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Protein lysosomal lipase

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https://www.readbyqxmd.com/read/27799810/novel-treatment-options-for-lysosomal-acid-lipase-deficiency-critical-appraisal-of-sebelipase-alfa
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
https://www.readbyqxmd.com/read/25951179/rab27a-is-present-in-mouse-pancreatic-acinar-cells-and-is-required-for-digestive-enzyme-secretion
#16
Yanan Hou, Stephen A Ernst, Edward L Stuenkel, Stephen I Lentz, John A Williams
The small G-protein Rab27A has been shown to regulate the intracellular trafficking of secretory granules in various cell types. However, the presence, subcellular localization and functional impact of Rab27A on digestive enzyme secretion by mouse pancreatic acinar cells are poorly understood. Ashen mice, which lack the expression of Rab27A due to a spontaneous mutation, were used to investigate the function of Rab27A in pancreatic acinar cells. Isolated pancreatic acini were prepared from wild-type or ashen mouse pancreas by collagenase digestion, and CCK- or carbachol-induced amylase secretion was measured...
2015: PloS One
https://www.readbyqxmd.com/read/25887678/novel-genes-in-ldl-metabolism-a-comprehensive-overview
#17
REVIEW
Mette Christoffersen, Anne Tybjærg-Hansen
PURPOSE OF REVIEW: To summarize recent findings from genome-wide association studies (GWAS), whole-exome sequencing of patients with familial hypercholesterolemia and 'exome chip' studies pointing to novel genes in LDL metabolism. RECENT FINDINGS: The genetic loci for ATP-binding cassette transporters G5 and G8, Niemann-Pick C1-Like protein 1, sortilin-1, ABO blood-group glycosyltransferases, myosin regulatory light chain-interacting protein and cholesterol 7α-hydroxylase have all consistently been associated with LDL cholesterol levels and/or coronary artery disease in GWAS...
June 2015: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/25620107/expression-and-functional-characterization-of-human-lysosomal-acid-lipase-gene-lipa-mutation-responsible-for-cholesteryl-ester-storage-disease-cesd-phenotype
#18
Francis Rajamohan, Allan R Reyes, Wanida Ruangsiriluk, Lise R Hoth, Seungil Han, Nicole Caspers, Meihua Tu, Jessica Ward, Ravi G Kurumbail
Lysosomal acid lipase (LAL) is a serine hydrolase which hydrolyzes cholesteryl ester and triglycerides delivered to the lysosomes into free cholesterol and free fatty acids. Mutations in the LAL gene (LIPA) result in accumulation of triglycerides and cholesterol esters in various tissues of the body, leading to pathological conditions such as Wolman's disease (WD) and cholesteryl ester storage disease (CESD). CESD patients homozygous for His295Tyr (H295Y) mutation have less than 5% of normal LAL activity. To shed light on the molecular basis for this loss-of-function phenotype, we have generated the recombinant H295Y enzyme and studied its biophysical and biochemical properties...
June 2015: Protein Expression and Purification
https://www.readbyqxmd.com/read/25554789/aging-lysosomal-signaling-molecules-regulate-longevity-in-caenorhabditis-elegans
#19
Andrew Folick, Holly D Oakley, Yong Yu, Eric H Armstrong, Manju Kumari, Lucas Sanor, David D Moore, Eric A Ortlund, Rudolf Zechner, Meng C Wang
Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4...
January 2, 2015: Science
https://www.readbyqxmd.com/read/25545384/absence-of-intracellular-ion-channels-tpc1-and-tpc2-leads-to-mature-onset-obesity-in-male-mice-due-to-impaired-lipid-availability-for-thermogenesis-in-brown-adipose-tissue
#20
Pamela V Lear, David González-Touceda, Begoña Porteiro Couto, Patricia Viaño, Vanessa Guymer, Elena Remzova, Ruth Tunn, Annapurna Chalasani, Tomás García-Caballero, Iain P Hargreaves, Patricia W Tynan, Helen C Christian, Rubén Nogueiras, John Parrington, Carlos Diéguez
Intracellular calcium-permeable channels have been implicated in thermogenic function of murine brown and brite/beige adipocytes, respectively transient receptor potential melastin-8 and transient receptor potential vanilloid-4. Because the endo-lysosomal two-pore channels (TPCs) have also been ascribed with metabolic functionality, we studied the effect of simultaneously knocking out TPC1 and TPC2 on body composition and energy balance in male mice fed a chow diet. Compared with wild-type mice, TPC1 and TPC2 double knockout (Tpcn1/2(-/-)) animals had a higher respiratory quotient and became obese between 6 and 9 months of age...
March 2015: Endocrinology
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