Database : MEDLINE
Search on : Lecithin and Acyltransferase and Deficiency [Words]
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[PMID]: 29491255
[Au] Autor:Kuroda M; Saito Y; Aso M; Yokote K
[Ad] Address:Center for Advanced Medicine, Chiba University Hospital, Chiba University.
[Ti] Title:A Novel Approach to the Treatment of Plasma Protein Deficiency: Ex Vivo-Manipulated Adipocytes for Sustained Secretion of Therapeutic Proteins.
[So] Source:Chem Pharm Bull (Tokyo);66(3):217-224, 2018.
[Is] ISSN:1347-5223
[Cp] Country of publication:Japan
[La] Language:eng
[Ab] Abstract:Despite the critical need for lifelong treatment of inherited and genetic diseases, there are no developmental efforts for most such diseases due to their rarity. Recent progress in gene therapy, including the approvals of two products (Glybera and Strimvelis) that may provide patients with sustained effects, has shed light on the development of gene therapy products. Most gene therapy products are based on either adeno-associated virus-mediated in vivo gene transfer to target tissues or administration of ex vivo gene-transduced hematopoietic cells. In such circumstances, there is room for different approaches to provide clinicians with other therapeutic options through a variety of principles based on studies not only to gain an understanding of the pathological mechanisms of diseases, but also to understand the physiological functions of target tissues and cells. In this review, we summarize recent progress in gene therapy-mediated enzyme replacement and introduce a different approach using adipocytes to enable lifelong treatment for intractable plasma protein deficiencies.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180301
[Lr] Last revision date:180301
[St] Status:In-Process
[do] DOI:10.1248/cpb.c17-00786

  2 / 736 MEDLINE  
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[PMID]: 29453250
[Au] Autor:Gao S; Kahremany S; Zhang J; Jastrzebska B; Querubin J; Petersen-Jones SM; Palczewski K
[Ad] Address:Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine.
[Ti] Title:Retinal-chitosan conjugates effectively deliver active chromophores to retinal photoreceptor cells in blind mice and dogs.
[So] Source:Mol Pharmacol;, 2018 Feb 16.
[Is] ISSN:1521-0111
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The retinoid (visual) cycle consists of a series of biochemical reactions needed to regenerate the visual chromophore, 11-cis-retinal and sustain vision. Genetic or environmental factors affecting chromophore production can lead to blindness. Using animal models that mimic human retinal diseases, we previously demonstrated that mechanism-based pharmacological interventions can maintain vision in otherwise incurable genetic diseases of the retina. Here, we report that after 9-cis-retinal administration to lecithin:retinol acyltransferase-deficient (Lrat-/-) mice, the drug was rapidly absorbed and then cleared within 1-2 h. However, when conjugated to form chitosan-9-cis-retinal, this pro-drug was slowly absorbed from the gastrointestinal tract resulting in sustainable plasma levels of 9-cis-retinol and recovery of visual function without causing elevated levels, as occurs with unconjugated drug treatment. Administration of chitosan-9-cis-retinal conjugate intravitreally in retinal pigment epithelium-specific 65 retinoid isomerase (RPE65)-deficient dogs improved photoreceptor function as assessed by electroretinography. Functional rescue was dose dependent and maintained for several weeks. Dosing via the gastrointestinal tract in canines was found ineffective, most likely due to peculiarities of vitamin A blood transport in canines. Use of the chitosan conjugate in combination with 11-cis-6-ring-retinal, a locked ring analog of 11-cis-retinal that selectively blocks rod opsin consumption of chromophore while largely sparing cone opsins, was found to prolong cone vision in Lrat-/- mice. Development of such combination low-dose regimens to selectively prolong useful cone vision could not only expand retinal disease treatments to include Leber congenital amaurosis but also the age-related decline in human dark adaptation from progressive retinoid cycle deficiency. .
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180217
[Lr] Last revision date:180217
[St] Status:Publisher

  3 / 736 MEDLINE  
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[PMID]: 29319258
[Au] Autor:Gopalakrishnan N; Arul R; Dhanapriya J; Kumar TD; Sakthirajan R; Balasubramaniyan T
[Ad] Address:Head of Department, Department of Nephrology, Madras Medical College and Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu.
[Ti] Title:Familial Lecithin Cholesterol Acyl Transferase Deficiency with Chronic Kidney Disease.
[So] Source:J Assoc Physicians India;65(10):90-91, 2017 Oct.
[Is] ISSN:0004-5772
[Cp] Country of publication:India
[La] Language:eng
[Ab] Abstract:Familial lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive (AR) disease caused by mutation in the LCAT gene. LCAT enzyme esterifies cholesterol molecules in high-density lipoprotein(HDL) and low density-lipoprotein (LDL) particles. This enzyme deficiency is characterised by progressive corneal opacification, glomerulopathy, mild - moderate haemolytic anaemia and very low plasma levels of HDL. We here report a 34 year-old lady who presented with hypertension, nephrotic proteinuria, renal failure, corneal ring opacities, anemia and dyslipidemia. The diagnosis of familial LCAT deficiency was confirmed by clinical examination, characteristic dyslipidemia, undetectable LCAT levels in plasma and positive family history.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180110
[Lr] Last revision date:180110
[St] Status:In-Data-Review

  4 / 736 MEDLINE  
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[PMID]: 28983876
[Au] Autor:Castro-Ferreira I; Carmo R; Silva SE; Corrêa O; Fernandes S; Sampaio S; Pedro RP; Praça A; Oliveira JP
[Ad] Address:Service of Nephrology, Centro Hospitalar São João, Alameda Prof. Hernâni Monteiro, 4200-319, Oporto, Portugal. inescastroferreira@sapo.pt.
[Ti] Title:Novel Missense LCAT Gene Mutation Associated with an Atypical Phenotype of Familial LCAT Deficiency in Two Portuguese Brothers.
[So] Source:JIMD Rep;, 2017 Oct 06.
[Is] ISSN:2192-8304
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Familial lecithin-cholesterol acyltransferase deficiency (FLD) is a rare recessive disorder of cholesterol metabolism, caused by loss-of-function mutations in the human LCAT gene, leading to alterations in the lipid/lipoprotein profile, with extremely low HDL levels.The classical FLD phenotype is characterized by diffuse corneal opacification, haemolytic anaemia and proteinuric chronic kidney disease (CKD); an incomplete form, only affecting the corneas, has been reported in a few families worldwide.We describe an intermediate phenotype of LCAT deficiency, with CKD preceding the development of corneal clouding, in two Portuguese brothers apparently homozygous for a novel missense LCAT gene mutation. The atypical phenotype, the diagnosis of membranous nephropathy in the proband's native kidney biopsy, the late-onset and delayed recognition of the corneal opacification, the co-segregation with Gilbert syndrome and the late recurrence of the primary disease in kidney allograft all contributed to obscure the diagnosis of an LCAT deficiency syndrome for many years.A major teaching point is that on standard light microscopy examination the kidney biopsies of patients with LCAT deficiency with residual enzyme activity may not show significant vacuolization and may be misdiagnosed as membranous nephropathy. The cases of these two patients also illustrate the importance of performing detailed physical examination in young adults presenting with proteinuric CKD, as the most important clue to the diagnosis of FLD is in the eyes.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1710
[Cu] Class update date: 171006
[Lr] Last revision date:171006
[St] Status:Publisher
[do] DOI:10.1007/8904_2017_57

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[PMID]: 28955127
[Au] Autor:Nagase M; Sakurai A; Sugita A; Matsumoto N; Kubo A; Miyazaki Y; Kinoshita K; Yamamoto Y
[Ad] Address:School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakura-cho, Hachioji, Tokyo 192-0982, Japan.
[Ti] Title:Oxidative stress and abnormal cholesterol metabolism in patients with post-cardiac arrest syndrome.
[So] Source:J Clin Biochem Nutr;61(2):108-117, 2017 Sep.
[Is] ISSN:0912-0009
[Cp] Country of publication:Japan
[La] Language:eng
[Ab] Abstract:Patients with post-cardiac arrest syndrome (PCAS) suffer from whole body ischemia/reperfusion injury similar to that experienced by newborn babies. Increased oxidative stress was confirmed in PCAS patients ( = 40) at the time of hospitalization by a significant increase in the percentage of the oxidized form of coenzyme Q10 in total coenzyme Q10 compared to age-matched healthy controls ( = 55). Tissue oxidative damage in patients was suggested by the significant increase in plasma levels of free fatty acids (FFA) and the significant decrease in polyunsaturated fatty acid contents in total FFA. A greater decrease in free cholesterol (FC) compared to cholesterol esters (CE) was observed. Therefore, the FC/CE ratio significantly increased, suggesting deficiency of lecithin-cholesterol acyltransferase secreted from the liver. Time course changes of the above parameters were compared among 6 groups of patients divided according to outcome severity. Rapid declines of FC and CE were observed in patients who died within a day, while levels remained unchanged in patients discharged in a week. These data suggest that liver function is one of the key factors determining the survival of patients. Interestingly, therapeutic hypothermia treatment enhanced the increment of plasma ratio of coenzyme Q10 to total cholesterol at the end of rewarming.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1709
[Cu] Class update date: 171001
[Lr] Last revision date:171001
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.3164/jcbn.17-30

  6 / 736 MEDLINE  
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[PMID]: 28942093
[Au] Autor:Rial-Crestelo D; Santos-Recuero I; Julve J; Blanco-Vaca F; Torralba M
[Ad] Address:Departamento de Medicina Interna, Servicio de Medicina Interna, Hospital Universitario de Guadalajara, Servicio de Salud de Castilla La Mancha, Guadalajara, Castilla la Mancha, Spain; Departamento de Medicina, Universidad de Alcalá, Madrid, Spain. Electronic address: davidrialcrestelo@gmail.com.
[Ti] Title:A novel homozygous mutation causing lecithin-cholesterol acyltransferase deficiency in a proband of Romanian origin with a record of extreme gestational hyperlipidemia.
[So] Source:J Clin Lipidol;11(6):1475-1479.e3, 2017 Nov - Dec.
[Is] ISSN:1933-2874
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:A patient from Romania with extraordinarily high total cholesterol levels and clinical and biochemical features consistent with familial lecithin-cholesterol acyltransferase deficiency is reported. The genetic analysis performed on our proband showed a novel homozygous mutation on codon 119 of lecithin-cholesterol acyltransferase gene that causes the substitution of glycine by aspartate. The same mutation, also in homozygosis, was observed in her older sister, whereas his brother presented it in heterozygosis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1709
[Cu] Class update date: 171121
[Lr] Last revision date:171121
[St] Status:In-Process

  7 / 736 MEDLINE  
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[PMID]: 28882064
[Au] Autor:Sakurai T; Sakurai A; Vaisman BL; Nishida T; Neufeld EB; Demosky SJ; Sampson ML; Shamburek RD; Freeman LA; Remaley AT
[Ad] Address:1 Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
[Ti] Title:Development of a novel fluorescent activity assay for lecithin:cholesterol acyltransferase.
[So] Source:Ann Clin Biochem;:4563217733285, 2017 Jan 01.
[Is] ISSN:1758-1001
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Background Lecithin:cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol. Recombinant human LCAT (rhLCAT) is now being developed as an enzyme replacement therapy for familial LCAT deficiency and as a possible treatment for acute coronary syndrome. The current 'gold standard' assay for LCAT activity involves the use of radioisotopes, thus making it difficult for routine clinical use. Methods We have developed a novel and more convenient LCAT activity assay using fluorescence-labelled cholesterol (BODIPY-cholesterol), which is incorporated into proteoliposomes as a substrate instead of radiolabelled cholesterol. Results The apparent K and V were 31.5 µmol/L and 55.8 nmol/h/nmoL, rhLCAT, respectively, for the H-cholesterol method and 103.1 µmol/L and 13.4 nmol/h/nmol rhLCAT, respectively, for the BODIPY-cholesterol method. Although the two assays differed in their absolute units of LCAT activity, there was a good correlation between the two test assays ( r = 0.849, P < 1.6 × 10 , y = 0.1378x + 1.106). The BODIPY-cholesterol assay had an intra-assay CV of 13.7%, which was superior to the intra-assay CV of 20.8% for the radioisotopic assay. The proteoliposome substrate made with BODIPY-cholesterol was stable to storage for at least 10 months. The reference range ( n = 20) for the fluorescent LCAT activity assay was 4.6-24.1 U/mL/h in healthy subjects. Conclusions In summary, a novel fluorescent LCAT activity assay that utilizes BODIPY-cholesterol as a substrate is described that yields comparable results to the radioisotopic method.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1709
[Cu] Class update date: 171103
[Lr] Last revision date:171103
[St] Status:Publisher
[do] DOI:10.1177/0004563217733285

  8 / 736 MEDLINE  
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[PMID]: 28646986
[Au] Autor:Najafian B; Lusco MA; Finn LS; Alpers CE; Fogo AB
[Ad] Address:Department of Pathology, University of Washington, Seattle, WA.
[Ti] Title:AJKD Atlas of Renal Pathology: Lecithin-Cholesterol Acyltransferase (LCAT) Deficiency.
[So] Source:Am J Kidney Dis;70(1):e5-e6, 2017 Jul.
[Is] ISSN:1523-6838
[Cp] Country of publication:United States
[La] Language:eng
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1706
[Cu] Class update date: 170625
[Lr] Last revision date:170625
[St] Status:In-Data-Review

  9 / 736 MEDLINE  
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[PMID]: 28576974
[Au] Autor:Freeman LA; Demosky SJ; Konaklieva M; Kuskovsky R; Aponte A; Ossoli AF; Gordon SM; Koby RF; Manthei KA; Shen M; Vaisman BL; Shamburek RD; Jadhav A; Calabresi L; Gucek M; Tesmer JJG; Levine RL; Remaley AT
[Ad] Address:Lipid Metabolism Section, Cardiovascular and Pulmonary Branch (L.A.F., S.J.D., S.M.G., B.L.V., R.D.S., A.T.R.), Systems Biology Center (A.A., M.G.), and Laboratory of Biochemistry (R.L.L.), National Institutes of Health National Heart, Lung, and Blood Institute, Bethesda, Maryland; Department of Che
[Ti] Title:Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31.
[So] Source:J Pharmacol Exp Ther;362(2):306-318, 2017 Aug.
[Is] ISSN:1521-0103
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Lecithin:cholesterol acyltransferase (LCAT) catalyzes plasma cholesteryl ester formation and is defective in familial lecithin:cholesterol acyltransferase deficiency (FLD), an autosomal recessive disorder characterized by low high-density lipoprotein, anemia, and renal disease. This study aimed to investigate the mechanism by which compound A [3-(5-(ethylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile], a small heterocyclic amine, activates LCAT. The effect of compound A on LCAT was tested in human plasma and with recombinant LCAT. Mass spectrometry and nuclear magnetic resonance were used to determine compound A adduct formation with LCAT. Molecular modeling was performed to gain insight into the effects of compound A on LCAT structure and activity. Compound A increased LCAT activity in a subset (three of nine) of LCAT mutations to levels comparable to FLD heterozygotes. The site-directed mutation LCAT-Cys31Gly prevented activation by compound A. Substitution of Cys31 with charged residues (Glu, Arg, and Lys) decreased LCAT activity, whereas bulky hydrophobic groups (Trp, Leu, Phe, and Met) increased activity up to 3-fold ( < 0.005). Mass spectrometry of a tryptic digestion of LCAT incubated with compound A revealed a +103.017 adduct on Cys31, consistent with the addition of a single hydrophobic cyanopyrazine ring. Molecular modeling identified potential interactions of compound A near Cys31 and structural changes correlating with enhanced activity. Functional groups important for LCAT activation by compound A were identified by testing compound A derivatives. Finally, sulfhydryl-reactive -lactams were developed as a new class of LCAT activators. In conclusion, compound A activates LCAT, including some FLD mutations, by forming a hydrophobic adduct with Cys31, thus providing a mechanistic rationale for the design of future LCAT activators.
[Mh] MeSH terms primary: Cysteine/physiology
Phosphatidylcholine-Sterol O-Acyltransferase/metabolism
Sulfhydryl Compounds/pharmacology
[Mh] MeSH terms secundary: Dose-Response Relationship, Drug
Enzyme Activation/drug effects
Enzyme Activation/physiology
Enzyme Activators/chemistry
Enzyme Activators/metabolism
Enzyme Activators/pharmacology
HEK293 Cells
Humans
Lecithin Cholesterol Acyltransferase Deficiency/metabolism
Models, Molecular
Phosphatidylcholine-Sterol O-Acyltransferase/chemistry
Sulfhydryl Compounds/chemistry
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Enzyme Activators); 0 (Sulfhydryl Compounds); EC 2.3.1.43 (Phosphatidylcholine-Sterol O-Acyltransferase); K848JZ4886 (Cysteine)
[Em] Entry month:1708
[Cu] Class update date: 170809
[Lr] Last revision date:170809
[Js] Journal subset:IM
[Da] Date of entry for processing:170604
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.240457

  10 / 736 MEDLINE  
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[PMID]: 28508023
[Au] Autor:Balwani MR; Ghodela VA; Kute VB; Shah PR; Patel HV; Gera DN; Vanikar A; Trivedi HL
[Ad] Address:Department of Nephrology and Clinical Transplantation, Laboratory Medicine, Transfusion Services and Immunohematology, Institute of Kidney Diseases and Research Center, Dr. HL Trivedi Institute of Transplantation Sciences (IKDRC-ITS), Ahmedabad, India.
[Ti] Title:An unusual presentation of LCAT deficiency as nephrotic syndrome with normal serum HDL-C level.
[So] Source:J Nephropharmacol;6(1):23-26, 2017.
[Is] ISSN:2345-4202
[Cp] Country of publication:Iran
[La] Language:eng
[Ab] Abstract:Clinical and biochemical manifestations of lecithin-cholesterol acyltransferase (LCAT) deficiency include an abnormal lipid profile (characterized by hypercholesterolemia with markedly decreased high-density lipoprotein cholesterol [HDL-C] and hypertriglyceridemia), corneal opacities, hematologic abnormalities (normochromic anemia of varying intensity), splenomegaly, variable early coronary artery disease and nephropathy (initially proteinuria followed by progressive deterioration of renal function). We presented a patient with nephrotic syndrome, which renal biopsy revealed classic features of LCAT deficiency. To our knowledge, the present case is the first reported case of LCAT deficiency presenting with symptoms related to nephrotic syndrome in a patient with no obvious family history without any corneal deposits and normal HDL-C levels.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1705
[Cu] Class update date: 170816
[Lr] Last revision date:170816
[St] Status:PubMed-not-MEDLINE


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