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Pesquisa : C16.320.565.398.500.330.500 [Categoria DeCS]
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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] Endereço: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] Título: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] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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] Termos MeSH primário: Cisteína/fisiologia
Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo
Compostos de Sulfidrila/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Ativação Enzimática/efeitos dos fármacos
Ativação Enzimática/fisiologia
Ativadores de Enzimas/química
Ativadores de Enzimas/metabolismo
Ativadores de Enzimas/farmacologia
Células HEK293
Seres Humanos
Deficiência da Lecitina Colesterol Aciltransferase/metabolismo
Modelos Moleculares
Fosfatidilcolina-Esterol O-Aciltransferase/química
Compostos de Sulfidrila/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Activators); 0 (Sulfhydryl Compounds); EC 2.3.1.43 (Phosphatidylcholine-Sterol O-Acyltransferase); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170604
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.240457


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[PMID]:27960011
[Au] Autor:Lucca F; Ossoli A; Boscutti G; Franceschini G; Calabresi L
[Ti] Título:[Lecithin:Cholesterol Acyltransferase Deficiency, from genes to therapy].
[Ti] Título:Deficit di lecitina:colesterolo aciltransferasi, dalla genetica alla terapia..
[So] Source:G Ital Nefrol;33(S68), 2016 Malattie Metaboliche e Rene.
[Is] ISSN:1724-5990
[Cp] País de publicação:Italy
[La] Idioma:ita
[Ab] Resumo:LCAT synthesizes most of the plasma cholesteryl esters, and plays a major role in HDL metabolism. Mutations in the LCAT gene cause two syndromes, familial LCAT deficiency (FLD) and fish-eye disease (FED), both characterized by severe alterations in plasma lipoprotein profile. Renal disease is the major cause of morbidity and mortality in FLD cases, but an established therapy is not currently available. The present therapy of LCAT deficiency is mainly aimed at correcting the dyslipidemia associated with the disease and at delaying evolution of chronic nephropathy. LCAT deficiency represents a candidate disease for enzyme replacement therapy. In vitro and in vivo studies proved the efficacy of recombinant human LCAT (rhLCAT) in correcting dyslipidemia, and rhLCAT is presently under development.
[Mh] Termos MeSH primário: Deficiência da Lecitina Colesterol Aciltransferase/genética
Deficiência da Lecitina Colesterol Aciltransferase/terapia
[Mh] Termos MeSH secundário: Seres Humanos
Deficiência da Lecitina Colesterol Aciltransferase/diagnóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161214
[St] Status:MEDLINE


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[PMID]:27150923
[Au] Autor:Kuroda M; Bujo H; Aso M; Saito Y; Yokote K
[Ad] Endereço:Chiba University Hospital Center for Advanced Medicine.
[Ti] Título:Gene-manipulated Adipocytes for the Treatment of Various Intractable Diseases.
[So] Source:Yakugaku Zasshi;136(5):705-9, 2016.
[Is] ISSN:1347-5231
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:Although protein replacement is an effective treatment for serum protein deficiencies such as diabetes and hemophilia, recombinant protein products are not available for all rare inherited diseases due to the instability of the recombinant proteins and/or to cost. Gene therapy is the most attractive option for treating patients with such rare diseases. To develop an effective ex vivo gene therapy-based protein replacement treatment requires recipient cells that differ from those used in standard gene therapy, which is performed to correct the function of the recipient cells. Adipose tissue is an expected source of proliferative cells for cell-based therapies, including regenerative medicine and gene transfer applications. Based on recent advances in cell biology and extensive clinical experience in transplantation therapy for adipose tissue, we focused on the mature adipocyte fraction, which is the floating fraction after collagenase digestion and centrifugation of adipose tissue. Proliferative adipocytes were propagated from the floating fraction by the ceiling culture technique. These cells are designated as ceiling culture-derived proliferative adipocytes (ccdPAs). We first focused on lecithin:cholesterol acyltransferase (LCAT) deficiency, an inherited metabolic disorder caused by lcat gene mutation, and ccdPAs as a therapeutic gene vehicle for LCAT replacement therapy. In our recent in vitro and animal model studies, we developed an adipose cell manipulation procedure using advanced gene transduction methods and transplantation scaffolds. We herein introduce the progress made in novel adipose tissue-based therapeutic strategies for the treatment of protein deficiencies and describe their future applications for other intractable diseases.
[Mh] Termos MeSH primário: Adipócitos
Terapia Genética/métodos
Terapia Genética/tendências
Deficiência da Lecitina Colesterol Aciltransferase/terapia
Transdução Genética/métodos
[Mh] Termos MeSH secundário: Adipócitos/transplante
Animais
Proteínas Sanguíneas/deficiência
Técnicas de Cultura de Células
Diabetes Mellitus/terapia
Modelos Animais de Doenças
Hemofilia A/terapia
Seres Humanos
Camundongos
Proteínas Recombinantes
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Blood Proteins); 0 (Recombinant Proteins)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160507
[St] Status:MEDLINE
[do] DOI:10.1248/yakushi.15-00262-4


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[PMID]:27090939
[Au] Autor:Bashiri A; Nesan D; Tavallaee G; Sue-Chue-Lam I; Chien K; Maguire GF; Naples M; Zhang J; Magomedova L; Adeli K; Cummins CL; Ng DS
[Ad] Endereço:Keenan Research Centre, Li Ka Shing Knowledge Institute, Department of Medicine, St Michael's Hospital, Toronto, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada.
[Ti] Título:Cellular cholesterol accumulation modulates high fat high sucrose (HFHS) diet-induced ER stress and hepatic inflammasome activation in the development of non-alcoholic steatohepatitis.
[So] Source:Biochim Biophys Acta;1861(7):594-605, 2016 Jul.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Non-alcoholic steatohepatitis (NASH), is the form of non-alcoholic fatty liver disease posing risk to progress into serious long term complications. Human and pre-clinical models implicate cellular cholesterol dysregulation playing important role in its development. Mouse model studies suggest synergism between dietary cholesterol and fat in contributing to NASH but the mechanisms remain poorly understood. Our laboratory previously reported the primary importance of hepatic endoplasmic reticulum cholesterol (ER-Chol) in regulating hepatic ER stress by comparing the responses of wild type, Ldlr-/-xLcat+/+ and Ldlr-/-xLcat-/- mice, to a 2% high cholesterol diet (HCD). Here we further investigated the roles of ER-Chol and ER stress in HFHS diet-induced NASH using the same strains. With HFHS diet feeding, both WT and Ldlr-/-xLcat+/+ accumulate ER-Chol in association with ER stress and inflammasome activation but the Ldlr-/-xLcat-/- mice are protected. By contrast, all three strains accumulate cholesterol crystal, in correlation with ER-Chol, albeit less so in Ldlr-/-xLcat-/- mice. By comparison, HCD feeding per se (i) is sufficient to promote steatosis and activate inflammasomes, and (ii) results in dramatic accumulation of cholesterol crystal which is linked to inflammasome activation in Ldlr-/-xLcat-/- mice, independent of ER-Chol. Our data suggest that both dietary fat and cholesterol each independently promote steatosis, cholesterol crystal accumulation and inflammasome activation through distinct but complementary pathways. In vitro studies using palmitate-induced hepatic steatosis in HepG2 cells confirm the key roles by cellular cholesterol in the induction of steatosis and inflammasome activations. These novel findings provide opportunities for exploring a cellular cholesterol-focused strategy for treatment of NASH.
[Mh] Termos MeSH primário: Colesterol na Dieta/metabolismo
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Fígado/metabolismo
Hepatopatia Gordurosa não Alcoólica/genética
Fosfatidilcolina-Esterol O-Aciltransferase/genética
Receptores de LDL/genética
[Mh] Termos MeSH secundário: Animais
Colesterol na Dieta/efeitos adversos
Dieta Hiperlipídica/efeitos adversos
Modelos Animais de Doenças
Estresse do Retículo Endoplasmático/genética
Feminino
Regulação da Expressão Gênica
Células Hep G2
Seres Humanos
Inflamassomos/efeitos dos fármacos
Inflamassomos/metabolismo
Deficiência da Lecitina Colesterol Aciltransferase/genética
Deficiência da Lecitina Colesterol Aciltransferase/metabolismo
Metabolismo dos Lipídeos/genética
Fígado/patologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Hepatopatia Gordurosa não Alcoólica/etiologia
Hepatopatia Gordurosa não Alcoólica/metabolismo
Hepatopatia Gordurosa não Alcoólica/fisiopatologia
Oxirredução
Ácido Palmítico/farmacologia
Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo
Receptores de LDL/deficiência
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholesterol, Dietary); 0 (Inflammasomes); 0 (Receptors, LDL); 2V16EO95H1 (Palmitic Acid); EC 2.3.1.43 (Phosphatidylcholine-Sterol O-Acyltransferase)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160420
[St] Status:MEDLINE


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[PMID]:27086477
[Au] Autor:Erdöl S; Saglam H
[Ti] Título:Endocrine Dysfunctions in Patients with Inherited Metabolic Diseases.
[So] Source:J Clin Res Pediatr Endocrinol;8(3):330-3, 2016 Sep 01.
[Is] ISSN:1308-5735
[Cp] País de publicação:Turkey
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Inherited metabolic diseases (IMDs) can affect many organ systems, including the endocrine system. There are limited data regarding endocrine dysfunctions related to IMDs in adults, however, no data exist in pediatric patients with IMDs. The aim of this study was to investigate endocrine dysfunctions in patients with IMDs by assessing their demographic, clinical, and laboratory data. METHODS: Data were obtained retrospectively from the medical reports of patients with IMDs who were followed by the division of pediatric metabolism and nutrition between June 2011 and November 2013. RESULTS: In total, 260 patients [139 males (53%) and 121 females (47%)] with an IMD diagnosis were included in the study. The mean age of the patients was 5.94 (range; 0.08 to 49) years and 95.8% (249 of 260 patients) were in the pediatric age group. Growth status was evaluated in 258 patients and of them, 27 (10.5%) had growth failure, all cases of which were attributed to non-endocrine reasons. There was a significant correlation between growth failure and serum albumin levels below 3.5 g/dL (p=0.002). Only three of 260 (1.1%) patients had endocrine dysfunction. Of these, one with lecithin-cholesterol acyltransferase deficiency and another with Kearns-Sayre syndrome had diabetes, and one with glycerol kinase deficiency had glucocorticoid deficiency. CONCLUSION: Endocrine dysfunction in patients with IMDs is relatively rare. For this reason, there is no need to conduct routine endocrine evaluations in most patients with IMDs unless a careful and detailed history and a physical examination point to an endocrine dysfunction.
[Mh] Termos MeSH primário: Sistema Endócrino/fisiopatologia
Doenças Metabólicas/fisiopatologia
[Mh] Termos MeSH secundário: Adolescente
Insuficiência Adrenal/fisiopatologia
Adulto
Erros Inatos do Metabolismo dos Carboidratos/fisiopatologia
Criança
Pré-Escolar
Diabetes Mellitus/fisiopatologia
Sistema Endócrino/metabolismo
Feminino
Glicerol Quinase/deficiência
Seres Humanos
Lactente
Recém-Nascido
Síndrome de Kearns-Sayre/fisiopatologia
Deficiência da Lecitina Colesterol Aciltransferase/fisiopatologia
Masculino
Doenças Metabólicas/genética
Doenças Metabólicas/metabolismo
Meia-Idade
Estudos Retrospectivos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.30 (Glycerol Kinase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170418
[Lr] Data última revisão:
170418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160419
[St] Status:MEDLINE
[do] DOI:10.4274/jcrpe.2288


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[PMID]:27055967
[Au] Autor:Shamburek RD; Bakker-Arkema R; Auerbach BJ; Krause BR; Homan R; Amar MJ; Freeman LA; Remaley AT
[Ad] Endereço:Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA. Electronic address: bobs@mail.nih.gov.
[Ti] Título:Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement.
[So] Source:J Clin Lipidol;10(2):356-67, 2016 Mar-Apr.
[Is] ISSN:1933-2874
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Humans with familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) have extremely low or undetectable high-density lipoprotein cholesterol (HDL-C) levels and by early adulthood develop many manifestations of the disorder, including corneal opacities, anemia, and renal disease. OBJECTIVE: To determine if infusions of recombinant human LCAT (rhLCAT) could reverse the anemia, halt progression of renal disease, and normalize HDL in FLD. METHODS: rhLCAT (ACP-501) was infused intravenously over 1 hour on 3 occasions in a dose optimization phase (0.3, 3.0, and 9.0 mg/kg), then 3.0 or 9.0 mg/kg every 1 to 2 weeks for 7 months in a maintenance phase. Plasma lipoproteins, lipids, LCAT levels, and several measures of renal function and other clinical labs were monitored. RESULTS: LCAT concentration peaked at the end of each infusion and decreased to near baseline over 7 days. Renal function generally stabilized or improved and the anemia improved. After infusion, HDL-C rapidly increased, peaking near normal in 8 to 12 hours; analysis of HDL particles by various methods all revealed rapid sequential disappearance of preß-HDL and small α-4 HDL and appearance of normal α-HDL. Low-density lipoprotein cholesterol increased more slowly than HDL-C. Of note, triglyceride routinely decreased after meals after infusion, in contrast to the usual postprandial increase in the absence of rhLCAT infusion. CONCLUSIONS: rhLCAT infusions were well tolerated in this first-in-human study in FLD; the anemia improved, as did most parameters related to renal function in spite of advanced disease. Plasma lipids transiently normalized, and there was rapid sequential conversion of small preß-HDL particles to mature spherical α-HDL particles.
[Mh] Termos MeSH primário: Deficiência da Lecitina Colesterol Aciltransferase/tratamento farmacológico
Fosfatidilcolina-Esterol O-Aciltransferase/uso terapêutico
[Mh] Termos MeSH secundário: Anemia/complicações
HDL-Colesterol/sangue
Progressão da Doença
Testes Hematológicos
Seres Humanos
Rim/efeitos dos fármacos
Deficiência da Lecitina Colesterol Aciltransferase/sangue
Deficiência da Lecitina Colesterol Aciltransferase/complicações
Deficiência da Lecitina Colesterol Aciltransferase/enzimologia
Masculino
Meia-Idade
Fosfatidilcolina-Esterol O-Aciltransferase/efeitos adversos
Fosfatidilcolina-Esterol O-Aciltransferase/farmacocinética
Fosfatidilcolina-Esterol O-Aciltransferase/farmacologia
Proteínas Recombinantes/efeitos adversos
Proteínas Recombinantes/farmacocinética
Proteínas Recombinantes/farmacologia
Proteínas Recombinantes/uso terapêutico
Segurança
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholesterol, HDL); 0 (Recombinant Proteins); EC 2.3.1.43 (Phosphatidylcholine-Sterol O-Acyltransferase)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170730
[Lr] Data última revisão:
170730
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160409
[St] Status:MEDLINE


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[PMID]:26919698
[Au] Autor:Ossoli A; Neufeld EB; Thacker SG; Vaisman B; Pryor M; Freeman LA; Brantner CA; Baranova I; Francone NO; Demosky SJ; Vitali C; Locatelli M; Abbate M; Zoja C; Franceschini G; Calabresi L; Remaley AT
[Ad] Endereço:Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
[Ti] Título:Lipoprotein X Causes Renal Disease in LCAT Deficiency.
[So] Source:PLoS One;11(2):e0150083, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice. Our in vitro and in vivo studies demonstrated an apoA-I and LCAT-dependent pathway for LpX conversion to HDL-like particles, which likely mediates normal plasma clearance of LpX. Plasma clearance of exogenous LpX was markedly delayed in Lcat-/- mice, which have low HDL, but only minimal amounts of endogenous LpX and do not spontaneously develop renal disease. Chronically administered exogenous LpX deposited in all renal glomerular cellular and matrical compartments of Lcat-/- mice, and induced proteinuria and nephrotoxic gene changes, as well as all of the hallmarks of FLD renal disease as assessed by histological, TEM, and SEM analyses. Extensive in vivo EM studies revealed LpX uptake by macropinocytosis into mouse glomerular endothelial cells, podocytes, and mesangial cells and delivery to lysosomes where it was degraded. Endocytosed LpX appeared to be degraded by both human podocyte and mesangial cell lysosomal PLA2 and induced podocyte secretion of pro-inflammatory IL-6 in vitro and renal Cxl10 expression in Lcat-/- mice. In conclusion, LpX is a nephrotoxic particle that in the absence of Lcat induces all of the histological and functional hallmarks of FLD and hence may serve as a biomarker for monitoring recombinant LCAT therapy. In addition, our studies suggest that LpX-induced loss of endothelial barrier function and release of cytokines by renal glomerular cells likely plays a role in the initiation and progression of FLD nephrosis.
[Mh] Termos MeSH primário: Glomérulos Renais/efeitos dos fármacos
Deficiência da Lecitina Colesterol Aciltransferase/metabolismo
Lipoproteína-X/toxicidade
Proteinúria/etiologia
[Mh] Termos MeSH secundário: Animais
Apolipoproteína A-I/metabolismo
Células Cultivadas
Citoesqueleto/efeitos dos fármacos
Citoesqueleto/ultraestrutura
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Matriz Extracelular/metabolismo
Perfilação da Expressão Gênica
Membrana Basal Glomerular/efeitos dos fármacos
Membrana Basal Glomerular/patologia
Mesângio Glomerular/citologia
Mesângio Glomerular/metabolismo
Mesângio Glomerular/patologia
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Interleucina-6/secreção
Glomérulos Renais/patologia
Deficiência da Lecitina Colesterol Aciltransferase/patologia
Lipoproteína-X/metabolismo
Lipoproteína-X/farmacocinética
Lipoproteínas HDL/metabolismo
Lisossomos/metabolismo
Taxa de Depuração Metabólica
Camundongos
Camundongos Endogâmicos C57BL
Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo
Fosfolipases A2/metabolismo
Pinocitose
Podócitos/metabolismo
Podócitos/patologia
Proteinúria/induzido quimicamente
Proteinúria/genética
Proteinúria/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoprotein A-I); 0 (Interleukin-6); 0 (Lipoprotein-X); 0 (Lipoproteins, HDL); 0 (interleukin-6, mouse); EC 2.3.1.43 (Phosphatidylcholine-Sterol O-Acyltransferase); EC 3.1.1.4 (Phospholipases A2)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160227
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0150083


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[PMID]:26693848
[Au] Autor:Liew H; Simpson I; Kanellis J; Mulley WR
[Ad] Endereço:Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
[Ti] Título:Recurrent glomerulopathy in a renal allograft due to lecithin cholesterol acyltransferase deficiency.
[So] Source:Nephrology (Carlton);21(1):73-4, 2016 Jan.
[Is] ISSN:1440-1797
[Cp] País de publicação:Australia
[La] Idioma:eng
[Mh] Termos MeSH primário: Glomerulonefrite Membranoproliferativa/cirurgia
Transplante de Rim
Rim/cirurgia
Deficiência da Lecitina Colesterol Aciltransferase/complicações
[Mh] Termos MeSH secundário: Adulto
Aloenxertos
Biópsia
Feminino
Glomerulonefrite Membranoproliferativa/diagnóstico
Glomerulonefrite Membranoproliferativa/etiologia
Seres Humanos
Rim/ultraestrutura
Deficiência da Lecitina Colesterol Aciltransferase/diagnóstico
Deficiência da Lecitina Colesterol Aciltransferase/terapia
Microscopia Eletrônica
Valor Preditivo dos Testes
Recidiva
Fatores de Risco
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; LETTER
[Em] Mês de entrada:1609
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151224
[St] Status:MEDLINE
[do] DOI:10.1111/nep.12554


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[PMID]:26494623
[Au] Autor:Nesan D; Tavallaee G; Koh D; Bashiri A; Abdin R; Ng DS
[Ad] Endereço:From the Keenan Research Centre, Li Ka Shing Knowledge Institute, Department of Medicine, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada and the Department of Physiology, Faculty of Medicine, and.
[Ti] Título:Lecithin:Cholesterol Acyltransferase (LCAT) Deficiency Promotes Differentiation of Satellite Cells to Brown Adipocytes in a Cholesterol-dependent Manner.
[So] Source:J Biol Chem;290(51):30514-29, 2015 Dec 18.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Our laboratory previously reported that lecithin:cholesterol acyltransferase (LCAT) and LDL receptor double knock-out mice (Ldlr(-/-)xLcat(-/-) or DKO) spontaneously develop functioning ectopic brown adipose tissue (BAT) in skeletal muscle, putatively contributing to protection from the diet-induced obesity phenotype. Here we further investigated their developmental origin and the mechanistic role of LCAT deficiency. Gene profiling of skeletal muscle in DKO newborns and adults revealed a classical lineage. Primary quiescent satellite cells (SC) from chow-fed DKO mice, not in Ldlr(-/-)xLcat(+/+) single-knock-out (SKO) or C57BL/6 wild type, were found to (i) express exclusively classical BAT-selective genes, (ii) be primed to express key functional BAT genes, and (iii) exhibit markedly increased ex vivo adipogenic differentiation into brown adipocytes. This gene priming effect was abrogated upon feeding the mice a 2% high cholesterol diet in association with accumulation of excess intracellular cholesterol. Ex vivo cholesterol loading of chow-fed DKO SC recapitulated the effect, indicating that cellular cholesterol is a key regulator of SC-to-BAT differentiation. Comparing adipogenicity of Ldlr(+/+)xLcat(-/-) (LCAT-KO) SC with DKO SC identified a role for LCAT deficiency in priming SC to express BAT genes. Additionally, we found that reduced cellular cholesterol is important for adipogenic differentiation, evidenced by increased induction of adipogenesis in cholesterol-depleted SC from both LCAT-KO and SKO mice. Taken together, we conclude that ectopic BAT in DKO mice is classical in origin, and its development begins in utero. We further showed complementary roles of LCAT deficiency and cellular cholesterol reduction in the SC-to-BAT adipogenesis.
[Mh] Termos MeSH primário: Adipócitos Marrons/metabolismo
Adipogenia
Diferenciação Celular
Colesterol/metabolismo
Deficiência da Lecitina Colesterol Aciltransferase/metabolismo
Células Satélites de Músculo Esquelético/metabolismo
[Mh] Termos MeSH secundário: Adipócitos Marrons/patologia
Animais
Colesterol/genética
Deficiência da Lecitina Colesterol Aciltransferase/genética
Deficiência da Lecitina Colesterol Aciltransferase/patologia
Camundongos
Camundongos Knockout
Células Satélites de Músculo Esquelético/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:161218
[Lr] Data última revisão:
161218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151024
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.676056


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[PMID]:26254103
[Au] Autor:Manzini S; Pinna C; Busnelli M; Cinquanta P; Rigamonti E; Ganzetti GS; Dellera F; Sala A; Calabresi L; Franceschini G; Parolini C; Chiesa G
[Ad] Endereço:Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy. Electronic address: stefano.manzini@gmail.com.
[Ti] Título:Beta2-adrenergic activity modulates vascular tone regulation in lecithin:cholesterol acyltransferase knockout mice.
[So] Source:Vascul Pharmacol;74:114-121, 2015 Nov.
[Is] ISSN:1879-3649
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with hypoalphalipoproteinemia, generally a predisposing factor for premature coronary heart disease. The evidence of accelerated atherosclerosis in LCAT-deficient subjects is however controversial. In this study, the effect of LCAT deficiency on vascular tone and endothelial function was investigated in LCAT knockout mice, which reproduce the human lipoprotein phenotype. Aortas from wild-type (Lcat(wt)) and LCAT knockout (Lcat(KO)) mice exposed to noradrenaline showed reduced contractility in Lcat(KO) mice (P<0.005), whereas acetylcholine exposure showed a lower NO-dependent relaxation in Lcat(KO) mice (P<0.05). Quantitative PCR and Western blotting analyses suggested an adequate eNOS expression in Lcat(KO) mouse aortas. Real-time PCR analysis indicated increased expression of ß2-adrenergic receptors vs wild-type mice. Aorta stimulation with noradrenaline in the presence of propranolol, to abolish the ß-mediated relaxation, showed the same contractile response in the two mouse lines. Furthermore, propranolol pretreatment of mouse aortas exposed to L-NAME prevented the difference in responses between Lcat(wt) and Lcat(KO) mice. The results indicate that LCAT deficiency leads to increased ß2-adrenergic relaxation and to a consequently decreased NO-mediated vasodilation that can be reversed to guarantee a correct vascular tone. The present study suggests that LCAT deficiency is not associated with an impaired vascular reactivity.
[Mh] Termos MeSH primário: Adrenérgicos/farmacologia
Deficiência da Lecitina Colesterol Aciltransferase/tratamento farmacológico
Deficiência da Lecitina Colesterol Aciltransferase/metabolismo
Lecitinas/metabolismo
Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo
[Mh] Termos MeSH secundário: Animais
Aorta/efeitos dos fármacos
Aorta/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo III/metabolismo
Receptores Adrenérgicos beta 2/metabolismo
Vasodilatação/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adrenergic Agents); 0 (Lecithins); 0 (Receptors, Adrenergic, beta-2); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 2.3.1.43 (Phosphatidylcholine-Sterol O-Acyltransferase)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150809
[St] Status:MEDLINE



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