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1.
Medicine (Baltimore) ; 98(48): e18143, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770251

RESUMO

INTRODUCTION: The occurrence of repeated and progressive rhabdomyolysis is rare in clinical settings, particularly in adults. The pathogenesis of rhabdomyolysis is often overlooked due to its rapid recovery. Carnitine palmitoyltransferase (CPT) II deficiency could be a rare etiology of repetitive nontraumatic rhabdomyolysis, and several mutations of CPT II have been reported. PATIENT CONCERNS: A 41-year-old man presented with high fever, general malaise, myalgia, dyspnea, and dark-colored urine, and then progressed to anuria. In the past 15 years, he experienced dark-colored urine twice due to exercise and high fever. Physical examination revealed oliguria, suppurated tonsils, poor hemoglobin saturation, alert consciousness, normal neurological signs and reflexes, hypertension, and tachypnea. Laboratory investigations showed positive test results for inflammation, high serum myogenic enzyme levels, and evidence of acute kidney injury (AKI). DIAGNOSES: Investigations revealed an extremely high serum myogenic enzyme levels and impaired renal function with serum creatinine level of 510 µmol/L, consistent with the diagnosis of rhabdomyolysis, AKI stage 3, and acute respiratory distress syndrome. High levels of acylcarnitine in the serum confirmed the diagnosis of CPT II deficiency. In addition, whole exome sequencing (WES) was conducted in the patient and his mother. INTERVENTIONS: Intubation, ventilator support, and hemodialysis were the major therapeutic interventions at the peak of disease progression. He was then administered valsartan tablets at a dosage of 80 mg per day and L-carnitine supplements. OUTCOMES: WES conducted in the patient and his mother revealed 2 novel mutations of CPT II (c.482G>A and c.1493G>T) in this patient. The patient recovered from the severe AKI but the renal function remained impaired at chronic kidney disease stage 3a. CONCLUSION: Thus, gene examination can help to understand the etiology of repetitive nontraumatic rhabdomyolysis. Accurate diagnosis can be beneficial for providing an individualized treatment for patients with repeated and progressive rhabdomyolysis.


Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Erros Inatos do Metabolismo/genética , Rabdomiólise/genética , Adulto , Carnitina O-Palmitoiltransferase/sangue , Humanos , Masculino , Erros Inatos do Metabolismo/complicações , Mutação , Recidiva , Rabdomiólise/sangue
2.
Molecules ; 24(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500110

RESUMO

Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6-N-trimethyllysine dioxygenase (TMLD), 3-hydroxy-6-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for ß-oxidation. This transport is achieved by mitochondrial carnitine-acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II). Carnitine inborn errors of metabolism could result from defects in carnitine biosynthesis, carnitine transport, or mitochondrial carnitine-acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. In this review, the metabolism and homeostasis of carnitine are discussed. Then we present details of different inborn errors of carnitine metabolism, including clinical presentation, diagnosis, and treatment options. At the end, we discuss some of the causes of secondary carnitine deficiency.


Assuntos
Cardiomiopatias/genética , Carnitina/deficiência , Carnitina/genética , Hiperamonemia/genética , Erros Inatos do Metabolismo/genética , Mitocôndrias/enzimologia , Doenças Musculares/genética , Aldeído Oxirredutases/genética , Cardiomiopatias/metabolismo , Carnitina/biossíntese , Carnitina/metabolismo , Carnitina Aciltransferases/genética , Carnitina O-Palmitoiltransferase/genética , Humanos , Hiperamonemia/metabolismo , Mitocôndrias/genética , Oxigenases de Função Mista/genética , Doenças Musculares/metabolismo , Oxirredução , Membro 5 da Família 22 de Carreadores de Soluto/genética , gama-Butirobetaína Dioxigenase/genética
3.
J Sci Food Agric ; 99(15): 6981-6988, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31414473

RESUMO

BACKGROUND: Diabetes mellitus is a serious chronic disease, characterized by hyperglycemia. This study administered either ß-mannanase-treated yeast cell autolysis supernatant (YCS) or yeast cell-wall residues after autolysis (YCR) to investigate their influence on the alleviation of diabetes in a diabetic mouse model. RESULTS: Application of either YCS or YCR led to body weight gain, blood glucose reduction, and an improvement in lipid composition in the diabetic mice. Administration of YCS was more effective in inhibiting oxidative stress than YCR. The expression of PPARα and CPT1α was enhanced, improving lipid biosynthesis, and Trx1 and HIF-1-α genes were downregulated due to the activation of thioredoxin following the interventions, indicating that the processes of lipid metabolism and oxidative stress were heavily involved in the reduction of diabetic characteristics following the interventions. The current study revealed that consumption of YCR also led to a reduction in hyperglycemia, this being associated with its richness in mineral elements, such as chromium and selenium. CONCLUSION: This study may highlight the potential of both YCS and YCR as functional ingredients in dietary formula for improving diabetic syndromes. © 2019 Society of Chemical Industry.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Saccharomyces cerevisiae/química , beta-Manosidase/química , Animais , Biocatálise , Glicemia/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Suplementos Nutricionais/análise , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Minerais/análise , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo
4.
Genes (Basel) ; 10(8)2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398921

RESUMO

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe some of the molecular targets and the duration of the effects. We treated rats with 500 mg grape seed proanthocyanidin extract (GSPE)/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on a cafeteria diet, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the mRNA of the key energy metabolism enzymes from the liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. The liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, muscle showed a higher fatty oxidation (Oxct1 and Cpt1b mRNA). However, after seventeen weeks, there was a completely different gene expression pattern. At the conclusion of the study, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle.


Assuntos
Adiposidade/efeitos dos fármacos , Depressores do Apetite/farmacologia , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Ocidental/efeitos adversos , Sobrepeso/prevenção & controle , Proantocianidinas/farmacologia , Tecido Adiposo/metabolismo , Animais , Depressores do Apetite/uso terapêutico , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Coenzima A-Transferases/genética , Coenzima A-Transferases/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Feminino , Leptina/genética , Leptina/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Sobrepeso/tratamento farmacológico , Proantocianidinas/uso terapêutico , Ratos , Vitis/química
5.
Anim Reprod Sci ; 208: 106104, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405453

RESUMO

The peri-calving period is characterized by a negative energy balance, which leads to lipid mobilization. Thus, during this period, the liver has important functions related to optimizing milk yield, preventing metabolic and infectious diseases, and improving fertility. To clarify the relationship between liver fatty acid metabolism and reproductive performance, the present study was conducted to assess the abundance of specific hepatic proteins related to lipid metabolism in both plasma and follicular fluid in dairy cattle with different days to conception (DC). Sixteen animals were grouped according to DC, as more and fewer DC (MDC and FDC, respectively). Blood and liver biopsies were sampled 14 days before the expected calving date and 4, 14 and 28 days after calving. The plasma beta-hydroxybutyric acid (BHBA) concentrations and the liver triacylglycerol (TAG) content were greater in the MDC group (P <  0.05), whereas the protein abundance of carnitine palmitoyl transferase 1 was greater in the FDC group (P < 0.05). Additionally, total bilirubin (TBil) concentration was less in the FDC than MDC group on day 28 (P < 0.05). These results indicate lipid mobilization and liver fatty acid oxidation capacity in dairy cows could contribute to the adaptations and reproductive performance.


Assuntos
Bovinos/fisiologia , Ácidos Graxos/metabolismo , Fígado/metabolismo , Reprodução/fisiologia , Acil-CoA Oxidase/genética , Acil-CoA Oxidase/metabolismo , Ração Animal , Criação de Animais Domésticos , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Bovinos/sangue , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Feminino , Regulação da Expressão Gênica , Metabolismo dos Lipídeos , PPAR alfa/genética , PPAR alfa/metabolismo , Período Periparto/sangue , Período Periparto/fisiologia , Gravidez , Triglicerídeos/metabolismo
6.
J Pediatr Endocrinol Metab ; 32(7): 781-783, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31199774

RESUMO

Background The clinical phenotypes of carnitine palmitoyltransferase type-2 deficiency (CPT2D) are classified into lethal neonatal, severe infantile and muscle forms. The rarest form is the lethal neonatal form. Case presentation The patient was hypotonic and bradycardic at admission. Blood urea nitrogen and creatinine were high. He had polycystic kidneys, patent foramen ovale and aortic valve insufficiency. Cranial magnetic resonance imaging (MRI) revealed increased signal intensities in the periventricular white matter. Tandem mass spectrometry (MS) analysis was compatible with CPT2D. We found a homozygous in-frame deletion in the CPT2 gene using next-generation sequencing. Conclusions We identified a novel mutation leading to the lethal form of CPT2D with polycystic kidney, cardiac malformation and cranial MRI findings. Our findings expand the spectrum of causative mutations and clinical findings in CPT2D.


Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Deleção de Genes , Erros Inatos do Metabolismo/patologia , Mutação , Pré-Escolar , Evolução Fatal , Homozigoto , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Fenótipo
7.
Acta Biochim Biophys Sin (Shanghai) ; 51(7): 707-714, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31187140

RESUMO

Alteration in cellular energy metabolism plays a critical role in the development and progression of cancer. Leptin is a hormone secreted by adipose tissue. Recent reports have shown that leptin can induce cancer cell proliferation and regulate cell energy metabolism, but the regulatory mechanism is still unclear. Here, we showed that leptin could promote cell proliferation and maintain high adenosine triphosphate levels in HCT116 and MCF-7 cells. The expression levels of carnitine palmitoyl transferase 1A (CPT1A), pyruvate dehydrogenase, succinate dehydrogenase subunit A and mitochondrial respiratory chain-associated proteins NADH dehydrogenase 1 (ND1), NADH:ubiquinone oxidoreductase subunit B8, and mitochondrial transcription factor A (TFAM) were distinctly increased in leptin-treated HCT116 and MCF-7 cells, while fatty acid synthase and lactate dehydrogenase expression were downregulated. Simultaneously, we found that c-Myc and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1) protein expression levels were significantly increased. These results indicated that leptin boosted fatty acid ß-oxidation and the tricarboxylic acid cycle, enhanced oxidative phosphorylation (OXPHOS) activity, and inhibited fatty acid synthesis and glycolysis in tumor cells. Gene transfection experiments revealed that leptin could induce the expression of c-Myc. Moreover, the expressions of PGC-1, CPT1A, and TFAM proteins were downregulated in HCT116 cells with low expression of c-Myc, and the expression levels of these proteins were increased in HCT116 cells overexpressing c-Myc. These findings suggest that leptin plays an important role in the regulation of energy metabolism in tumor cells. It may regulate fatty acid oxidation and OXPHOS of tumor cells by regulating the c-Myc/PGC-1 pathway. Targeting metabolic pathways for cancer treatment has been investigated as potential preventive or therapeutic methods. This study has important implications for the clinical therapy of tumor cell metabolism through hormone regulation.


Assuntos
Ácidos Graxos/metabolismo , Leptina/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HEK293 , Humanos , Leptina/genética , Leptina/metabolismo , Células MCF-7 , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução/efeitos dos fármacos
8.
J Mol Neurosci ; 69(2): 188-196, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201655

RESUMO

Mutations of the CPT2 gene cause CPT2 deficiency and affect the ß-oxidation of fatty acids. This study examined the consequence of a polymorphism of rs1799822 in the CPT2 gene with respect to EV71 encephalitis in Chinese children. The study included 406 cases of both mild and severe EV71 infection diagnosed by RT-PCR, together with controls (n = 348). We used an improved multiplex ligation detection reaction technique to detect the polymorphism of rs1799822 in the CPT2 gene. The frequency of the (AG+GG) genotype and G allele in the EV71 infection group and in the severe EV71 encephalitis group was significantly lower than in the control group (p = 0.012 vs. p = 0.005, and p = 0.022 vs. p = 0.006, respectively). The frequency of the (AG+GG) genotype and G allele in the severe EV71 encephalitis group was markedly lower than in the mild EV71 encephalitis group (p = 0.045, p = 0.033). The ATP levels in the blood of the (AG+GG) genotype were distinctly higher than in the AA genotype in mild and severe EV71 encephalitis patients (P = 0.037, P = 0.040). A polymorphism of rs1799822 in the CPT2 gene is associated with the severity of EV71 encephalitis and may be one of the protection factors of severe EV71 encephalitis.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Encefalite Viral/genética , Infecções por Enterovirus/genética , Polimorfismo de Nucleotídeo Único , Trifosfato de Adenosina/sangue , Criança , Pré-Escolar , China , Encefalite Viral/sangue , Encefalite Viral/virologia , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/sangue , Infecções por Enterovirus/virologia , Feminino , Humanos , Lactente , Masculino
9.
Food Funct ; 10(6): 3696-3705, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31168538

RESUMO

The consumption of diets rich in fat and refined sugars is recognized to be one of the causes of lifestyle disorders, and dietary fibres are being advocated to ameliorate the complications associated with these disorders. In the present study, the effects of two soluble fermentable fibres, viz., gum acacia and inulin on the progression of adiposity, insulin resistance, and the expression of genes related to metabolism were examined in C57BL/6 mice fed a high-fat and sucrose diet for 18 weeks. The feeding of either type of fibre resulted in decrease in body weight, epididymal fat mass, adipocyte size, hyperlipidaemia, hyperglycaemia and hyperinsulinemia. In the fibre-fed groups, the expressions of adiponectin and glucose transporter 4 in the epididymal fat increased significantly, while the expressions of leptin, interleukin 6 and tumor necrosis factor alpha decreased significantly. Moreover, the expressions of genes related to beta-oxidation, viz., carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptor gamma co-activator 1ß, and peroxisome proliferator-activated receptor alpha in the liver tissue of the fibre-fed groups enhanced significantly. Furthermore, due to the feeding of either type of fibre, the expressions of zonula occludens 1 and fasting-induced adipose factor in the distal ileum and proglucagon in the colon increased significantly. From the results of the present study, it can be concluded that the beneficial effects of the fibres are mediated due to enhanced energy expenditure, improved intestinal integrity, and reduced inflammation.


Assuntos
Adiposidade , Goma Arábica/metabolismo , Resistência à Insulina , Inulina/metabolismo , Obesidade/tratamento farmacológico , Adiponectina/genética , Adiponectina/metabolismo , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/efeitos adversos , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Insulina/metabolismo , Leptina/genética , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia
10.
Neoplasia ; 21(7): 713-720, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31151054

RESUMO

Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymerase II, is a candidate drug target for cancers driven by transcriptional deregulation. Here we report a multi-omics-profiling of prostate cancer cell responses to CDK9 inhibition to identify synthetic lethal interactions. These interactions were validated using live-cell imaging, mitochondrial flux-, viability- and cell death activation assays. We show that CDK9 inhibition induces acute metabolic stress in prostate cancer cells. This is manifested by a drastic down-regulation of mitochondrial oxidative phosphorylation, ATP depletion and induction of a rapid and sustained phosphorylation of AMP-activated protein kinase (AMPK), the key sensor of cellular energy homeostasis. We used metabolomics to demonstrate that inhibition of CDK9 leads to accumulation of acyl-carnitines, metabolic intermediates in fatty acid oxidation (FAO). Acyl-carnitines are produced by carnitine palmitoyltransferase enzymes 1 and 2 (CPT), and we used both genetic and pharmacological tools to show that inhibition of CPT-activity is synthetically lethal with CDK9 inhibition. To our knowledge this is the first report to show that CDK9 inhibition dramatically alters cancer cell metabolism.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Quinase 9 Dependente de Ciclina/genética , Neoplasias da Próstata/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinase 9 Dependente de Ciclina/metabolismo , Ácidos Graxos/metabolismo , Humanos , Masculino , Oxirredução , Fosforilação Oxidativa , Fosforilação , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdução de Sinais/genética
11.
Cancer Sci ; 110(6): 2050-2062, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30945396

RESUMO

The PPAR coactivator-1α (PGC1α) is an important transcriptional co-activator in control of fatty acid metabolism. Mitochondrial fatty acid oxidation (FAO) is the primary pathway for the degradation of fatty acids and promotes NADPH and ATP production. Our previous study demonstrated that upregulation of carnitine palmitoyl transferase 1 A (CPT1A), the key regulator of FAO, promotes radiation resistance of nasopharyngeal carcinoma (NPC). In this study, we found that high expression of PGC1α is associated with poor overall survival in NPC patients after radiation treatment. Targeting PGC1α could sensitize NPC cells to radiotherapy. Mechanically, PGC1α binds to CCAAT/enhancer binding protein ß (CEBPB), a member of the transcription factor family of CEBP, to promote CPT1A transcription, resulting in activation of FAO. Our results revealed that the PGC1α/CEBPB/CPT1A/FAO signaling axis promotes radiation resistance of NPC. These findings indicate that the expression of PGC1α could be a prognostic indicator of NPC, and targeting FAO in NPC with high expression of PGC1α might improve the therapeutic efficacy of radiotherapy.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Carnitina O-Palmitoiltransferase/genética , Ácidos Graxos/metabolismo , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Oxirredução/efeitos da radiação , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos da radiação , Interferência de RNA
12.
Lipids Health Dis ; 18(1): 89, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954075

RESUMO

BACKGROUND: Elevation of exogenous free fatty acid (FFA) level leads to insulin resistance (IR) in liver, IR is manifested by elevated hepatic glucose production. We aim to study whether inhibition of endogenous fatty acid synthesis could decrease hepatic glucose production. METHODS: Low-passage HepG2 cells derived from human liver tissue were cultured in medium supplemented with FFA to induce IR, the influences of sterol regulatory element binding protein-1c (SREBP-1c) silencing on glucose production of HepG2 cells were investigated, and genes responsible for fatty acid and glucose metabolism were detected by real-time PCR. RESULTS: Compared with HepG2 cells cultured in normal growth medium, glucose production of HepG2 cells treated by FFA was significantly increased {[(0.28 ± 0.01) vs (0.83 ± 0.02)] umol.ug- 1 protein, n = 6 wells, P < 0.01}; the mRNA expression of phosphoenolpyruvate carboxylase kinase (PEPCK) and glucose-6-phosphatase (G6PC) in HepG2 cells increased by more than 5-fold and 3-fold, respectively; the mRNA expression of fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1) increased by approximately 4-fold and 1.1-fold, respectively; the mRNA expression of carnitine palmitoyltransferase-1 (CPT-1) changed slightly. Compared with the scrambled siRNA control, glucose production of HepG2 cells treated by FFA significantly increased after SREBP-1c silencing {[(0.018 ± 0.001) vs (0.028 ± 0.002)] umol.ug- 1 protein, n = 6 wells, P < 0.01}; the mRNA expression of PEPCK and G6PC increased by approximately 1.5-fold and 5-fold, respectively, but the mRNA expression of FAS, SCD1 and CPT-1 changed slightly. CONCLUSIONS: SREBP-1c silencing further augmented glucose production of HepG2 cells treated by FFA significantly, genes responsible for fatty acid synthesis and gluconeogenesis played an important role in this process. SREBP-1c functions not only as a lipid regulator but also plays an important role in regulation of glucose metabolism.


Assuntos
Meios de Cultura/farmacologia , Ácidos Graxos não Esterificados/farmacologia , Glucose/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Carnitina O-Palmitoiltransferase/genética , Ácido Graxo Sintases/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Resistência à Insulina/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Triglicerídeos/metabolismo
13.
Anim Sci J ; 90(5): 637-648, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30854727

RESUMO

This study evaluated the effects of condensed barley distillers soluble (CBDS) on growth rate, rumen fermentation, plasma metabolite, and myofiber properties, and gene expression related to metabolism in the skeletal muscles of Japanese Black calves, compared with soybean meal and corn. Twenty-four calves were divided into four groups: fed 5% CBDS based on the hay dry matter weight (low CBDS) and fed soybean meal and corn at the same nutrition level (control); and fed 15% CBDS based on the hay dry matter weight (high CBDS) and fed soybean meal and corn at the same nutrition level (high soy). The daily gain was larger in the low (p = 0.08) and high (p < 0.05) CBDS groups compared with the control group. In the CBDS-fed groups, plasma ß-hydroxybutyric acid concentrations were significantly higher at 6 months of age (p < 0.05), the percentage of type I myofibers was significantly lower and their diameters were significantly larger at 9 months of age (p < 0.05), and carnitine palmitoyltransferase 1b mRNA expression was significantly lower (p < 0.05) and citrate synthase mRNA expression tended to be lower (low; p = 0.06, high; p = 0.05) compared with control group. Thus, feeding CBDS promotes growth and leads to animals with more glycolytic and less oxidative muscle metabolism.


Assuntos
Ácido 3-Hidroxibutírico/sangue , Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Bovinos/crescimento & desenvolvimento , Bovinos/metabolismo , Dieta/veterinária , Fermentação , Expressão Gênica , Hordeum , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Miofibrilas , Rúmen/metabolismo , Silagem , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Citrato (si)-Sintase/genética , Citrato (si)-Sintase/metabolismo , Glicólise , Masculino , Oxirredução , RNA Mensageiro/genética , Soja , Zea mays
14.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897730

RESUMO

Fibroblast growth factor 21 (FGF-21) is known to be a biomarker for mitochondrial disorders. An upregulation of FGF-21 in serum and muscle of carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) knock-out mice has been reported. In human CPT II deficiency, enzyme activity and protein content are normal, but the enzyme is abnormally regulated by malonyl-CoA and is abnormally thermolabile. Citrate synthase (CS) activity is increased in patients with CPT II deficiency. This may indicate a compensatory response to an impaired function of CPT II. In this study, FGF-21 serum levels in patients with CPT II deficiency during attack free intervals and in healthy controls were measured by enzyme linked immunosorbent assay (ELISA). The data showed no significant difference between FGF-21 concentration in the serum of patients with CPT II deficiency and that in the healthy controls. The results of the present work support the hypothesis that in muscle CPT II deficiency, in contrast to the mouse knockout model, mitochondrial fatty acid utilization is not persistently reduced. Thus, FGF-21 does not seem to be a useful biomarker in the diagnosis of CPT II deficiency.


Assuntos
Carnitina O-Palmitoiltransferase/sangue , Carnitina O-Palmitoiltransferase/deficiência , Fatores de Crescimento de Fibroblastos/sangue , Erros Inatos do Metabolismo/sangue , Doenças Mitocondriais/sangue , Adulto , Animais , Biomarcadores/sangue , Carnitina O-Palmitoiltransferase/genética , Citrato (si)-Sintase/genética , Citrato (si)-Sintase/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Malonil Coenzima A/genética , Malonil Coenzima A/metabolismo , Erros Inatos do Metabolismo/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Doenças Mitocondriais/genética
15.
Metabolism ; 95: 27-35, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30902749

RESUMO

BACKGROUND AND PURPOSE: In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin. METHODS: The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo. RESULTS: We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice. CONCLUSIONS: We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO.


Assuntos
Cisteína Endopeptidases/metabolismo , Ácidos Graxos/metabolismo , Leptina/farmacologia , Músculo Esquelético/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Células Cultivadas , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Cisteína Endopeptidases/biossíntese , Cisteína Endopeptidases/genética , Técnicas de Silenciamento de Genes , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Oxirredução
16.
Int J Mol Sci ; 20(5)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823689

RESUMO

Mid-to-late gestation is a unique period in which women experience dynamic changes in lipid metabolism. Although the recent intensive epigenome-wide association studies (EWAS) using peripheral leukocytes have revealed that lipid-related traits alter DNA methylation, the influence of pregnancy-induced metabolic changes on the methylation levels of these differentially methylated sites is not well known. In this study, we performed a prospective cohort study of pregnant women (n = 52) using the MassARRAY EpiTYPER assay and analyzed the methylation levels of variably methylated sites, including CPT1A intron 1 and SREBF1 intron 1 CpGs, which were previously verified to be robustly associated with adiposity traits. Although methylation of SREBF1 was associated with body mass index (BMI) and low-density lipoprotein cholesterol at mid-gestation, this association was attenuated at late gestation, which was consistent with the metabolic switch from an anabolic to a catabolic state. However, the BMI association with CPT1A intron 1 methylation appeared to strengthen at late gestation; this association was mediated by pre-pregnancy BMI-dependent change in the leukocyte proportion during mid-to-late gestation. Thus, the methylation of adiposity-related differentially methylated regions was sensitive to metabolic and immunological changes during mid-to-late gestation.


Assuntos
Adiposidade/genética , Carnitina O-Palmitoiltransferase/genética , Metilação de DNA , Ganho de Peso na Gestação/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto , Índice de Massa Corporal , Carnitina O-Palmitoiltransferase/metabolismo , LDL-Colesterol/sangue , Feminino , Humanos , Gravidez , Terceiro Trimestre da Gravidez , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
17.
Lipids Health Dis ; 18(1): 55, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819205

RESUMO

BACKGROUND: Non-human primates (NHPs) are important models of medical research on obesity and cardiovascular diseases. As two of the most commonly used NHPs, cynomolgus macaque (CM) and African green monkey (AGM) own different capacities in lipid metabolism of which the mechanism is unknown. This study investigated the expression profiles of lipid metabolism-related microRNAs (miRNAs) in CM and AGM and their possible roles in controlling lipid metabolism-related gene expression. METHODS: By small RNA deep sequencing, the plasma miRNA expression patterns of CM and AGM were compared. The lipid metabolism-related miRNAs were validated through quantitative reverse-transcription (RT) polymerase chain reaction (PCR). Related-target genes were predicted by TargetScan and validated in Vero cells. RESULTS: Compared to CM, 85 miRNAs were upregulated with over 1.5-fold change in AGM of which 12 miRNAs were related to lipid metabolism. miR-122, miR-9, miR-185, miR-182 exhibited the greatest fold changes(fold changes are 51.2, 3.8, 3.7, 3.3 respectively; all P < 0.01). And 77 miRNAs were downregulated with over 1.5-fold change in AGM of which 3, miR-370, miR-26, miR-128 (fold changes are 9.3, 1.8, 1.7 respectively; all P < 0.05) were related to lipid metabolism. The lipid metabolism-related gene targets were predicted by TargetScan and confirmed in the Vero cells. CONCLUSION: We report for the first time a circulating lipid metabolism-related miRNA profile for CM and AGM, which may add to knowledge of differences between these two non-human primate species and miRNAs' roles in lipid metabolism.


Assuntos
/genética , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Macaca fascicularis/genética , MicroRNAs/genética , Transportador 1 de Cassete de Ligação de ATP/sangue , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Carnitina O-Palmitoiltransferase/sangue , Carnitina O-Palmitoiltransferase/genética , Proteína 7 com Repetições F-Box-WD/sangue , Proteína 7 com Repetições F-Box-WD/genética , Ácido Graxo Sintase Tipo I/sangue , Ácido Graxo Sintase Tipo I/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Macaca fascicularis/sangue , MicroRNAs/sangue , Anotação de Sequência Molecular , Isoformas de Proteínas/sangue , Isoformas de Proteínas/genética , Receptores de Lipoproteínas/sangue , Receptores de Lipoproteínas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esterol O-Aciltransferase/sangue , Esterol O-Aciltransferase/genética , Células Vero
18.
Lipids Health Dis ; 18(1): 53, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764880

RESUMO

BACKGROUND: Supplemented fatty acids can incorporate into cardiolipin (CL) and affect its remodeling. The change in CL species may alter the mitochondrial membrane composition, potentially disturbing the mitochondrial structure and function during inflammation. METHOD: To investigate the effect of the unsaturation of fatty acids on CL, we supplemented macrophage-like RAW264.7 cells with 18-carbon unsaturated fatty acids including oleic acid (OA, 18:1), linoleic acid (LA, 18:2), α-linolenic acid (ALA, 18:3), γ-linolenic acid (GLA, 18:3), and stearidonic acid (SDA, 18:4). Mitochondrial changes in CL were measured through mass spectrometry. RESULT: Our data indicated that OA(18:1) was the most efficient fatty acid that incorporated into CL, forming symmetrical CL without fatty acid elongation and desaturation. In addition, LA(18:2) and ALA(18:3) were further elongated before incorporation, significantly increasing the number of double bonds and the chain length of CL. GLA and SDA were not optimal substrates for remodeling enzymes. The findings of RT-qPCR experiments revealed that none of these changes in CL occurred through the regulation of CL remodeling- or synthesis-related genes. The fatty acid desaturase and transportation genes-Fads2 and Cpt1a, respectively-were differentially regulated by the supplementation of five unsaturated 18-carbon fatty acids. CONCLUSIONS: The process of fatty acid incorporation to CL was regulated by the fatty acid desaturation and transportation into mitochondria in macrophage. The double bonds of fatty acids significantly affect the incorporation process and preference. Intact OA(18:1) was incorporated to CL; LA(18:2) and ALA(18:3) were desaturated and elongated to long chain fatty acid before the incorporation; GLA(18:3) and SDA(18:4) were unfavorable for the CL incorporation.


Assuntos
Cardiolipinas/biossíntese , Ácidos Graxos Ômega-3/farmacologia , Ácido Linoleico/farmacologia , Membranas Mitocondriais/efeitos dos fármacos , Ácido Oleico/farmacologia , Ácido alfa-Linoleico/farmacologia , Ácido gama-Linolênico/farmacologia , Animais , Transporte Biológico , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Ômega-3/química , Ácidos Graxos Ômega-3/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ácido Linoleico/química , Ácido Linoleico/metabolismo , Camundongos , Mitocôndrias/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Membranas Mitocondriais/química , Membranas Mitocondriais/metabolismo , Ácido Oleico/química , Ácido Oleico/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Ácido alfa-Linoleico/química , Ácido alfa-Linoleico/metabolismo , Ácido gama-Linolênico/química , Ácido gama-Linolênico/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-30735773

RESUMO

Carnitine palmitoyltransferase 1 (CPT1) plays an essential role in maintaining energy supply via fatty acid oxidation, especially under fasting. In this study, the complete cDNA sequence of cpt1a was cloned from liver of large yellow croaker (Larimichthys crocea), with an open reading frame of 2319 bp encoding a protein of 772 amino acids. Bioinformatics analysis predicted the presence of conserved functional motifs and amino acid residues. The highest mRNA expression of cpt1a was observed in the liver. Phylogenetic tree clearly shows that CPT1A protein is a homologue of mammalian CPT1A. Recombinant protein rCPT1A showed catalytic activity, with Michaelis constant (km) (≈1.38 mM) and maximal reaction rates (Vmax) for carnitine (≈12.66 nmols/min/mg protein). The cpt1a mRNA expression dramatically increased and CPT1 activity remained unchanged after fasting. Fasting did not significantly change Vmax and free carnitine (FC) content in liver. Interestingly, catalytic efficiency (Vmax/Km) and FC/Km increased in fish fasted for 4 days, implying FC contents might be enough to ensure the optimal fatty acid oxidation. Contrarily, both indicators declined when fish fasted for 12 days. The present results demonstrated cpt1a has a biological function and showed that the transcriptional and kinetic regulation of CPT1 during fasting, emphasizing that fasting-induced fatty acid oxidation depends on changes in kinetic properties instead of CPT1 activity and transcription.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Jejum , Regulação Enzimológica da Expressão Gênica , Perciformes/genética , Transcrição Genética , Sequência de Aminoácidos , Animais , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/química , Carnitina O-Palmitoiltransferase/metabolismo , DNA Complementar/genética , Humanos , Cinética , Metabolismo dos Lipídeos , Fígado/metabolismo , Perciformes/metabolismo , Perciformes/fisiologia , Filogenia , Alinhamento de Sequência
20.
Int J Food Sci Nutr ; 70(7): 834-844, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30764676

RESUMO

The aim of this study was to examine the effects of α-lipoic acid (α-LA) on liver mitochondrial bioenergetics and oxidative status for 8 weeks in normal-healthy animals. A pair-fed group was included to differentiate between α-LA direct effects and those changes due to reduced food intake. α-LA decreased body weight gain, liver weight and insulin levels with no differences compared to its pair-fed group. α-LA significantly reduced energy efficiency, the activity of the electron transport chain complexes and induced a lower efficiency of oxidative phosphorylation with reduced ATP production. α-LA supplementation directly decreased plasma triglycerides (TGs), free fatty acids and ketone bodies levels. A significant reduction in hepatic TG content was also observed. A significant up-regulation of Cpt1a, Acadl and Sirt3, all ß-oxidation genes, along with a significant deacetylation of the forkhead transcription factor 3a (FOXO3A) was found in α-LA-treated animals. Thus, α-LA along with a standard chow diet has direct actions on lipid metabolism and liver by modulating mitochondrial function in normal-weight rats. These results should be taken into account when α-LA is administered or recommended to a healthy population.


Assuntos
Carnitina O-Palmitoiltransferase/metabolismo , Metabolismo Energético , Proteína Forkhead Box O3/metabolismo , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sirtuínas/metabolismo , Ácido Tióctico/farmacologia , Animais , Glicemia , Carnitina O-Palmitoiltransferase/genética , Ácidos Graxos não Esterificados/sangue , Proteína Forkhead Box O3/genética , Corpos Cetônicos/sangue , Metabolismo dos Lipídeos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Mitocôndrias/metabolismo , Fosforilação , Ratos , Ratos Wistar , Sirtuínas/genética , Triglicerídeos/sangue , Regulação para Cima
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