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[PMID]:29304079
[Au] Autor:Okada T; Ohama T; Okazaki M; Kanno K; Matsuda H; Sairyo M; Zhu Y; Saga A; Kobayashi T; Masuda D; Koseki M; Nishida M; Sakata Y; Yamashita S
[Ad] Endereço:Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
[Ti] Título:Particle number analysis of lipoprotein subclasses by gel permeation HPLC in patients with cholesteryl ester transfer protein deficiency.
[So] Source:PLoS One;13(1):e0190875, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We previously reported that patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) have a higher prevalence of atherosclerotic cardiovascular disease, in spite of increased HDL-C levels. However, characterization of HDL in CETP-D has not been well described. Therefore, we examined HDL particle number (PN) rather than HDL-C level. APPROACH AND RESULTS: Nine patients with CETP-D and 9 normolipidemic subjects were enrolled. We performed gel permeation high-performance liquid chromatography (GP-HPLC) analysis, determined the cholesterol and triglyceride composition of all lipoprotein subclasses, and calculated the PN of each subclass, which consisted of 3 VLDL (large, medium, and small), 4 LDL (large, medium, small, and very small), and 5 HDL (very large, large, medium, small, and very small) subclasses. The PNs of large and medium LDL were significantly lower in CETP-D than that in healthy subjects (0.66- and 0.63-fold decrease, respectively; p<0.001), whereas the PN of very small LDL, which is known to be atherogenic, was significantly higher (1.36-fold increase, p = 0.016). The PNs of very large and large HDL in CETP-D were markedly higher than that in healthy subjects (19.9- and 4.5-fold increase, respectively; p<0.001), whereas the PNs of small and very small HDL, which have more potent anti-atherogenic functions, were significantly lower (0.76- and 0.61-fold decrease, respectively; p<0.001). CONCLUSION: We have assessed the PNs of detailed subclasses of patients with CETP-D for the first time. The PN of larger HDL was markedly increased, that of smaller HDL was decreased, and that of very small LDL was increased, suggesting that CETP-D has pro-atherogenic lipoprotein properties.
[Mh] Termos MeSH primário: Proteínas de Transferência de Ésteres de Colesterol/deficiência
Cromatografia em Gel/métodos
Cromatografia Líquida de Alta Pressão/métodos
Erros Inatos do Metabolismo Lipídico/sangue
Lipoproteínas/classificação
[Mh] Termos MeSH secundário: Adulto
Proteínas de Transferência de Ésteres de Colesterol/sangue
Feminino
Seres Humanos
Lipoproteínas/sangue
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cholesterol Ester Transfer Proteins); 0 (Lipoproteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190875


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[PMID]:29016649
[Au] Autor:Ohn JH; Hwang JY; Moon MK; Ahn HY; Kim HH; Koo YD; Kim KI; Chang HJ; Lee HS; Jang HC; Park YJ
[Ad] Endereço:Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
[Ti] Título:Small heterodimer partner (SHP) deficiency protects myocardia from lipid accumulation in high fat diet-fed mice.
[So] Source:PLoS One;12(10):e0186021, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The small heterodimer partner (SHP) regulates fatty acid oxidation and lipogenesis in the liver by regulating peroxisome proliferator-activated receptor (PPAR) γ expression. SHP is also abundantly expressed in the myocardium. We investigated the effect of SHP expression on myocardia assessing not only heart structure and function but also lipid metabolism and related gene expression in a SHP deletion animal model. Transcriptional profiling with a microarray revealed that genes participating in cell growth, cytokine signalling, phospholipid metabolism, and extracellular matrix are up-regulated in the myocardia of SHP knockout (KO) mice compared to those of wild-type (WT) mice (nominal p value < 0.05). Consistent with these gene expression changes, the left ventricular masses of SHP KO mice were significantly higher than WT mice (76.8 ± 20.5 mg vs. 52.8 ± 6.8 mg, P = 0.0093). After 12 weeks of high fat diet (HFD), SHP KO mice gained less weight and exhibited less elevation in serum-free fatty acid and less ectopic lipid accumulation in the myocardium than WT mice. According to microarray analysis, genes regulated by PPARγ1 and PPARα were down-regulated in myocardia of SHP KO mice compared to their expression in WT mice after HFD, suggesting that the reduction in lipid accumulation in the myocardium resulted from a decrease in lipogenesis regulated by PPARγ. We confirmed the reduced expression of PPARγ1 and PPARα target genes such as CD36, medium-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, and very long-chain acyl-CoA dehydrogenase by SHP KO after HFD.
[Mh] Termos MeSH primário: Lipogênese/genética
Miocárdio/metabolismo
Obesidade/genética
Receptores Citoplasmáticos e Nucleares/genética
Transcriptoma
[Mh] Termos MeSH secundário: Acil-CoA Desidrogenase/genética
Acil-CoA Desidrogenase/metabolismo
Acil-CoA Desidrogenase de Cadeia Longa/deficiência
Acil-CoA Desidrogenase de Cadeia Longa/genética
Acil-CoA Desidrogenase de Cadeia Longa/metabolismo
Animais
Antígenos CD36/genética
Antígenos CD36/metabolismo
Citocinas/genética
Citocinas/metabolismo
Dieta Hiperlipídica
Ácidos Graxos/metabolismo
Perfilação da Expressão Gênica
Erros Inatos do Metabolismo Lipídico/genética
Erros Inatos do Metabolismo Lipídico/metabolismo
Fígado/metabolismo
Fígado/patologia
Masculino
Camundongos
Camundongos Knockout
Doenças Mitocondriais/genética
Doenças Mitocondriais/metabolismo
Doenças Musculares/genética
Doenças Musculares/metabolismo
Miocárdio/patologia
Obesidade/etiologia
Obesidade/metabolismo
Obesidade/patologia
Análise de Sequência com Séries de Oligonucleotídeos
PPAR alfa/genética
PPAR alfa/metabolismo
PPAR gama/genética
PPAR gama/metabolismo
Fatores de Proteção
Receptores Citoplasmáticos e Nucleares/deficiência
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD36 Antigens); 0 (Cytokines); 0 (Fatty Acids); 0 (PPAR alpha); 0 (PPAR gamma); 0 (Receptors, Cytoplasmic and Nuclear); 0 (nuclear receptor subfamily 0, group B, member 2); EC 1.3.8.7 (Acyl-CoA Dehydrogenase); EC 1.3.8.8 (Acyl-CoA Dehydrogenase, Long-Chain)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186021


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[PMID]:28791828
[Au] Autor:Mozrzymas R; Konikowska K; Regulska-Ilow B
[Ad] Endereço:Regional Specialist Hospital in Wroclaw, Research and Development Center, Poland.
[Ti] Título:Energy exchangers with LCT as a precision method for diet control in LCHADD.
[So] Source:Adv Clin Exp Med;26(3):515-525, 2017 May-Jun.
[Is] ISSN:1899-5276
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare genetic disease. The LCHADD treatment is mainly based on special diet. In this diet, energy from long-chain triglycerides (LCT) cannot exceed 10%, however energy intake from the consumption of medium-chain triglycerides (MCTs) should increase. The daily intake of energy should be compatible with energy requirements and treatment should involve frequent meals including during the night to avoid periods of fasting. In fact, there are no recommendations for total content of LCT in all of the allowed food in the LCHADD diet. The aim of the study was to present a new method of diet composition in LCHADD with the use of blocks based on energy exchangers with calculated LCT content. In the study, the diet schema was shown for calculating the energy requirements and LCT content in the LCHADD diet. How to create the diet was also shown, based on a food pyramid developed for patients with LCHADD. The blocks will make it possible, in a quick and simple way, to create a balanced diet which provides adequate energy value, essential nutrients and LCT content. This method can be used by doctors and dietitians who specialize in treating rare metabolic diseases. It can also be used by patients and their families for accurate menu planning with limited LCT content.
[Mh] Termos MeSH primário: 3-Hidroxiacil-CoA Desidrogenases/deficiência
Cardiomiopatias/dietoterapia
Ingestão de Energia/fisiologia
Erros Inatos do Metabolismo Lipídico/dietoterapia
Miopatias Mitocondriais/dietoterapia
Proteína Mitocondrial Trifuncional/deficiência
Doenças do Sistema Nervoso/dietoterapia
Rabdomiólise/dietoterapia
Triglicerídeos/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Cardiomiopatias/metabolismo
Criança
Pré-Escolar
Dieta/métodos
Feminino
Seres Humanos
Lactente
Recém-Nascido
Erros Inatos do Metabolismo Lipídico/metabolismo
Masculino
Meia-Idade
Miopatias Mitocondriais/metabolismo
Proteína Mitocondrial Trifuncional/metabolismo
Doenças do Sistema Nervoso/metabolismo
Rabdomiólise/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Triglycerides); EC 1.1.1.- (3-Hydroxyacyl CoA Dehydrogenases); EC 2.3.1.16 (Mitochondrial Trifunctional Protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.17219/acem/62132


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[PMID]:28625503
[Au] Autor:Othman RA; Myrie SB; Mymin D; Roullet JB; DeBarber AE; Steiner RD; Jones PJH
[Ad] Endereço:Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Richardson Center for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg, Manitoba, Canada.
[Ti] Título:Thyroid Hormone Status in Sitosterolemia Is Modified by Ezetimibe.
[So] Source:J Pediatr;188:198-204.e1, 2017 Sep.
[Is] ISSN:1097-6833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: To assess the association between biomarkers of thyroid status and 5α-stanols in patients with sitosterolemia treated with ezetimibe (EZE). STUDY DESIGN: Eight patients with sitosterolemia (16-56 years of age) were studied during 14 weeks off EZE therapy and 14 weeks on EZE (10 mg/day). Serum thyroid biomarkers (free triiodothyronine [FT3], free thyroxine [FT4], FT3/FT4 ratio, thyroid-stimulating hormone), 5α-stanols (sitostanol and cholestanol), and cholestanol precursors (total cholesterol and its synthesis marker lathosterol, and 7α-hydroxy-4-cholesten-3-one cholestenol) were measured at baseline and during the 14 weeks off EZE and on EZE. RESULTS: EZE increased FT3/FT4 (10% ± 4%; P = .02). EZE reduced plasma and red blood cells sitostanol (-38% ± 6% and -20% ± 4%; all P < .05) and cholestanol (-18% ± 6% and -13% ± 3%; all P < .05). The change in plasma cholestanol level on EZE inversely correlated with the change in FT3/FT4 (r = -0.86; P = .01). EZE lowered total cholesterol (P < .0001) and did not affect 7α-hydroxy-4-cholesten-3-one cholestanol. EZE increased (P < .0001) lathosterol initially, but the level was not sustained, resulting in similar levels at week 14 off EZE and on EZE. CONCLUSION: In patients with STSL, 5α-stanols levels might be associated with thyroid function. EZE reduces circulating 5α-stanols while increasing FT3/FT4, implying increased conversion of T4 to T3, thus possibly improving thyroid hormone status. TRIAL REGISTRATION: ClinicalTrials.govNCT01584206.
[Mh] Termos MeSH primário: Anticolesterolemiantes/uso terapêutico
Ezetimiba/uso terapêutico
Hipercolesterolemia/sangue
Hipercolesterolemia/tratamento farmacológico
Enteropatias/sangue
Enteropatias/tratamento farmacológico
Erros Inatos do Metabolismo Lipídico/sangue
Erros Inatos do Metabolismo Lipídico/tratamento farmacológico
Fitosteróis/efeitos adversos
[Mh] Termos MeSH secundário: Adolescente
Adulto
Colestanol/sangue
Colestenonas/sangue
Colesterol/sangue
Feminino
Seres Humanos
Masculino
Meia-Idade
Fitosteróis/sangue
Sitosteroides/sangue
Tireotropina/sangue
Tiroxina/sangue
Tri-Iodotironina/sangue
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticholesteremic Agents); 0 (Cholestenones); 0 (Phytosterols); 0 (Sitosterols); 06LU7C9H1V (Triiodothyronine); 3862-25-7 (7 alpha-hydroxy-4-cholesten-3-one); 80-99-9 (lathosterol); 8M308U816E (Cholestanol); 9002-71-5 (Thyrotropin); 97C5T2UQ7J (Cholesterol); C2NJ9WO6O7 (stigmastanol); EOR26LQQ24 (Ezetimibe); Q51BO43MG4 (Thyroxine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE


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[PMID]:28428219
[Au] Autor:Zhang J; Niimi M; Yang D; Liang J; Xu J; Kimura T; Mathew AV; Guo Y; Fan Y; Zhu T; Song J; Ackermann R; Koike Y; Schwendeman A; Lai L; Pennathur S; Garcia-Barrio M; Fan J; Chen YE
[Ad] Endereço:From the Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine (J.Z., D.Y., J.L., J.X., Y.G., Y.F., T.Z., J.S., Y.K., M.G.-B., Y.E.C.), Department of Internal Medicine, Nephrology (A.V.M., S.P.), University of Michigan Medical Center, Ann Arbor; Depa
[Ti] Título:Deficiency of Cholesteryl Ester Transfer Protein Protects Against Atherosclerosis in Rabbits.
[So] Source:Arterioscler Thromb Vasc Biol;37(6):1068-1075, 2017 Jun.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: CETP (cholesteryl ester transfer protein) plays an important role in lipoprotein metabolism; however, whether inhibition of CETP activity can prevent cardiovascular disease remains controversial. APPROACH AND RESULTS: We generated CETP knockout (KO) rabbits by zinc finger nuclease gene editing and compared their susceptibility to cholesterol diet-induced atherosclerosis to that of wild-type (WT) rabbits. On a chow diet, KO rabbits showed higher plasma levels of high-density lipoprotein (HDL) cholesterol than WT controls, and HDL particles of KO rabbits were essentially rich in apolipoprotein AI and apolipoprotein E contents. When challenged with a cholesterol-rich diet for 18 weeks, KO rabbits not only had higher HDL cholesterol levels but also lower total cholesterol levels than WT rabbits. Analysis of plasma lipoproteins revealed that reduced plasma total cholesterol in KO rabbits was attributable to decreased apolipoprotein B-containing particles, while HDLs remained higher than that in WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. Apolipoprotein B-depleted plasma isolated from CETP KO rabbits showed significantly higher capacity for cholesterol efflux from macrophages than that from WT rabbits. Furthermore, HDLs isolated from CETP KO rabbits suppressed tumor necrosis factor-α-induced vascular cell adhesion molecule 1 and E-selectin expression in cultured endothelial cells. CONCLUSIONS: These results provide evidence that genetic ablation of CETP activity protects against cholesterol diet-induced atherosclerosis in rabbits.
[Mh] Termos MeSH primário: Doenças da Aorta/prevenção & controle
Aterosclerose/prevenção & controle
Proteínas de Transferência de Ésteres de Colesterol/deficiência
Colesterol na Dieta
Doença da Artéria Coronariana/prevenção & controle
Erros Inatos do Metabolismo Lipídico/metabolismo
Macrófagos/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Doenças da Aorta/genética
Doenças da Aorta/metabolismo
Doenças da Aorta/patologia
Apolipoproteína A-I/sangue
Apolipoproteínas B/sangue
Apolipoproteínas E/sangue
Aterosclerose/genética
Aterosclerose/metabolismo
Aterosclerose/patologia
Linhagem Celular
Proteínas de Transferência de Ésteres de Colesterol/sangue
Proteínas de Transferência de Ésteres de Colesterol/genética
Proteínas de Transferência de Ésteres de Colesterol/metabolismo
HDL-Colesterol/sangue
Doença da Artéria Coronariana/genética
Doença da Artéria Coronariana/metabolismo
Doença da Artéria Coronariana/patologia
Modelos Animais de Doenças
Selectina E/metabolismo
Feminino
Edição de Genes
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
Células Endoteliais da Veia Umbilical Humana/metabolismo
Erros Inatos do Metabolismo Lipídico/sangue
Erros Inatos do Metabolismo Lipídico/genética
Masculino
Camundongos
Coelhos
Fatores de Tempo
Fator de Necrose Tumoral alfa/farmacologia
Molécula 1 de Adesão de Célula Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoprotein A-I); 0 (Apolipoproteins B); 0 (Apolipoproteins E); 0 (Cholesterol Ester Transfer Proteins); 0 (Cholesterol, Dietary); 0 (Cholesterol, HDL); 0 (E-Selectin); 0 (SELE protein, human); 0 (Tumor Necrosis Factor-alpha); 0 (Vascular Cell Adhesion Molecule-1)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309114


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[PMID]:28397225
[Au] Autor:Cui D; Hu Y; Shen D; Tang G; Zhang M; Duan J; Wen P; Liao J; Ma D; Chen S
[Ad] Endereço:Laboratory for Inborn Error of Metabolism, Institute of Pediatric Research, Affiliated Shenzhen Children's Hospital of Shantou University Medical College, Shenzhen, Guangdong 518038, China. 13008803656@163.com.
[Ti] Título:[Clinical features and genetic analysis of a case with carnitine palmitoyltransferase 1A deficiency].
[So] Source:Zhonghua Yi Xue Yi Chuan Xue Za Zhi;34(2):228-231, 2017 Apr 10.
[Is] ISSN:1003-9406
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: To analyze the clinical and molecular features of a child with carnitine palmitoyltransferase 1A (CPT1A) deficiency. METHODS: Clinical data of the child was collected. Blood acylcarnitine was determined with tandem mass spectrometry. DNA was extracted from the child and his parents. All exons and flanking regions of the CPT1A gene were analyzed by PCR and Sanger sequencing. RESULTS: Analysis showed that the patient carried compound heterozygous mutations c.1787T>C and c.2201T>C of the CPT1A gene, which derived his father and mother, respectively. Both mutations were verified as novel through the retrieval of dbSNP, HGMD and 1000 genome databases. Bioinformatic analysis suggested that the mutations can affect protein function. CONCLUSION: Acyl carnitine analysis has been the main method for the diagnosis of CPT1A deficiency. The c.1787T>C and c.2201T>C mutations of the CPT1A gene probably underlie the disease in this patient. Gene testing can provide important clues for genetic counseling and prenatal diagnosis.
[Mh] Termos MeSH primário: Carnitina O-Palmitoiltransferase/deficiência
Hipoglicemia/genética
Erros Inatos do Metabolismo Lipídico/genética
[Mh] Termos MeSH secundário: Sequência de Bases
Carnitina O-Palmitoiltransferase/genética
Éxons
Feminino
Seres Humanos
Hipoglicemia/enzimologia
Lactente
Erros Inatos do Metabolismo Lipídico/enzimologia
Masculino
Dados de Sequência Molecular
Mutação Puntual
Gravidez
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.3.1.21 (Carnitine O-Palmitoyltransferase); EC 2.3.1.21 (carnitine palmitoyltransferase 1A, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170412
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.1003-9406.2017.02.017


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[PMID]:28247148
[Au] Autor:Tucci S
[Ad] Endereço:Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, Medical Centre - University of Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany. sara.tucci@uniklinik-freiburg.de.
[Ti] Título:Very long-chain acyl-CoA dehydrogenase (VLCAD-) deficiency-studies on treatment effects and long-term outcomes in mouse models.
[So] Source:J Inherit Metab Dis;40(3):317-323, 2017 May.
[Is] ISSN:1573-2665
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Very-long-chain-acyl-CoA-dehydrogenase deficiency is the most common disorder of mitochondrial long-chain fatty acid (LCFA) oxidation, with an incidence of 1:50,000-1:100,000 in newborns. Catabolic situations contribute to the aggravation of symptoms and induce severe metabolic derangement. Treatment for VLCAD-deficiency includes avoidance of fasting and a long-chain fat-restricted and fat-modified diet in which LCFAs are fully or partially replaced by medium-chain triglycerides (MCT). The aim of this work was to investigate the outcome and the effects of long-term treatment in a mouse model of VLCAD-deficiency. The application of a single MCT bolus in a mouse model of VLCAD-deficiency (VLCAD mice) immediately prior to exercise protected the muscles from the accumulation of acylcarnitines providing the required energy and it did not affect hepatic lipid metabolism. However, when MCT was applied over the course of a year as a regular part of the diet, female VLCAD mice developed a severe clinical phenotype comparable to the human metabolic syndrome. Indeed, they were characterized by massive visceral fat infiltration, hepatosteatosis, disturbed fatty acid composition, hyperlipidemia, and systemic oxidative stress. In contrast, male VLCAD mice seemed to be protected and displayed only signs of insulin resistance. Besides the sex-specific response to MCT supplementation with regard to the lipid metabolism, all VLCAD mice developed progressive cardiac dysfunction over time which worsened when they were treated with regular MCT resulting in severe dilated cardiomyopathy. While long term use of MCT oil in mice has adverse effects, no such effects have been demonstrated in humans, likely reflecting the differences in long chain fatty acid oxidation between the two species.
[Mh] Termos MeSH primário: Acil-CoA Desidrogenase de Cadeia Longa/deficiência
Acil-CoA Desidrogenase de Cadeia Longa/metabolismo
Erros Inatos do Metabolismo Lipídico/terapia
Doenças Mitocondriais/terapia
Doenças Musculares/terapia
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Ácidos Graxos/metabolismo
Seres Humanos
Metabolismo dos Lipídeos/fisiologia
Erros Inatos do Metabolismo Lipídico/metabolismo
Camundongos
Doenças Mitocondriais/metabolismo
Doenças Musculares/metabolismo
Triglicerídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Triglycerides); EC 1.3.8.8 (Acyl-CoA Dehydrogenase, Long-Chain)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170302
[St] Status:MEDLINE
[do] DOI:10.1007/s10545-017-0016-8


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[PMID]:28190699
[Au] Autor:Minkler PE; Stoll MS; Ingalls ST; Hoppel CL
[Ad] Endereço:Center for Mitochondrial Diseases, Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
[Ti] Título:Correcting false positive medium-chain acyl-CoA dehydrogenase deficiency results from newborn screening; synthesis, purification, and standardization of branched-chain C8 acylcarnitines for use in their selective and accurate absolute quantitation by UHPLC-MS/MS.
[So] Source:Mol Genet Metab;120(4):363-369, 2017 Apr.
[Is] ISSN:1096-7206
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:While selectively quantifying acylcarnitines in thousands of patient samples using UHPLC-MS/MS, we have occasionally observed unidentified branched-chain C8 acylcarnitines. Such observations are not possible using tandem MS methods, which generate pseudo-quantitative acylcarnitine "profiles". Since these "profiles" select for mass alone, they cannot distinguish authentic signal from isobaric and isomeric interferences. For example, some of the samples containing branched-chain C8 acylcarnitines were, in fact, expanded newborn screening false positive "profiles" for medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Using our fast, highly selective, and quantitatively accurate UHPLC-MS/MS acylcarnitine determination method, we corrected the false positive tandem MS results and reported the sample results as normal for octanoylcarnitine (the marker for MCADD). From instances such as these, we decided to further investigate the presence of branched-chain C8 acylcarnitines in patient samples. To accomplish this, we synthesized and chromatographically characterized several branched-chain C8 acylcarnitines (in addition to valproylcarnitine): 2-methylheptanoylcarnitine, 6-methylheptanoylcarnitine, 2,2-dimethylhexanoylcarnitine, 3,3-dimethylhexanoylcarnitine, 3,5-dimethylhexanoylcarnitine, 2-ethylhexanoylcarnitine, and 2,4,4-trimethylpentanoylcarnitine. We then compared their behavior with branched-chain C8 acylcarnitines observed in patient samples and demonstrated our ability to chromographically resolve, and thus distinguish, octanoylcarnitine from branched-chain C8 acylcarnitines, correcting false positive MCADD results from expanded newborn screening.
[Mh] Termos MeSH primário: Acil-CoA Desidrogenase/deficiência
Carnitina/análogos & derivados
Carnitina/metabolismo
Erros Inatos do Metabolismo Lipídico/diagnóstico
Triagem Neonatal/normas
[Mh] Termos MeSH secundário: Carnitina/síntese química
Carnitina/isolamento & purificação
Cromatografia Líquida de Alta Pressão/métodos
Reações Falso-Positivas
Seres Humanos
Recém-Nascido
Sensibilidade e Especificidade
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 1.3.8.7 (Acyl-CoA Dehydrogenase); S1HB7P0O16 (octanoylcarnitine); S7UI8SM58A (Carnitine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170214
[St] Status:MEDLINE


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[PMID]:28189603
[Au] Autor:Vockley J; Burton B; Berry GT; Longo N; Phillips J; Sanchez-Valle A; Tanpaiboon P; Grunewald S; Murphy E; Humphrey R; Mayhew J; Bowden A; Zhang L; Cataldo J; Marsden DL; Kakkis E
[Ad] Endereço:University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. Electronic address: gerard.vockley@chp.edu.
[Ti] Título:UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.
[So] Source:Mol Genet Metab;120(4):370-377, 2017 Apr.
[Is] ISSN:1096-7206
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death. Triheptanoin is a medium odd-chain fatty acid. Anaplerotic metabolites of triheptanoin have the potential to replace deficient tricarboxylic acid (TCA) cycle intermediates, resulting in net glucose production as a novel energy source for the treatment of LC-FAOD. STUDY DESIGN: A single-arm, open-label, multicenter Phase 2 safety and efficacy study evaluated patients with severe LC-FAOD evidenced by ongoing related musculoskeletal, cardiac, and/or hepatic events despite treatment. After a four-week run-in on current regimen, investigational triheptanoin (UX007) was titrated to a target dose of 25-35% of total daily caloric intake. Patients were evaluated on several age/condition-eligible endpoints, including submaximal exercise tests to assess muscle function/endurance (12-minute walk test; 12MWT) and exercise tolerance (cycle ergometry), and health related quality of life (HR-QoL). Results through 24weeks of treatment are presented; total study duration is 78weeks. RESULTS: Twenty-nine patients (0.8 to 58years) were enrolled; most qualified based on severe musculoskeletal disease. Twenty-five patients (86%) completed the 24-week treatment period. At Week 18, eligible patients (n=8) demonstrated a 28% increase (LS mean=+181.9 meters; p=0.087) from baseline (673.4meters) in 12MWT distance. At Week 24, eligible patients (n=7) showed a 60% increase in watts generated (LS mean=+409.3W; p=0.149) over baseline (744.6W) for the exercise tolerance test. Improvements in exercise tests were supported by significant improvements from baseline in the adult (n=5) self-reported SF-12v2 physical component summary score (LS mean=+8.9; p<0.001). No difference from baseline was seen in pediatric parent-reported (n=5) scores (SF-10) at Week 24. Eighteen patients (62%) had treatment-related adverse events, predominantly gastrointestinal (55%), mild-to-moderate in severity, similar to that seen with prior treatment with medium chain triglyceride (MCT) oil. One patient experienced a treatment-related serious adverse event of gastroenteritis. One patient discontinued from study due to diarrhea of moderate severity; the majority of patients (25/29; 86%) elected to continue treatment in the extension period. CONCLUSIONS: In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.
[Mh] Termos MeSH primário: Ácidos Graxos/toxicidade
Erros Inatos do Metabolismo Lipídico/tratamento farmacológico
Resistência Física/efeitos dos fármacos
Triglicerídeos/administração & dosagem
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Feminino
Seres Humanos
Lactente
Recém-Nascido
Erros Inatos do Metabolismo Lipídico/metabolismo
Erros Inatos do Metabolismo Lipídico/fisiopatologia
Masculino
Meia-Idade
Estudos Prospectivos
Qualidade de Vida
Resultado do Tratamento
Triglicerídeos/farmacologia
Teste de Caminhada
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Triglycerides); 2P6O7CFW5K (triheptanoin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170213
[St] Status:MEDLINE


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[PMID]:28132977
[Au] Autor:Yamamoto Y; Matsui N; Hiramatsu Y; Miyazaki Y; Nodera H; Izumi Y; Takashima H; Kaji R
[Ad] Endereço:Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School.
[Ti] Título:Mitochondrial trifunctional protein deficiency: an adult patient with similar progress to Charcot-Marie-Tooth disease.
[So] Source:Rinsho Shinkeigaku;57(2):82-87, 2017 02 25.
[Is] ISSN:1882-0654
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:A 45-year-old man presented to us due to slowly progressive muscle weakness and sensory disturbances in his lower limbs since his 40's. He reported multiple episodes of exercise-induced severe muscle fatigue and brown urine in his childhood, which disappeared by age 20. A nerve conduction study showed peripheral axonal neuropathy and then Charcot-Marie-Tooth disease (CMT) was considered as the most likely diagnosis; however, exome sequencing failed to identify a mutation in the known genes of CMTs. Since age 55, he recurrently developed severe rhabdomyolysis that required hospitalization. On suspicion of lipid metabolism disorders, we performed serum acylcarnitine analysis, and which revealed mildly elevated long-chain fatty acids. We re-examined variants obtained via exome sequencing and found a mutation in HADHB. Mitochondrial trifunctional protein (MTP) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid beta-oxidation caused by HADHA or HADHB mutation. It can be a life-threatening multiorgan disorder with early infantile onset, but it can also present in childhood or adolescence with peripheral neuropathy and recurrent rhabdomyolysis. This case of adult-diagnosed MTP deficiency was characterized by slowly progressive peripheral neuropathy masquerading CMT in addition to muscular symptoms. MTP deficiency should be considered in patients with the combination of peripheral neuropathy and recurrent rhabdomyolysis.
[Mh] Termos MeSH primário: Cardiomiopatias/diagnóstico
Erros Inatos do Metabolismo Lipídico/diagnóstico
Miopatias Mitocondriais/diagnóstico
Proteína Mitocondrial Trifuncional/deficiência
Doenças do Sistema Nervoso/diagnóstico
Rabdomiólise/diagnóstico
[Mh] Termos MeSH secundário: Biomarcadores/sangue
Cardiomiopatias/complicações
Cardiomiopatias/genética
Carnitina/análogos & derivados
Carnitina/sangue
Doença de Charcot-Marie-Tooth
Diagnóstico Diferencial
Progressão da Doença
Testes Genéticos
Seres Humanos
Erros Inatos do Metabolismo Lipídico/complicações
Erros Inatos do Metabolismo Lipídico/genética
Masculino
Meia-Idade
Miopatias Mitocondriais/complicações
Miopatias Mitocondriais/genética
Proteína Mitocondrial Trifuncional/genética
Subunidade beta da Proteína Mitocondrial Trifuncional/genética
Mutação
Doenças do Sistema Nervoso/complicações
Doenças do Sistema Nervoso/genética
Doenças do Sistema Nervoso Periférico/etiologia
Recidiva
Rabdomiólise/complicações
Rabdomiólise/etiologia
Rabdomiólise/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (acylcarnitine); EC 2.3.1.16 (HADHB protein, human); EC 2.3.1.16 (Mitochondrial Trifunctional Protein); EC 2.3.1.16 (Mitochondrial Trifunctional Protein, beta Subunit); S7UI8SM58A (Carnitine)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170131
[St] Status:MEDLINE
[do] DOI:10.5692/clinicalneurol.cn-000976



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