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1.
Life Sci ; 254: 117785, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32416167

RESUMO

As the most important bioactive substance in Garcinia cambogia, (-)-hydroxycitric acid (HCA) is widely used in food additives to regulate obesity and diabetes in animals or humans, while the mechanism is poorly understood. The purpose of this study was to elucidate the regulatory effect and mechanism of (-)-HCA in regulating glucose and lipid metabolism in chicken primary hepatocytes. The results showed that (-)-HCA obviously decreased triglyceride content through inhibiting the fatty acid synthase protein level, and enhancing the protein level of phosphorylated acetyl CoA carboxylase, enoyl coenzyme A hydratase short chain 1 and carnitine palmitoyltransferase 1A in hepatocytes. Moreover, (-)-HCA markedly enhanced the protein level of phosphofructokinase-1, pyruvate dehydrogenase, succinate dehydrogenase A and complex IV, and which led to the enhancing of glucose uptake and catabolism in hepatocytes. Importantly, the regulation of (-)-HCA on these key factors associated with lipid and glucose metabolism in hepatocytes was mainly achieved through activation of AMP-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α-nuclear respiratory factor 1 signaling pathway. These results convincingly demonstrated the mechanism of (-)-HCA's regulating on glucose and lipid metabolism, and provided a strategy in prevention of diseases associated with glycolipid metabolic abnormalities in animals, even in humans.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Citratos/farmacologia , Metabolismo Energético/fisiologia , Hepatócitos/metabolismo , Fator 1 Relacionado a NF-E2/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Galinhas , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Enoil-CoA Hidratase/metabolismo , Glucose/metabolismo , Fosfofrutoquinase-1/metabolismo , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Piruvato Desidrogenase (Lipoamida)/metabolismo , Transdução de Sinais/fisiologia , Succinato Desidrogenase/metabolismo , Triglicerídeos/metabolismo
2.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906305

RESUMO

Lipid metabolism dysfunction and obesity are serious health issues to human beings. The current study investigated the effects of hyperbaric oxygen (HBO) against high fat diet (HFD)-induced lipid metabolism dysfunction and the roles of L-carnitine. C57/B6 mice were fed with HFD or normal chew diet, with or without HBO treatment. Histopathological methods were used to assess the adipose tissues, serum free fatty acid (FFA) levels were assessed with enzymatic methods, and the endogenous circulation and skeletal muscle L-carnitine levels were assessed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, western blotting was used to assess the expression levels of PPARα, CPT1b, pHSL/HSL, and UCP1. HFD treatment increased body/adipose tissue weight, serum FFA levels, circulation L-carnitines and decreased skeletal muscle L-carnitine levels, while HBO treatment alleviated such changes. Moreover, HFD treatment increased fatty acid deposition in adipose tissues and decreased the expression of HSL, while HBO treatment alleviated such changes. Additionally, HFD treatment decreased the expression levels of PPARα and increased those of CPT1b in skeletal muscle, while HBO treatment effectively reverted such changes as well. In brown adipose tissues, HFD increased the expression of UCP1 and the phosphorylation of HSL, which was abolished by HBO treatment as well. In summary, HBO treatment may alleviate HFD-induced fatty acid metabolism dysfunction in C57/B6 mice, which seems to be associated with circulation and skeletal muscle L-carnitine levels and PPARα expression.


Assuntos
Tecido Adiposo/metabolismo , Carnitina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Tecido Adiposo/citologia , Animais , Carnitina/sangue , Carnitina/química , Carnitina O-Palmitoiltransferase/metabolismo , Cromatografia Líquida , Oxigenação Hiperbárica , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Obesidade/tratamento farmacológico , PPAR alfa/metabolismo , Fosforilação , Esterol Esterase/química , Esterol Esterase/metabolismo , Espectrometria de Massas em Tandem , Proteína Desacopladora 1/metabolismo
3.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906370

RESUMO

l-Carnitine is an amino acid derivative widely known for its involvement in the transport of long-chain fatty acids into the mitochondrial matrix, where fatty acid oxidation occurs. Moreover, l-Carnitine protects the cell from acyl-CoA accretion through the generation of acylcarnitines. Circulating carnitine is mainly supplied by animal-based food products and to a lesser extent by endogenous biosynthesis in the liver and kidney. Human muscle contains high amounts of carnitine but it depends on the uptake of this compound from the bloodstream, due to muscle inability to synthesize carnitine. Mitochondrial fatty acid oxidation represents an important energy source for muscle metabolism particularly during physical exercise. However, especially during high-intensity exercise, this process seems to be limited by the mitochondrial availability of free l-carnitine. Hence, fatty acid oxidation rapidly declines, increasing exercise intensity from moderate to high. Considering the important role of fatty acids in muscle bioenergetics, and the limiting effect of free carnitine in fatty acid oxidation during endurance exercise, l-carnitine supplementation has been hypothesized to improve exercise performance. So far, the question of the role of l-carnitine supplementation on muscle performance has not definitively been clarified. Differences in exercise intensity, training or conditioning of the subjects, amount of l-carnitine administered, route and timing of administration relative to the exercise led to different experimental results. In this review, we will describe the role of l-carnitine in muscle energetics and the main causes that led to conflicting data on the use of l-carnitine as a supplement.


Assuntos
Carnitina/análogos & derivados , Carnitina/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Carnitina/administração & dosagem , Carnitina/biossíntese , Carnitina/química , Carnitina/farmacologia , Carnitina O-Palmitoiltransferase/metabolismo , Suplementos Nutricionais/efeitos adversos , Exercício Físico/fisiologia , Humanos , Metilaminas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Oxirredução
4.
FASEB J ; 34(1): 1546-1557, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914600

RESUMO

G protein-coupled receptors (GPCRs) comprise the largest group of membrane receptors in eukaryotic genomes and collectively they regulate nearly all cellular processes. Despite the widely recognized importance of this class of proteins, many GPCRs remain understudied. G protein-coupled receptor 27 (Gpr27) is an orphan GPCR that displays high conservation during vertebrate evolution. Although, GPR27 is known to be expressed in tissues that regulate metabolism including the pancreas, skeletal muscle, and adipose tissue, its functions are poorly characterized. Therefore, to investigate the potential roles of Gpr27 in energy metabolism, we generated a whole body gpr27 knockout zebrafish line. Loss of gpr27 potentiated the elevation in glucose levels induced by pharmacological or nutritional perturbations. We next leveraged a mass spectrometry metabolite profiling platform to identify other potential metabolic functions of Gpr27. Notably, genetic deletion of gpr27 elevated medium-chain acylcarnitines, in particular C6-hexanoylcarnitine, C8-octanoylcarnitine, C9-nonanoylcarnitine, and C10-decanoylcarnitine, lipid species known to be associated with insulin resistance in humans. Concordantly, gpr27 deletion in zebrafish abrogated insulin-dependent Akt phosphorylation and glucose utilization. Finally, loss of gpr27 increased the expression of key enzymes in carnitine shuttle complex, in particular the homolog to the brain-specific isoform of CPT1C which functions as a hypothalamic energy senor. In summary, our findings shed light on the biochemical functions of Gpr27 by illuminating its role in lipid metabolism, insulin signaling, and glucose homeostasis.


Assuntos
Carnitina/análogos & derivados , Glucose/metabolismo , Homeostase/genética , Resistência à Insulina/genética , Receptores Acoplados a Proteínas-G/genética , Peixe-Zebra/genética , Animais , Carnitina/genética , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Deleção de Genes , Glucose/genética , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Peixe-Zebra/metabolismo
5.
Biochim Biophys Acta Biomembr ; 1862(2): 183094, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31705849

RESUMO

Carnitine Palmitoyltransferase 1A (CPT 1A) is an enzyme anchored to the outer mitochondrial membrane (OMM), where it regulates the passage of fatty acids into the mitochondria and intervenes in the process of ß-oxidation of long-chain fatty acids. Although CPT 1A is inhibited by malonyl-CoA, its activity is also modulated by the curvature of OMM. This modulation depends on the behavior of the N-terminal domain (NTD), which can be adsorbed onto the OMM (nonactive CPT 1A) or interacting with the C-terminal domain (active CPT 1A). Aimed to provide mechanistic insights on the regulatory mechanism of CPT 1A, we studied the influence of the bilayer curvature on the NTD behavior through a series of coarse-grained (CG) molecular dynamics simulations using curved and planar membranes. Comparative analysis suggests that the main determinant for the activation/deactivation of the enzyme is the tilt angle orientation of the transmembrane (TM) domains. Planar membranes induce a wide variation on the tilt angle orientation of TM helices, while curved geometries promote small angles with the membrane normal. Our results identify the first TM domain as an important component of the membrane sensing mechanism.


Assuntos
Carnitina O-Palmitoiltransferase/metabolismo , Membranas Mitocondriais/metabolismo , Simulação de Dinâmica Molecular , Humanos , Membranas Mitocondriais/ultraestrutura , Domínios Proteicos
6.
Dev Cell ; 52(2): 196-209.e9, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31866205

RESUMO

Saturated fatty acids (SFAs) (the "bad" fat), especially palmitate (PA), in the human diet are blamed for potential health risks such as obesity and cancer because of SFA-induced lipotoxicity. However, epidemiological results demonstrate a latent benefit of SFAs, and it remains elusive whether a certain low level of SFAs is physiologically essential for maintaining cell metabolic hemostasis. Here, we demonstrate that although high-level PA (HPA) indeed induces lipotoxic effects in liver cells, low-level PA (LPA) increases mitochondrial functions and alleviates the injuries induced by HPA or hepatoxic agent carbon tetrachloride (CCl4). LPA treatment in mice enhanced liver mitochondrial activity and reduced CCl4 hepatotoxicity with improved blood levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and mitochondrial aspartate transaminase (m-AST). LPA-mediated mitochondrial homeostasis is regulated by CDK1-mediated SIRT3 phosphorylation, which in turn deacetylates and dimerizes CPT2 to enhance fatty acid oxidation. Thus, an advantageous effect is suggested by the consumption of LPA that augments mitochondrial metabolic homeostasis via CDK1-SIRT3-CPT2 cascade.


Assuntos
Proteína Quinase CDC2/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hepatócitos/citologia , Mitocôndrias/metabolismo , Palmitatos/farmacologia , Sirtuína 3/metabolismo , Animais , Proteína Quinase CDC2/genética , Tetracloreto de Carbono/toxicidade , Carnitina O-Palmitoiltransferase/genética , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Sirtuína 3/genética
7.
J Med Food ; 22(12): 1262-1270, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31834842

RESUMO

The aim of this study was to investigate the potential protective effects of the hot water extract of Eriobotrya japonica (EJW) on EtOH- or free fatty acid (FFA)-induced fatty liver injury in vitro. HepG2/2E1 cells were exposed to EtOH and HepG2 cells were exposed to a mixture of FFAs (oleic acid:palmitic acid, 2:1) to stimulate oxidative stress and to induce lipid accumulation, respectively. Antioxidant activity was significantly increased and lipid accumulation was inhibited in cells pretreated with EJW compared to those in cells exposed to EtOH or FFA only. Also, 5'adenosine monophosphate (AMP)-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase (ACC) phosphorylations were considerably increased, indicating activation of AMPK. Furthermore, EJW reduced the messenger RNA (mRNA) expression of lipogenesis-associated factors such as ACC, sterol regulatory element binding protein-1c (SREBP-1c), and fatty acid synthase (FAS), and increased mRNA expression related to components of the fatty acid ß-oxidation pathway, such as AMPK, carnitine palmitoyltransferase 1 (CPT-1), and peroxisome proliferator-activated receptor alpha (PPARα). These results suggest that EJW possessed potential preventive effects against both EtOH- and FFA-induced fatty liver disease by alleviation of oxidative stress and lipid accumulation in hepatocytes.


Assuntos
Eriobotrya/química , Fígado Gorduroso Alcoólico/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Etanol/efeitos adversos , Ácido Graxo Sintases/metabolismo , Ácidos Graxos não Esterificados/efeitos adversos , Células Hep G2/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Produto da Acumulação Lipídica , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ácido Oleico/efeitos adversos , Estresse Oxidativo , PPAR alfa/genética , Ácido Palmítico/efeitos adversos , Fosforilação/efeitos dos fármacos , Proteínas Quinases/metabolismo , RNA Mensageiro/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Água
8.
Elife ; 82019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868590

RESUMO

Anterograde transport of late endosomes or lysosomes (LE/Lys) is crucial for proper axon growth. However, the role of energetic nutrients has been poorly explored. Malonyl-CoA is a precursor of fatty acids, and its intracellular levels highly fluctuate depending on glucose availability or the energy sensor AMP-activated protein kinase (AMPK). We demonstrate in HeLa cells that carnitine palmitoyltransferase 1C (CPT1C) senses malonyl-CoA and enhances LE/Lys anterograde transport by interacting with the endoplasmic reticulum protein protrudin and facilitating the transfer of Kinesin-1 from protrudin to LE/Lys. In cultured mouse cortical neurons, glucose deprivation, pharmacological activation of AMPK or inhibition of malonyl-CoA synthesis decreases LE/Lys abundance at the axon terminal, and shortens axon length in a CPT1C-dependent manner. These results identify CPT1C as a new regulator of anterograde LE/Lys transport in response to malonyl-CoA changes, and give insight into how axon growth is controlled by nutrients.


Assuntos
Axônios/metabolismo , Carnitina O-Palmitoiltransferase/genética , Neurônios/metabolismo , Proteínas Quinases/genética , Animais , Axônios/fisiologia , Transporte Biológico/genética , Encéfalo/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Endossomos/genética , Endossomos/metabolismo , Glucose/metabolismo , Células HeLa , Humanos , Cinesina/genética , Cinesina/metabolismo , Lisossomos/genética , Lisossomos/metabolismo , Malonil Coenzima A/metabolismo , Camundongos , Nutrientes/metabolismo
9.
Lipids Health Dis ; 18(1): 207, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775868

RESUMO

OBJECTIVE: Endoplasmic reticulum (ER) stress and mitochondrial function affected intramuscular fat accumulation. However, there is no clear evident on the effect of the regulation of ER stress and mitochondrial function by Angiotensin-converting enzyme 2 (ACE2) on the prevention of intramuscular fat metabolism. We investigated the effects of ACE2 on ER stress and mitochondrial function in skeletal muscle lipid metabolism. METHODS: The triglyceride (TG) content in skeletal muscle of ACE2 knockout mice and Ad-ACE2-treated db/db mice were detected by assay kits. Meanwhile, the expression of lipogenic genes (ACCα, SREBP-1c, LXRα, CPT-1α, PGC-1α and PPARα), ER stress and mitochondrial function related genes (GRP78, eIF2α, ATF4, BCL-2, and SDH6) were analyzed by RT-PCR. Lipid metabolism, ER stress and mitochondrial function related genes were analyzed by RT-PCR in ACE2-overexpression C2C12 cell. Moreover, the IKKß/NFκB/IRS-1 pathway was determined using lysate sample from skeletal muscle of ACE2 knockout mice. RESULTS: ACE2 deficiency in vivo is associated with increased lipid accumulation in skeletal muscle. The ACE2 knockout mice displayed an elevated level of ER stress and mitochondrial dysfunctions in skeletal muscle. In contrast, activation of ACE2 can ameliorate ER stress and mitochondrial function, which slightly accompanied by reduced TG content and down-regulated the expression of skeletal muscle lipogenic proteins in the db/db mice. Additionally, ACE2 improved skeletal muscle lipid metabolism and ER stress genes in the C2C12 cells. Mechanistically, endogenous ACE2 improved lipid metabolism through the IKKß/NFκB/IRS-1 pathway in skeletal muscle. CONCLUSIONS: ACE2 was first reported to play a notable role on intramuscular fat regulation by improving endoplasmic reticulum and mitochondrial function. This study may provide a strategy for treating insulin resistance in skeletal muscle.


Assuntos
Estresse do Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Metabolismo dos Lipídeos/genética , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Peptidil Dipeptidase A/genética , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Peptidil Dipeptidase A/deficiência , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Triglicerídeos/metabolismo
10.
Cryobiology ; 91: 97-103, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31589831

RESUMO

This study aimed to investigate whether exogenous application of carnitine stimulates transportation of fatty acids into mitochondria, which is an important part of fatty acid trafficking in cells, and mitochondrial respiration in the leaves of maize seedlings grown under normal and cold conditions. Cold stress led to significant increases in lipase activity, which is responsible for the breakdown of triacylglycerols, and carnitine acyltransferase (carnitine acyltransferase I and II) activities, which are responsible for the transport of activated long-chain fatty acids into mitochondria. While exogenous application of carnitine has a similar promoting effect with cold stress on lipase activity, it resulted in further increases in the activity of carnitine acyltransferases compared to cold stress. The highest activity levels for these enzymes were recorded in the seedlings treated with cold plus carnitine. In addition, these increases were correlated with positive increases in the contents of free- and long-chain acylcarnitines (decanoyl-l-carnitine, lauroyl-l-carnitine, myristoyl-l-carnitine, and stearoyl-l-carnitine), and with decreases in the total lipid content. The highest values for free- and long-chain acylcarnitines and the lowest value for total lipid content were recorded in the seedlings treated with cold plus carnitine. On the other hand, carnitine with and without cold stress significantly upregulated the expression level of citrate synthase, which is responsible for catalysing the first reaction of the citric acid cycle, and cytochrome oxidase, which is the membrane-bound terminal enzyme in the electron transfer chain, as well as lipase. All these results revealed that on the one hand, carnitine enhanced transport of fatty acids into mitochondria by increasing the activities of lipase and carnitine acyltransferases, and, on the other hand, stimulated mitochondrial respiration in the leaves of maize seedlings grown under normal and cold conditions.


Assuntos
Transporte Biológico/fisiologia , Carnitina/metabolismo , Ácidos Graxos/metabolismo , Mitocôndrias/metabolismo , Zea mays/metabolismo , Animais , Carnitina/análogos & derivados , Carnitina O-Palmitoiltransferase/metabolismo , Citrato (si)-Sintase/metabolismo , Temperatura Baixa , Resposta ao Choque Frio/fisiologia , Criopreservação/métodos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Lauratos/metabolismo , Oxirredução , Plântula/crescimento & desenvolvimento , Plântula/metabolismo
11.
Nagoya J Med Sci ; 81(3): 477-487, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31579338

RESUMO

Treatment of cancer patients undergoing chemotherapy with L-carnitine (LC) supplementation is becoming increasingly popular in the clinic. The present study aimed to examine the possible effects of polymorphisms in CPT1B and CPT2 (CPT1B G320D, S427C, c.282-18 C>T, and p.E531K, and CPT2 V368I) on the plasma concentration of carnitine in humans. The subjects were the 218 participants of the Iga Cohort Study. Differences in plasma-free carnitine levels by genotype were examined. Genotyping was conducted by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). The plasma carnitine levels were significantly higher in males (P<0.001; Student's t-test), and there was no significant difference in plasma carnitine levels between the age groups (P=0.202; ANOVA). One-way ANOVA revealed the plasma levels of carnitine were neither significantly different by CPT1B G320D, S427C, c.282-18 C>T, or p.E531K, nor by CPT2 V368I genotypes (P=0.133, P=0.538, P=0.636, P=0.509, and P=0.398, respectively). When analysis of covariance (ANCOVA) adjusted for age and sex was applied, the plasma levels of carnitine were not statistically significantly different according to these genotypes (P=0.299, P=0.715, P=0.980, P=0.851, and P=0.674, respectively). The present study did not identify any statistically significant differences in plasma carnitine levels between subjects with different CPT1 and CPT2 genotypes, suggesting that there may be no need to tailor treatments to patients' genotypes when determining the dose/amount of LC to be administered to cancer patients undergoing palliative care.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina/sangue , Neoplasias/genética , Polimorfismo Genético/genética , Genótipo , Humanos , Neoplasias/metabolismo
12.
Lipids Health Dis ; 18(1): 179, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639005

RESUMO

BACKGROUND: Ceramide plays pathogenic roles in nonalcoholic fatty liver disease (NAFLD) via multiple mechanisms, and as such inhibition of ceramide de novo synthesis in the liver may be of therapeutically beneficial in patients with NAFLD. In this study, we aimed to explore whether inhibition of ceramide signaling by myriocin is beneficial in animal model of NAFLD via regulating autophagy. METHODS: Sprague Dawley rats were randomly divided into three groups: standard chow (n = 10), high-fat diet (HFD) (n = 10) or HFD combined with oral administration of myriocin (0.3 mg/kg on alternate days for 8 weeks) (n = 10). Liver histology and autophagy function were measured. HepG2 cells were incubated with fatty acid with or without myriocin treatment. Lipid accumulation and autophagy markers in the HepG2 cells were analyzed. Serum ceramide changes were studied in 104 subjects consisting healthy adults, liver biopsy-proven patients with NAFLD and liver biopsy-proven patients with chronic hepatitis B (CHB). RESULTS: Myriocin reversed the elevated body weight and serum transaminases and alleviated dyslipidemia in HFD fed rats. Myriocin treatment significantly attenuated liver pathology including steatosis, lobular inflammation and ballooning. By qPCR analysis, it was revealed that myriocin corrected the expression pattern of fatty acid metabolism associated genes including Fabp1, Pparα, Cpt-1α and Acox-2. Further, myriocin also restored the impaired hepatic autophagy function in rats with HFD-induced NASH, and this has been verified in HepG2 cells. Among the sphingolipid species that we screened in lipidomic profiles, significantly increased ceramide was observed in NASH patients as compared to the controls and non-NASH patients, regardless of whether or not they have active CHB. CONCLUSIONS: Ceramide may play an important regulatory role in the autophagy function in the pathogenesis of NASH. Hence, blockade of ceramide signaling by myriocin may be of therapeutically beneficial in NASH. TRIAL REGISTRATION: Registration ID: ChiCTR-DDT-13003983 . Data of registration: 13 May, 2013, retrospectively registered.


Assuntos
Autofagia/efeitos dos fármacos , Ceramidas/metabolismo , Dislipidemias/tratamento farmacológico , Ácidos Graxos Monoinsaturados/farmacologia , Hipolipemiantes/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Animais , Autofagia/genética , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Estudos de Casos e Controles , Ceramidas/antagonistas & inibidores , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/etiologia , Dislipidemias/genética , Dislipidemias/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatite B Crônica/genética , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácido Oleico/antagonistas & inibidores , Ácido Oleico/farmacologia , Oxirredutases/genética , Oxirredutases/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Ácido Palmítico/antagonistas & inibidores , Ácido Palmítico/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
13.
Int J Oncol ; 55(5): 1125-1136, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485672

RESUMO

Previous studies revealed that the long non­coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) exhibits abnormal expression in numerous cancer types, including breast cancer (BC); however, the regulatory mechanism of NEAT1 in BC remains unclear. In the present study, the effect of NEAT1 on the progression of BC and its regulation mechanism was investigated. The expression levels of NEAT1 and microRNA­107 (miR­107) in BC cells were analyzed using the reverse transcription­quantitative polymerase chain reaction (RT­qPCR). NEAT1 was knocked down in BC cells, and mimics­miR­107 or inhibitor­miR­107 were transfected into BC cells. Subsequently, cell proliferation, invasion and migration, apoptosis and cell cycle distribution were determined. The regulatory mechanism of NEAT1, miR­107 and carnitine palmitoyltransferase­1 (CPT1A) was analyzed using a luciferase reporter assay system, western blotting and RT­qPCR. NEAT1 expression was increased in BC cells, whereas miR­107 expression was decreased, compared with normal mammary gland cells. NEAT1 promoted the progression of BC cells through inhibiting apoptosis­associated genes and promoting cell cycle­ and invasion­associated gene expression, whereas miR­107 served the opposite function. Furthermore, NEAT1 promoted the expression of CPT1A, which was mediated by miR­107. The results of the present study indicate that NEAT1 promotes the expression of CPT1A by inhibiting miR­107 to improve the progression of BC cells; therefore, NEAT1 is a potential therapeutic target of BC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carnitina O-Palmitoiltransferase/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carnitina O-Palmitoiltransferase/genética , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Humanos , Metástase Linfática , Células Tumorais Cultivadas
14.
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
15.
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
16.
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
17.
Clin Immunol ; 207: 58-67, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279855

RESUMO

To determine whether aging affects the ability of T cells to undergo metabolic reprogramming upon activation, we compared CD4 T cell responses after polyclonal in vitro stimulation. Compared to younger adults, CD4 memory T cells from healthy older individuals exhibited a higher upregulation of oxidative phosphorylation with increased production of reactive oxygen species and intracellular and secreted ATP. Increased ATP secretion led to increased purinergic signaling and P2X7-dependent increases in cytoplasmic calcium. The increased mitochondrial activity was not due to a difference in activation-induced mitochondrial biogenesis. Expression of carnitine palmitoyl transferase 1 was higher, conversely that of fatty acid synthase was reduced in older T cells, resulting in increased fatty acid oxidation, while depleting intracellular lipid stores. The aged CD4 memory T cells therefore maintain a more catabolic state in lipid metabolism, while their ability to upregulate glycolysis upon activation is preserved.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Reprogramação Celular/fisiologia , Adulto , Idoso , Envelhecimento , Linfócitos T CD4-Positivos/imunologia , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Mitocôndrias/metabolismo , Consumo de Oxigênio
18.
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
19.
Aquat Toxicol ; 213: 105220, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202166

RESUMO

Tamoxifen (TAM) is an antiestrogenic agent and can enter the aquatic environment in wastewater. It has been reported that TAM can induce hepatic steatosis in vertebrates, however, the effects of TAM exposure on lipid metabolism of hepatopancreas in crustaceans remains unclear. In this study, four TAM concentrations (0, 6.7, 13.4 and 20 µg g-1 crab body weight) were injected into the swimming-leg of swimming crabs Portunus trituberculatus, as a means of evaluating the effects of TAM on the expression levels of lipid metabolism-related genes, lipid composition, and hepatopancreas histology. The results showed that the mRNA levels of three lipogenic related genes (diacylglycerol acyltransferase 1 (DGAT1), acetyl-CoA carboxylase (ACC) and fatty acyl desaturase (FAD)) decreased significantly in the 6.7 µg g-1 and 20 µg g-1 TAM treatments compare to the control. The mRNA levels of fatty acid synthase (FAS) decreased significantly in a dose-dependent manner as TAM concentration increased. The mRNA levels of two lipid catabolism-related genes (acyl-CoA oxidase (ACOX) and fatty acid transport protein (FATP)) were down-regulated among the three TAM treatments, while the enzyme activity and mRNA level of carnitine palmitoyltransferase I (CPT-I) was up-regulated by TAM treatments. Compared to the control, the lowest levels of total lipids and phospholipids were detected in the 6.7 µg g-1 TAM treatment, while the 20 µg g-1 TAM treatment had the lowest free fatty acids concentration. The 6.7 µg g-1 TAM treatment had the lowest percentages of 16:1n-7, 18:1n-9, 18:1n-7 and total monounsaturated fatty acids (∑MUFA), whilst simultaneously recording the highest percentages of 18:2n-6 and 20:2n-6 in this treatment. Moreover, histological observations indicated that TAM caused the walls of the hepatopancreatic tubules to become brittle, with a concurrent increase in the number of blister-like cells. These results suggest that TAM damages the hepatopancreas and leads to a reduction in hepatopancreatic lipid deposition in P. trituberculatus.


Assuntos
Braquiúros/metabolismo , Hepatopâncreas/metabolismo , Hepatopâncreas/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Natação , Tamoxifeno/toxicidade , Animais , Braquiúros/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Feminino , Hepatopâncreas/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Oxirredução , Poluentes Químicos da Água/toxicidade
20.
J Biol Chem ; 294(31): 11944-11951, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31209109

RESUMO

Insulin-like growth factor 2 mRNA-binding proteins 1-3 (IGF2BP1-3, also known as IMP1-3) contribute to the regulation of RNAs in a transcriptome-specific context. Global deletion of the mRNA-binding protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2 or IMP2) in mice causes resistance to obesity and fatty liver induced by a high-fat diet (HFD), whereas liver-specific IMP2 overexpression results in steatosis. To better understand the role of IMP2 in hepatic triglyceride metabolism, here we crossed mice expressing albumin-Cre with mice bearing a floxed Imp2 gene to generate hepatocyte-specific IMP2 knockout (LIMP2 KO) mice. Unexpectedly, the livers of LIMP2 KO mice fed an HFD accumulated more triglyceride. Although hepatocyte-specific IMP2 deletion did not alter lipogenic gene expression, it substantially decreased the levels of the IMP2 client mRNAs encoding carnitine palmitoyltransferase 1A (CPT1A) and peroxisome proliferator-activated receptor α (PPARα). This decrease was associated with their more rapid turnover and accompanied by significantly diminished rates of palmitate oxidation by isolated hepatocytes and liver mitochondria. HFD-fed control and LIMP2 KO mice maintained a similar glucose tolerance and insulin sensitivity up to 6 months; however, by 6 months, blood glucose and serum triglycerides in LIMP2 KO mice were modestly elevated but without evidence of liver damage. In conclusion, hepatocyte-specific IMP2 deficiency promotes modest diet-induced fatty liver by impairing fatty acid oxidation through increased degradation of the IMP2 client mRNAs PPARα and CPT1A This finding indicates that the previously observed marked protection against fatty liver conferred by global IMP2 deficiency in mice is entirely due to their reduced adiposity.


Assuntos
Ácidos Graxos/metabolismo , Fígado/metabolismo , Proteínas de Ligação a RNA/genética , Triglicerídeos/metabolismo , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular , Dieta Hiperlipídica , Teste de Tolerância a Glucose , Hipertrigliceridemia/etiologia , Peroxidação de Lipídeos , Masculino , Camundongos , Camundongos Knockout , PPAR alfa/genética , PPAR alfa/metabolismo , Palmitatos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Triglicerídeos/sangue
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