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Protein lysosomal lipase

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https://www.readbyqxmd.com/read/28642584/molecular-switching-system-using-glycosylphosphatidylinositol-to-select-cells-highly-expressing-recombinant-proteins
#1
Emmanuel Matabaro, Zeng'an He, Yi-Shi Liu, Hui-Jie Zhang, Xiao-Dong Gao, Morihisa Fujita
Although many pharmaceutical proteins are produced in mammalian cells, there remains a challenge to select cell lines that express recombinant proteins with high productivity. Since most biopharmaceutical proteins are secreted by cells into the medium, it is difficult to select cell lines that produce large amounts of the target protein. To address this issue, a new protein expression system using the glycosylphosphatidylinositol (GPI)-anchor was developed. PGAP2 is involved in processing GPI-anchored proteins (GPI-APs) during transport...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28415797/rab7-gtpase-controls-lipid-metabolic-signaling-in-myeloid-derived-suppressor-cells
#2
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/28321238/association-of-non-synonymous-variants-in-wipf3-and-lipa-genes-with-abdominal-aortic-aneurysm-an-autopsy-study
#3
Yuko Maeda, Noriko Sato, Makiko Naka-Mieno, Seijiro Mori, Tomio Arai, Masashi Tanaka, Masaaki Muramatsu, Motoji Sawabe
BACKGROUND: Abdominal aortic aneurysm (AAA) is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease. METHODS: We examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals (The JG-SNP study). The presence of AAA was determined with a pathological diagnosis during autopsy...
December 2016: Journal of Geriatric Cardiology: JGC
https://www.readbyqxmd.com/read/28279971/coronary-artery-disease-associated-lipa-coding-variant-rs1051338-reduces-lysosomal-acid-lipase-levels-and-activity-in-lysosomes
#4
Gavin E Morris, Peter S Braund, Jasbir S Moore, Nilesh J Samani, Veryan Codd, Tom R Webb
OBJECTIVE: Genome-wide association studies have linked variants at chromosome 10q23 with increased coronary artery disease risk. The disease-associated variants fall in LIPA, which encodes lysosomal acid lipase (LAL), the enzyme responsible for lysosomal cholesteryl ester hydrolysis. Loss-of-function mutations in LIPA result in accelerated atherosclerosis. Surprisingly, the coronary artery disease variants are associated with increased LIPA expression in some cell types. In this study, we address this apparent contradiction...
June 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27997605/role-of-myeloperoxidase-oxidants-in-the-modulation-of-cellular-lysosomal-enzyme-function-a-contributing-factor-to-macrophage-dysfunction-in-atherosclerosis
#5
Fahd O Ismael, Tessa J Barrett, Diba Sheipouri, Bronwyn E Brown, Michael J Davies, Clare L Hawkins
Low-density lipoprotein (LDL) is the major source of lipid within atherosclerotic lesions. Myeloperoxidase (MPO) is present in lesions and forms the reactive oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). These oxidants modify LDL and have been strongly linked with the development of atherosclerosis. In this study, we examined the effect of HOCl, HOSCN and LDL pre-treated with these oxidants on the function of lysosomal enzymes responsible for protein catabolism and lipid hydrolysis in murine macrophage-like J774A...
2016: PloS One
https://www.readbyqxmd.com/read/27799810/novel-treatment-options-for-lysosomal-acid-lipase-deficiency-critical-appraisal-of-sebelipase-alfa
#6
REVIEW
Kim Su, Emma Donaldson, Reena Sharma
Lysosomal acid lipase deficiency (LAL-D) is a rare disorder of cholesterol metabolism with an autosomal recessive mode of inheritance. The absence or deficiency of the LAL enzyme gives rise to pathological accumulation of cholesterol esters in various tissues. A severe LAL-D phenotype manifesting in infancy is associated with adrenal calcification and liver and gastrointestinal involvement with characteristic early mortality. LAL-D presenting in childhood and adulthood is associated with hepatomegaly, liver fibrosis, cirrhosis, and premature atherosclerosis...
2016: Application of Clinical Genetics
https://www.readbyqxmd.com/read/27662254/lysosomal-lipases-plrp2-and-lpla2-process-mycobacterial-multi-acylated-lipids-and-generate-t-cell-stimulatory-antigens
#7
Martine Gilleron, Marco Lepore, Emilie Layre, Diane Cala-De Paepe, Naila Mebarek, James A Shayman, Stéphane Canaan, Lucia Mori, Frédéric Carrière, Germain Puzo, Gennaro De Libero
Complex antigens require processing within antigen-presenting cells (APCs) to form T cell stimulatory complexes with CD1 antigen-presenting molecules. It remains unknown whether lipids with multi-acylated moieties also necessitate digestion by lipases to become capable of binding CD1 molecules and stimulate T cells. Here, we show that the mycobacterial tetra-acylated glycolipid antigens phosphatidyl-myo-inositol mannosides (PIM) are digested to di-acylated forms by pancreatic lipase-related protein 2 (PLRP2) and lysosomal phospholipase A2 (LPLA2) within APCs...
September 22, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27646002/cell-surface-cd36-protein-in-monocyte-macrophage-contributes-to-phagocytosis-during-the-resolution-phase-of-ischemic-stroke-in-mice
#8
Moon-Sook Woo, Jiwon Yang, Cesar Beltran, Sunghee Cho
Infiltrating monocyte-derived macrophages (M-MΦ) influence stroke-induced brain injury. Although the inflammatory nature of M-MΦ in acute stroke has been well documented, their role during the resolution phase of stroke is less clear. With emerging evidence for the involvement of scavenger receptors in innate immunity, this study addresses an M-MΦ CD36 role in mediating phagocytosis during the recovery phase of stroke. Stroke increases CD36 and TSP-1/2 mRNA levels in the ipsilateral hemisphere at acute (3-day (d)) and recovery (7d) periods...
November 4, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27341145/telemetric-control-of-peripheral-lipophagy-by-hypothalamic-autophagy
#9
Nuria Martinez-Lopez, Rajat Singh
Autophagy maintains cellular quality control by degrading organelles, and cytosolic proteins and their aggregates in lysosomes. Autophagy also degrades lipid droplets (LD) through a process termed lipophagy. During lipophagy, LD are sequestered within autophagosomes and degraded by lysosomal acid lipases to generate free fatty acids that are β-oxidized for energy. Lipophagy was discovered in hepatocytes, and since then has been shown to function in diverse cell types. Whether lipophagy degrades LD in the major fat storing cell-the adipocyte-remained unclear...
August 2, 2016: Autophagy
https://www.readbyqxmd.com/read/27319346/the-processing-and-presentation-of-lipids-and-glycolipids-to-the-immune-system
#10
REVIEW
Vincent F Vartabedian, Paul B Savage, Luc Teyton
The recognition of CD1-lipid complexes by T cells was discovered 20 years ago and has since been an emerging and expanding field of investigation. Unlike protein antigens, which are presented on MHC class I and II molecules, lipids can only be presented by CD1 molecules, a unique family of MHC-like proteins whose singularity is a hydrophobic antigen-binding groove. The processing and loading of lipid antigens inside this groove of CD1 molecules require localization to endosomal and lysosomal subcellular compartments and their acidic pHs...
July 2016: Immunological Reviews
https://www.readbyqxmd.com/read/27153842/lysosomal-acid-lipase-regulates-vldl-synthesis-and-insulin-sensitivity-in-mice
#11
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
https://www.readbyqxmd.com/read/27095633/quantification-of-age-related-changes-of-%C3%AE-tocopherol-in-lysosomal-membranes-in-murine-tissues-and-human-fibroblasts
#12
Jeannette König, Fabian Besoke, Wolfgang Stuetz, Angelika Malarski, Gerhard Jahreis, Tilman Grune, Annika Höhn
Considering the biological function of α-tocopherol (α-Toc) as a potent protective factor against oxidative stress, this antioxidant is in the focus of aging research. To understand the role of α-Toc during aging we investigated α-Toc concentrations in young and aged primary human fibroblasts after supplementation with RRR-α-Toc. Additionally, α-Toc contents were determined in brain, kidney, and liver tissue of 10 week-, 18 month-, and 24 month-old mice, which were fed a standard diet containing 100 mg/kg dl-α-tocopheryl acetate...
May 2016: BioFactors
https://www.readbyqxmd.com/read/26865708/distinct-entry-mechanisms-for-nonenveloped-and-quasi-enveloped-hepatitis-e-viruses
#13
Xin Yin, Charuta Ambardekar, Yurong Lu, Zongdi Feng
UNLABELLED: The hepatitis E virus (HEV) sheds into feces as nonenveloped virions but circulates in the blood in a membrane-associated, quasi-enveloped form (eHEV). Since the eHEV virions lack viral proteins on the surface, we investigated the entry mechanism for eHEV. We found that compared to nonenveloped HEV virions, eHEV attachment to the cell was much less efficient, requiring a longer inoculation time to reach its maximal infectivity. A survey of cellular internalization pathways identified clathrin-mediated endocytosis as the main route for eHEV entry...
April 2016: Journal of Virology
https://www.readbyqxmd.com/read/26461411/long-lived-reactive-species-formed-on-proteins-induce-changes-in-protein-and-lipid-turnover
#14
Michael Davies
Proteins are major targets for oxidative damage in vivo due to their high abundance and rapid rates of reaction with both one-electron (radical) and two-electron oxidants (e.g. singlet oxygen, hypochlorous acid, peroxynitrous acid, reactive aldehydes). The turnover of both native and modified proteins is critical for maintenance of cell homeostasis, with this occurring via multiple pathways including proteasomes (for cytosolic species), the Lon protease (in mitochondria), and the endo-lysosomal systems (both extra- and intra-cellular species)...
October 2014: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/26283692/prd125-a-potent-and-selective-inhibitor-of-sterol-o-acyltransferase-2-markedly-reduces-hepatic-cholesteryl-ester-accumulation-and-improves-liver-function-in-lysosomal-acid-lipase-deficient-mice
#15
Adam M Lopez, Jen-Chieh Chuang, Kenneth S Posey, Taichi Ohshiro, Hiroshi Tomoda, Lawrence L Rudel, Stephen D Turley
In most organs, the bulk of cholesterol is unesterified, although nearly all possess a varying capability of esterifying cholesterol through the action of either sterol O-acyltransferase (SOAT) 1 or, in the case of hepatocytes and enterocytes, SOAT2. Esterified cholesterol (EC) carried in plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease or cholesteryl ester storage disease (CESD)...
November 2015: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/26212911/hepatocyte-specific-expression-of-human-lysosome-acid-lipase-corrects-liver-inflammation-and-tumor-metastasis-in-lal-mice
#16
Hong Du, Ting Zhao, Xinchun Ding, Cong Yan
The liver is a major organ for lipid synthesis and metabolism. Deficiency of lysosomal acid lipase (LAL; official name Lipa, encoded by Lipa) in mice (lal(-/-)) results in enlarged liver size due to neutral lipid storage in hepatocytes and Kupffer cells. To test the functional role of LAL in hepatocyte, hepatocyte-specific expression of human LAL (hLAL) in lal(-/-) mice was established by cross-breeding of liver-activated promoter (LAP)-driven tTA transgene and (tetO)7-CMV-hLAL transgene with lal(-/-) knockout (KO) (LAP-Tg/KO) triple mice...
September 2015: American Journal of Pathology
https://www.readbyqxmd.com/read/26162625/lipid-droplets-and-their-component-triglycerides-and-steryl-esters-regulate-autophagosome-biogenesis
#17
Tomer Shpilka, Evelyn Welter, Noam Borovsky, Nira Amar, Muriel Mari, Fulvio Reggiori, Zvulun Elazar
Autophagy is a major catabolic process responsible for the delivery of proteins and organelles to the lysosome/vacuole for degradation. Malfunction of this pathway has been implicated in numerous pathological conditions. Different organelles have been found to contribute to the formation of autophagosomes, but the exact mechanism mediating this process remains obscure. Here, we show that lipid droplets (LDs) are important for the regulation of starvation-induced autophagy. Deletion of Dga1 and Lro1 enzymes responsible for triacylglycerol (TAG) synthesis, or of Are1 and Are2 enzymes responsible for the synthesis of steryl esters (STE), results in the inhibition of autophagy...
August 13, 2015: EMBO Journal
https://www.readbyqxmd.com/read/26143381/active-autophagy-but-not-lipophagy-in-macrophages-with-defective-lipolysis
#18
Madeleine Goeritzer, Nemanja Vujic, Stefanie Schlager, Prakash G Chandak, Melanie Korbelius, Benjamin Gottschalk, Christina Leopold, Sascha Obrowsky, Silvia Rainer, Prakash Doddapattar, Elma Aflaki, Martin Wegscheider, Vinay Sachdev, Wolfgang F Graier, Dagmar Kolb, Branislav Radovic, Dagmar Kratky
During autophagy, autophagosomes fuse with lysosomes to degrade damaged organelles and misfolded proteins. Breakdown products are released into the cytosol and contribute to energy and metabolic building block supply, especially during starvation. Lipophagy has been defined as the autophagy-mediated degradation of lipid droplets (LDs) by lysosomal acid lipase. Adipose triglyceride lipase (ATGL) is the major enzyme catalyzing the initial step of lipolysis by hydrolyzing triglycerides (TGs) in cytosolic LDs. Consequently, most organs and cells, including macrophages, lacking ATGL accumulate TGs, resulting in reduced intracellular free fatty acid concentrations...
October 2015: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/26076903/autophagy-and-lipid-droplets-in-the-liver
#19
REVIEW
Nuria Martinez-Lopez, Rajat Singh
Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy. Starvation and an acute lipid stimulus increase autophagic sequestration of lipid droplets and their degradation in lysosomes. Accordingly, liver-specific deletion of the autophagy gene Atg7 increases hepatic fat content, mimicking the human condition termed nonalcoholic fatty liver disease. In this review, we provide insights into the molecular regulation of lipophagy, discuss fundamental questions related to the mechanisms by which autophagosomes recognize lipid droplets and how ATG proteins regulate membrane curvature for lipid droplet sequestration, and comment on the possibility of cross talk between lipophagy and cytosolic lipases in lipid mobilization...
2015: Annual Review of Nutrition
https://www.readbyqxmd.com/read/25961502/degradation-of-lipid-droplet-associated-proteins-by-chaperone-mediated-autophagy-facilitates-lipolysis
#20
Susmita Kaushik, Ana Maria Cuervo
Chaperone-mediated autophagy (CMA) selectively degrades a subset of cytosolic proteins in lysosomes. A potent physiological activator of CMA is nutrient deprivation, a condition in which intracellular triglyceride stores or lipid droplets (LDs) also undergo hydrolysis (lipolysis) to generate free fatty acids for energetic purposes. Here we report that the LD-associated proteins perilipin 2 (PLIN2) and perilipin 3 (PLIN3) are CMA substrates and their degradation through CMA precedes lipolysis. In vivo studies revealed that CMA degradation of PLIN2 and PLIN3 was enhanced during starvation, concurrent with elevated levels of cytosolic adipose triglyceride lipase (ATGL) and macroautophagy proteins on LDs...
June 2015: Nature Cell Biology
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