current Opinion in Lipidology
Ting Zhao, Hong Du, Janice S Blum, Cong Yan
Lysosomal acid lipase (LAL) is a key enzyme controlling neutral lipid metabolic signaling in myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient (lal-/-) mice directly stimulate cancer cell proliferation. PPARγ ligand treatment inhibited lal-/- MDSCs stimulation of tumor cell growth and metastasis in vivo, and tumor cell proliferation and migration in vitro. In addition, PPARγ ligand treatment impaired lal-/- MDSCs transendothelial migration, and differentiation from lineage-negative cells...
January 12, 2016: Oncotarget
Francesco Baratta, Daniele Pastori, Licia Polimeni, Giulia Tozzi, Francesco Violi, Francesco Angelico, Maria Del Ben
Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents the early onset phenotype of LAL deficiency rapidly leading to death. Cholesterol Ester Storage Disease is a late onset phenotype that occurs with fatty liver, elevated aminotransferase levels, hepatomegaly and dyslipidaemia, the latter characterized by elevated LDL-C and low HDL-C. The natural history and the clinical manifestations of the LAL deficiency in adults are not well defined, and the diagnosis is often incidental...
2015: International Journal of Molecular Sciences
Carla E M Hollak, G Kees Hovingh
Lysosomal acid lipase deficiency can lead to liver failure and early death. A recently published placebo-controlled trial shows that enzyme-replacement therapy improves plasma levels of lipids and aminotransferases, and reduces liver fat content. However, the effect on clinical end points and an appropriate indication for treatment remain to be established.
December 2015: Nature Reviews. Endocrinology
Matt Shirley
Sebelipase alfa (Kanuma™) is a recombinant human lysosomal acid lipase (LAL) developed by Synageva BioPharma Corp. (now Alexion Pharmaceuticals, Inc.) for long-term enzyme replacement therapy in patients with LAL deficiency. The agent, administered by intravenous infusion once weekly or once every other week, acts to replace the deficient enzyme activity in patients with LAL deficiency, reducing lysosomal lipid accumulation, and thereby improving disease-related abnormalities such as dyslipidaemia and liver abnormalities...
November 2015: Drugs
Irene Fernández Ruiz
No abstract text is available yet for this article.
December 2015: Nature Reviews. Cardiology
Naomi Kuranobu, Jun Murakami, Ken Okamoto, Rei Nishimura, Kei Murayama, Ayumi Takamura, Toshiko Umeda, Yoshikatsu Eto, Susumu Kanzaki
Cholesterol ester storage disease (CESD) is an autosomal recessive disorder caused by deficient lysosomal acid lipase (LAL) activity, resulting in cholesteryl ester (CE) accumulation. CESD patients have liver disease associated with mixed dyslipidemia leading to liver failure. We here report the case of an 11-year-old male CESD patient with a novel mutation who had the chief complaint of massive hepatomegaly. The patient's liver reached to his pelvis, and his spleen was 2 cm below the costal margin. The patient had elevated serum liver enzymes and mixed dyslipidemia...
March 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
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