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1.
Life Sci ; 272: 119243, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607157

RESUMO

High fat consumption leads to reactive oxygen species (ROS) which is associated with age-progressive neurological disorders. Cu/Zn superoxide dismutase (SOD1) is a critical enzyme against ROS. However, the relationship between SOD1 and the high-fat-induced ROS and neurodegeneration is poorly known. Here we showed that, upon treatment with a saturated fatty acid palmitic acid (PA), the SOD1 activity was decreased in mouse neuronal HT-22 cell line accompanied by elevation of ROS, but not in mouse microglial BV-2 cell line. We further showed that PA decreased the levels of copper chaperone for SOD1 (CCS) in HT-22 cells, which promoted the nuclear import of SOD1 and decreased its activity. We demonstrated that the reduction of CCS is involved in the PA-induced decrease of SOD1 activity and elevation of ROS. In addition, compared with the adult mice fed with a standard diet, the high-fat-diet adult mice presented an increase of plasma free fatty acids, reduction of hippocampal SOD1 activity and CCS, mitochondrial degeneration and long-term memory decline. Taken together, our findings suggest that the high-fat-induced lower CCS level is essential for SOD1 suppression which may be associated with neurodegeneration and cognitive decline.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Chaperonas Moleculares/metabolismo , Superóxido Dismutase-1/metabolismo , Animais , Linhagem Celular , China , Cobre/metabolismo , Masculino , Memória , Transtornos da Memória , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/fisiologia
2.
Proc Natl Acad Sci U S A ; 118(2)2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33372146

RESUMO

Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.


Assuntos
Lipase/metabolismo , Esterol Esterase/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Ésteres/química , Ácidos Graxos/metabolismo , Feminino , Células HEK293 , Humanos , Lipólise/fisiologia , Metabolismo/fisiologia , Camundongos , Camundongos Knockout , Ácido Palmítico/metabolismo , Ácidos Esteáricos/metabolismo , Triglicerídeos/metabolismo
3.
Life Sci ; 259: 118391, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32891610

RESUMO

AIMS: Dyslipidemia-associated diabetic retinopathy is featured by macular edema and retinal angiogenesis. This study investigated the in vitro lipotoxicity of free fatty acids and their modulatory roles in regulation of autophagy and angiogenic factor production in cultured human retinal pigment epithelium (RPE) ARPE-19 cells. MAIN METHODS: ARPE-19 cells were exposed to monounsaturated oleic acid (OA), saturated palmitic acid (PA), or both. Cell viability, cell cycle distribution, migration, and autophagy of the treated cells were monitored. Angiogenic factor production was determined by RT-qPCR and ELISA. KEY FINDINGS: OA, but not PA, at doses higher than 500 µM significantly induced cytostasis and lipotoxicity in ARPE-19 cells. OA exposure not only markedly enhanced autophagy flux, but also enhanced cell migration, while PA suppressed motility of RPE cells. Meanwhile, OA stimulated de novo synthesis of angiogenic factors including VEGF and bFGF in ARPE-19 cells. Mechanistically, OA treatment stimulated not only AMPK/mTOR/p70S6K signaling, but also induced hyperphosphorylation of MAPK pathway mediators, including ERK, JNK and p38 MAPK, as well as NF-κB activation. Kinase inhibition assays showed that blockade of PI3K/Akt, MAPK and NF-κB pathways prevented the OA-upregulated VEGF transcription and its peptide release. Comparatively, only NF-κB inhibition significantly suppressed bFGF peptide release from ARPE-19 cells. SIGNIFICANCE: Out findings support the OA-exhibited cytostasis, autophagy modulation and angiogenic factor production in RPE cells. This study sheds light on the interrelationship between metabolic disorder and retinopathy and provides molecular strategies for preventing and treating choroidal neovascularization in diabetic retinopathy.


Assuntos
Indutores da Angiogênese/metabolismo , Autofagia , Ácido Oleico/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Western Blotting , Movimento Celular , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Sistema de Sinalização das MAP Quinases , Ácido Palmítico/metabolismo , Epitélio Pigmentado da Retina/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
4.
PLoS One ; 15(5): e0233180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437392

RESUMO

Lipoprotein lipase (LPL) is upregulated in atherosclerotic lesions and it may promote the progression of atherosclerosis, but the mechanisms behind this process are not completely understood. We previously showed that the phosphorylation of Akt within THP-1 macrophages is increased in response to the lipid hydrolysis products generated by LPL from total lipoproteins. Notably, the free fatty acid (FFA) component was responsible for this effect. In the present study, we aimed to reveal more detail as to how the FFA component may affect Akt signalling. We show that the phosphorylation of Akt within THP-1 macrophages increases with total FFA concentration and that phosphorylation is elevated up to 18 hours. We further show that specifically the palmitoleate component of the total FFA affects Akt phosphorylation. This is tied with changes to the levels of select molecular species of phosphoinositides. We further show that the total FFA component, and specifically palmitoleate, reduces apolipoprotein A-I-mediated cholesterol efflux, and that the reduction can be reversed in the presence of the Akt inhibitor MK-2206. Overall, our data support a negative role for the FFA component of lipoprotein hydrolysis products generated by LPL, by impairing macrophage cholesterol efflux via Akt activation.


Assuntos
Colesterol/metabolismo , Macrófagos/metabolismo , Ácido Palmítico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apolipoproteína A-I/metabolismo , Ativação Enzimática/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Lipase Lipoproteica/metabolismo , Macrófagos/citologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Células THP-1
5.
Nucleic Acids Res ; 48(11): 5967-5985, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32406921

RESUMO

During infection of a host, Pseudomonas aeruginosa orchestrates global gene expression to adapt to the host environment and counter the immune attacks. P. aeruginosa harbours hundreds of regulatory genes that play essential roles in controlling gene expression. However, their contributions to the bacterial pathogenesis remain largely unknown. In this study, we analysed the transcriptomic profile of P. aeruginosa cells isolated from lungs of infected mice and examined the roles of upregulated regulatory genes in bacterial virulence. Mutation of a novel regulatory gene pvrA (PA2957) attenuated the bacterial virulence in an acute pneumonia model. Chromatin immunoprecipitation (ChIP)-Seq and genetic analyses revealed that PvrA directly regulates genes involved in phosphatidylcholine utilization and fatty acid catabolism. Mutation of the pvrA resulted in defective bacterial growth when phosphatidylcholine or palmitic acid was used as the sole carbon source. We further demonstrated that palmitoyl coenzyme A is a ligand for the PvrA, enhancing the binding affinity of PvrA to its target promoters. An arginine residue at position 136 was found to be essential for PvrA to bind palmitoyl coenzyme A. Overall, our results revealed a novel regulatory pathway that controls genes involved in phosphatidylcholine and fatty acid utilization and contributes to the bacterial virulence.


Assuntos
Proteínas de Bactérias/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Genes Bacterianos/genética , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidade , Animais , Arginina/metabolismo , Sequência de Bases , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Ligantes , Camundongos , Modelos Moleculares , Mutação , Ácido Palmítico/metabolismo , Palmitoil Coenzima A/metabolismo , Fosfatidilcolinas/metabolismo , Pneumonia Bacteriana/microbiologia , Regiões Promotoras Genéticas , Pseudomonas aeruginosa/genética , Transcriptoma , Virulência/genética
6.
Am J Physiol Endocrinol Metab ; 318(6): E995-E1003, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315213

RESUMO

Glucocorticoids (GCs) play critical roles in adipose tissue metabolism. Here, we compare in a mouse model the effects of chronic glucocorticoid excess and diet-induced obesity on white adipose tissue mass and distribution, by focusing on visceral adipose tissue (VAT) fatty acid composition changes, the role of de novo lipogenesis (DNL) and the inflammatory state. We used a noninvasive mouse model of hypercortisolism to compare GC-induced effects on adipose tissue with diet-induced obesity [high-fat diet (HFD) 45%] and control mice after 10 wk of treatment. Subcutaneous adipose tissue (SAT) and VAT mass and distribution were measured by nuclear magnetic resonance imaging (NMRI). Fatty acid composition in VAT was analyzed by NMR spectroscopy and gas chromatography. Gene expression of key enzymes involved in DNL was analyzed in liver and VAT. Macrophage infiltration markers and proinflammatory cytokines were measured by gene expression in VAT. HFD or GC treatment induced similar fat mass expansion with comparable distribution between SAT and VAT depots. However, in VAT, GCs induce DNL, higher palmitic acid (PA), macrophage infiltration, and proinflammatory cytokine levels, accompanied by systemic nonesterified fatty acid (NEFA) elevation, hyperinsulinemia, and higher homeostatic model assessment for insulin resistance (HOMA-IR) levels compared with diet-induced obesity. Thus, chronic hypercortisolism induces DNL and fatty acid composition changes toward increased SFA and reduced polyunsaturated fatty acid (PUFA) levels in VAT, promoting macrophage recruitment and proinflammatory cytokines, suggesting a worse cardiometabolic profile even compared with HFD mice.


Assuntos
Síndrome de Cushing/metabolismo , Citocinas/imunologia , Ácidos Graxos não Esterificados/metabolismo , Ácidos Graxos Insaturados/metabolismo , Inflamação/imunologia , Gordura Intra-Abdominal/metabolismo , Lipogênese , Macrófagos/imunologia , Animais , Corticosterona/farmacologia , Síndrome de Cushing/imunologia , Citocinas/efeitos dos fármacos , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Insulina/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/imunologia , Macrófagos/efeitos dos fármacos , Imageamento por Ressonância Magnética , Camundongos , Obesidade/imunologia , Obesidade/metabolismo , Ácido Palmítico/metabolismo
7.
PLoS One ; 15(4): e0232164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32330189

RESUMO

Maize (Zea mays L) is one of main nutrients sources for humans and animals worldwide. In Africa, storage of maize ensures food resources availability throughout the year. However, it often suffers losses exceeding 20% due to insects such as the larger grain borer, Prostephanus truncatus (Horn) (Coleoptera; Bostrichidae), major pest of stored maize in the tropical countries. This study aims to select resistant varieties to reduce maize storage losses and explain the physicochemical parameters role in grains susceptibility. In the first study, maize grains were artificially infested under no-choice method with insects. Susceptibility parameters such as weight loss, grain damage, number of emerged insects, median development time and susceptibility index varied significantly through maize varieties. Dobie susceptibility index (SI) was assessed as a major indicator of resistance. The most resistant varieties were Early-Thaï, DMR-ES and Tzee-Yellow. Conversely, Synth-9243, Obatampa and Synth-C varieties were susceptible. SWAN, Across-Pool and Tzee-White were classified as moderately resistant varieties. The insect reproductive potential was significantly different in the nine maize varieties and Early-Thaï, DMR-ES and Tzee-Yellow varieties were the least favourable host. To assess the relationship between grains physicochemical characteristics and varietal susceptibility, moisture, total phenolics, palmitic acid, proteins, amylose, density and grain hardness were evaluated according to standardized methods. Palmitic acid, SI, insects emerged and grain damage were significantly and positively correlated with each other, and negatively correlated with grains hardness, phenolics and amylose contents. Maize susceptibility index was significantly and negatively correlated to amylose, and phenolics contents and positively correlated to palmitic acid content. This study identified three resistant maize varieties to P. tuncatus and revealed that the major factors involved in this resistance were hardness, phenolic and amylose contents of grains.


Assuntos
Besouros/patogenicidade , Zea mays/crescimento & desenvolvimento , Zea mays/parasitologia , África , Amilose/metabolismo , Animais , Grão Comestível/crescimento & desenvolvimento , Grão Comestível/metabolismo , Ácido Palmítico/metabolismo , Fenol/metabolismo , Estruturas Vegetais/crescimento & desenvolvimento , Estruturas Vegetais/metabolismo , Estruturas Vegetais/parasitologia , Zea mays/metabolismo
8.
J Leukoc Biol ; 108(1): 105-112, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32272499

RESUMO

The Charcot-Leyden crystal protein (CLC-P), a constituent of human and not mouse eosinophils, is one of the most abundant proteins within human eosinophils. It has a propensity to form crystalline structures, Charcot-Leyden crystals, which are hallmarks in their distinctive extracellular crystalline forms as markers of eosinophilic inflammation. The functions of CLC-P within eosinophils have been uncertain. Although the action of CLC-P as a lysophospholipase has been questioned, assays of chromatographically purified CLC-P and crystal-derived CLC-P as well as studies of transfected recombinant CLC-P have consistently documented that CLC-P endogenously expresses lysophospholipase activity, releasing free palmitate from substrate lysopalmitoylphosphatidylcholine. Rather than acting solely as a hydrolytic enzyme to release palmitate from a lysolipid substrate, some other lysophospholipases function more dominantly as acyl-protein thioesterases (APTs), enzymes that catalyze the removal of thioester-linked, long chain fatty acids, such as palmitate, from cysteine residues of proteins. As such APTs participate in palmitoylation, a post-translational modification that can affect membrane localization, vesicular transport, and secretion. CLC-P has attributes of an APT. Thus, whereas CLC-P expresses inherent lysophospholipase activity, like some other lysophospholipase enzymes, it likely also functions in regulating the dynamic palmitoylation cycle, including, given its dominant subplasmalemmal location, at the human eosinophil's plasma membrane.


Assuntos
Glicoproteínas/metabolismo , Lisofosfolipase/metabolismo , Eosinófilos/enzimologia , Glicoproteínas/química , Humanos , Lisofosfolipase/química , Ácido Palmítico/metabolismo
9.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165763, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32169502

RESUMO

Excess circulating fatty acids contribute to endothelial dysfunction that subsequently aggravates the metabolic conditions such as fatty liver diseases. However, the exact mechanism of this event is not fully understood, and the investigation on the effect of a direct exposure to fatty acids together with their subsequent fate is of interest. In this work we employed a chemically specific and label-free techniques such as Raman and CARS microscopies, to investigate the process of lipid droplets (LDs) formation in endothelial cells and hepatocytes after exposure to oleic and palmitic acid. We aimed to observe the changes in the composition of LDs associated with metabolism and degradation of lipids. We were able to characterize the diversity in the formation of LDs in endothelium as compared to hepatocytes, as well as the differences in the formation of LDs and degradation manner with respect to the used fatty acid. Thus, for the first time the spectral characteristics of LDs formed in endothelial cells after incubation with oleic and palmitic acid is presented, including the time-dependent changes in their chemical composition.


Assuntos
Hepatócitos/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Endotélio/patologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Hepatócitos/efeitos dos fármacos , Humanos , Gotículas Lipídicas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Ácido Oleico/farmacologia , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Análise Espectral Raman
10.
J Agric Food Chem ; 68(14): 4215-4226, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32181656

RESUMO

Ginsenoside Rg2 has been previously reported to reduce glucose production and adipogenesis in adipose tissue. However, the effects of ginsenosides Rg2 on hepatic lipid metabolism remain vacant. In this study, we found that ginsenoside Rg2 treatment significantly attenuated oleic acid and palmitic acid (OA&PA)-induced intracellular lipid deposition and oxidative stress in mouse primary hepatocytes. C57BL/6J mice that are fed with a high-fat diet (HFD) and treated with ginsenosides Rg2 displayed decreased body weight, reversed hepatic steatosis, and improved glucose tolerance and insulin sensitivity. Ginsenoside Rg2 administration significantly ameliorated HFD-induced hepatic oxidative stress and apoptosis. Moreover, Ginsenoside Rg2 had a good affinity with Sirtuin1 (SIRT1) and regulated its expression in vivo and in vitro. Deficiency of SIRT1 eliminated the therapeutic effect of ginsenoside Rg2 on lipid accumulation and overproduction of reactive oxygen species (ROS) in OA&PA-induced mice primary hepatocytes. Ginsenoside Rg2 treatment failed to alter the lipid and glucose disorder in hepatic SIRT1 deficient mice feeding on HFD. SIRT1 deficiency dissolves the therapeutic effect of ginsenoside Rg2 on oxidative stress and hepatocyte apoptosis induced by HFD. In summary, ginsenoside Rg2 plays a therapeutic role in HFD-induced hepatosteatosis of mice by decreasing the lipogenesis process and improving antioxidant capacity in an SIRT1-dependent manner.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ginsenosídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Sirtuína 1/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Ácido Oleico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-32045699

RESUMO

Untargeted lipidomics is a powerful tool to discover new biomarkers and to understand the physiology and pathology of lipids. The use of stable isotopes as tracers to investigate the kinetics of lipids is another tool able to supply dynamic information on lipid synthesis and catabolism. Coupling the two methodology is then very appealing in the study of lipid metabolism. The main issue to face is to perform thousands of calculations in order to obtain kinetic parameters starting from the MS raw data. An automated computerized routine able to do accomplish such task is presented in this paper. We analyzed the lipid kinetics of palmitic acid (PA) in hepatoma liver cells cultured in vitro in which insulin resistance has been induced by high glucose supplementation. The deuterated palmitate tracer (d5PA) was administered as a bolus and the cells were harvested daily for 48 h. 5dPA was incorporated into 326 monoisotopic compounds and in 84 of their [M + 1] isotopologues detected by high resolution orbitrap MS. The differences between the kinetics curves showed that at least four long chain triglycerides (TG) species incorporated more PA in glucose treated cells, while phosphocholines, sphingomyelins, mono- and di-glycerides and ceramides (Cer) incorporated less tracer under glucose treatment. Nevertheless, Cer amount was increased by glucose treatment. In conclusion we developed an automated powerful algorithm able to model simultaneously hundreds of kinetic curves obtained in a cell culture spiked with a stable isotope tracer, and to analyze the difference between the two different cell models.


Assuntos
Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Lipidômica/métodos , Esfingolipídeos/metabolismo , Algoritmos , Meios de Cultura/metabolismo , Deutério , Ácidos Graxos não Esterificados/análise , Ácidos Graxos não Esterificados/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Glucose/metabolismo , Células Hep G2 , Humanos , Resistência à Insulina , Marcação por Isótopo/métodos , Cinética , Ácido Palmítico/análise , Ácido Palmítico/metabolismo , Software , Esfingolipídeos/análise , Fluxo de Trabalho
12.
J Dermatol Sci ; 97(2): 152-160, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32001116

RESUMO

BACKGROUND: Radiation-induced skin injury is a serious concern during radiotherapy and radiation accidents. Skin fat represents the dominant architectural component of the human skin. However, the interplay between skin fat and the progression of radiation-induced skin injury remains largely unexplored. OBJECTIVE: This study aims to elucidate the interplay between skin fat and the progression of radiation-induced skin injury. METHODS: SD rats were irradiated with an electron beam. mRNA profiles were determined by RNA-Seq. The skin lipid mass was monitored by magnetic resonance imaging (MRI) and lipid profiles were measured by liquid chromatography-mass spectrometry (LC-MS). Human mature adipocytes isolated from dermal and subcutaneous white adipose tissues (WATs) were co-cultured with human keratinocytes (HaCaT) and skin fibroblasts (WS1) in the transwell culture system. Cell migration ability was measured by migration assay. RESULTS: Radiation modulated cutaneous lipid metabolism by downregulating multiple pathways. Moreover, radiation decreased skin fat mass with altered lipid metabolite profiles. The rats fed with a high-fat diet showed resistance to radiogenic skin injury compared with that with a control diet, indicating that skin lipid plays a radioprotective role. Mature adipocytes promoted the migration but not the proliferation of co-cultured skin keratinocytes and fibroblasts. Palmitic acid, the most abundant fatty acid in skin tissues, facilitated the migration of WS1 cells. Moreover, fatty acid-binding protein 4 (FABP4) could be incorporated into skin cells and promote DNA damage repair in irradiated skin fibroblasts. CONCLUSION: Radiation induces cutaneous lipid remolding, and skin adipocytes confer a protective role against radiation-induced skin injury.


Assuntos
Adipócitos/fisiologia , Resistência à Doença/fisiologia , Lesões por Radiação/patologia , Reepitelização/fisiologia , Dermatopatias/patologia , Adipócitos/efeitos da radiação , Animais , Movimento Celular , Técnicas de Cocultura , Dano ao DNA/efeitos da radiação , Reparo do DNA , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/metabolismo , Fibroblastos , Humanos , Queratinócitos , Metabolismo dos Lipídeos/fisiologia , Metabolismo dos Lipídeos/efeitos da radiação , Ácido Palmítico/metabolismo , Cultura Primária de Células , RNA-Seq , Lesões por Radiação/etiologia , Ratos , Pele/metabolismo , Pele/patologia , Pele/efeitos da radiação , Dermatopatias/etiologia , Gordura Subcutânea/citologia , Gordura Subcutânea/efeitos da radiação
13.
World J Microbiol Biotechnol ; 36(1): 17, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31912247

RESUMO

In this study, the effects of limited and excess nitrate on biomass, lipid production, and fatty acid profile in Messastrum gracile SE-MC4 were determined. The expression of fatty acid desaturase genes, namely stearoyl-ACP desaturase (SAD), omega-6 fatty acid desaturase (ω-6 FAD), omega-3 fatty acid desaturase isoform 1 (ω-3 FADi1), and omega-3 fatty acid desaturase isoform 2 (ω-3 FADi2) was also assessed. It was found that nitrate limitation generally increased the total oil, α-linolenic acid (C18:3n3) and total polyunsaturated fatty acid (PUFA) contents in M. gracile. The reduction of nitrate concentration from 1.76 to 0.11 mM increased the total oil content significantly from 32.5 to 41.85% (dry weight). Palmitic (C16:0) and oleic (C18:1) acids as the predominant fatty acids in this microalgae constituted between 82 and 87% of the total oil content and were relatively consistent throughout all nitrate concentrations tested. The expression of SAD, ω-6 FAD, and ω-3 FADi2 genes increased under nitrate limitation, especially at 0.11 mM nitrate. The ω-3 FADi1 demonstrated a binary up-regulation pattern of expression under both nitrate-deficient (0.11 mM) and -excess (3.55 mM) conditions. Thus, findings from this study suggested that limited or excess nitrate could be used as part of a cultivation strategy to increase oil and PUFA content following media optimisation and more efficient culture methodology. Data obtained from the expression of desaturase genes would provide valuable insights into their roles under excess and limited nitrate conditions in M. gracile, potentially paving the way for future genetic modifications.


Assuntos
Ácidos Graxos Dessaturases/genética , Ácidos Graxos/análise , Microalgas/crescimento & desenvolvimento , Nitrogênio/metabolismo , Biomassa , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Insaturados/metabolismo , Regulação Enzimológica da Expressão Gênica , Metabolismo dos Lipídeos , Microalgas/genética , Microalgas/metabolismo , Ácido Oleico/metabolismo , Ácido Palmítico/metabolismo , Ácido alfa-Linoleico/metabolismo
14.
Int J Mol Sci ; 21(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979102

RESUMO

Maintaining an active fatty acid metabolism is important for renal growth, development, and health. We evaluated the effects of anaplerotic and ketogenic energy sources on fatty acid oxidation during stimulation with clofibrate, a pharmacologic peroxisome proliferator-activated receptor α (PPARα) agonist. Suckling newborn pigs (n = 72) were assigned into 8 dietary treatments following a 2 × 4 factorial design: ± clofibrate (0.35%) and diets containing 5% of either (1) glycerol-succinate (GlySuc), (2) tri-valerate (TriC5), (3) tri-hexanoate (TriC6), or (4) tri-2-methylpentanoate (Tri2MPA). Pigs were housed individually and fed the iso-caloric milk replacer diets for 5 d. Renal fatty acid oxidation was measured in vitro in fresh tissue homogenates using [1-14C]-labeled palmitic acid. The oxidation was 30% greater in pig received clofibrate and 25% greater (p < 0.05) in pigs fed the TriC6 diet compared to those fed diets with GlySuc, TriC5, and Tri2MPA. Addition of carnitine also stimulated the oxidation by twofold (p < 0.05). The effects of TriC6 and carnitine on palmitic acid oxidation were not altered by clofibrate stimulation. However, renal fatty acid composition was altered by clofibrate and Tri2MPA. In conclusion, modification of anaplerosis or ketogenesis via dietary substrates had no influence on in vitro renal palmitic acid oxidation induced by PPARα activation.


Assuntos
Ácidos Graxos/metabolismo , Corpos Cetônicos/metabolismo , Rim/metabolismo , Animais , Animais Recém-Nascidos , Carnitina/farmacologia , Clofibrato/farmacologia , Dieta , Rim/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Leite/metabolismo , Oxirredução/efeitos dos fármacos , PPAR alfa/metabolismo , Ácido Palmítico/metabolismo , Suínos
15.
Am J Physiol Endocrinol Metab ; 318(3): E430-E439, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961705

RESUMO

Chronic exposure to high concentrations of stearic acid (C18:0) can result in ß-cell dysfunction, leading to development of type 2 diabetes. However, the molecular mechanisms underlying the destructive effects of stearic acid on ß-cells remain largely unknown. In this study, we aimed to investigate the role of miR-297b-5p on stearic acid-induced ß-cell apoptosis. Differential expression of microRNAs (miRNAs) was assessed in a ß-TC6 cell line exposed to stearic acid, palmitic acid, or a normal culture medium by high-throughput sequencing. The apoptosis rate was measured by flow cytometry after miR-297b-5p mimic/inhibitor transfection, and large-tumor suppressor kinase 2 (LATS2) was identified as a target of miR-297b-5p using a luciferase activity assay. In vivo, C57BL/6 mice were fed with normal and high-stearic-acid diet, respectively. Mouse islets were used for similar identification of miR-297b-5p and Lats2 in ß-TC6 cell. We selected two differentially expressed miRNAs in stearic acid compared with those in the palmitic acid and control groups. miR-297b-5p expression was significantly lower in ß-TC6 cells and mouse islets in stearic acid than in control group. Upregulation of miR-297b-5p alleviated the stearic acid-induced cell apoptosis and reduction in insulin secretion by inhibiting Lats2 expression in vitro. Meanwhile, silencing Lats2 significantly reversed the stearic acid-stimulated ß-cell dysfunction in both ß-TC6 cells and islets. Our findings indicate a suppressive role for miR-297b-5p in stearic acid-induced ß-cell apoptosis, which may reveal a potential target for the treatment of ß-cell dysfunction in the pathogenesis of type 2 diabetes.


Assuntos
Apoptose/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/genética , Ácidos Esteáricos/farmacologia , Proteínas Supressoras de Tumor/genética , Animais , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/sangue , Citometria de Fluxo , Humanos , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido Palmítico/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L429-L441, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31850803

RESUMO

Insulin resistance and right ventricular (RV) dysfunction are associated with lipotoxicity in heritable forms of pulmonary arterial hypertension (PAH), commonly due to mutations in bone morphogenetic protein receptor type 2 (BMPR2). How BMPR2 dysfunction in cardiomyocytes alters glucose metabolism and the response of these cells to insulin are unknown. We hypothesized that BMPR2 mutation in cardiomyocytes alters glucose-supported mitochondrial respiration and impairs cellular responses to insulin, including glucose and lipid uptake. We performed metabolic assays, immunofluorescence and Western analysis, RNA profiling, and radioactive isotope uptake studies in H9c2 cardiomyocyte cell lines with and without patient-derived BMPR2 mutations (mutant cells), with and without insulin. Unlike control cells, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity as indicated by reduced mitochondrial respiration with increased mitochondrial superoxide production. These mutant cells show enhanced baseline phosphorylation of insulin-signaling protein as indicated by increased Akt, AMPK, and acetyl-CoA carboxylase phosphorylation that may negatively influence fatty acid oxidation and enhance lipid uptake, and are insulin insensitive. Furthermore, mutant cells demonstrate an increase in milk fat globule-EGF factor-8 protein (MFGE8), which influences the insulin-signaling pathway by phosphorylating AktSer473 via phosphatidylinositol 3-kinase and mammalian target of rapamycin. In conclusion, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity and fail to respond to glucose. These cells have enhanced baseline insulin-signaling pattern favoring insulin resistance with failure to augment this pattern in response to insulin. BMPR2 mutation possibly blunts glucose uptake and enhances lipid uptake in these cardiomyocytes. The MFGE8-driven signaling pathway may suggest a new mechanism underlying RV lipotoxicity in PAH.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Glucose/metabolismo , Homeostase , Insulina/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Animais , Antígenos de Superfície/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Antígenos CD36/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Resistência à Insulina , Camundongos , Proteínas do Leite/metabolismo , Mitocôndrias/metabolismo , Mutação/genética , Consumo de Oxigênio , Ácido Palmítico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ratos , Superóxidos/metabolismo , Serina-Treonina Quinases TOR/metabolismo
17.
J Clin Invest ; 130(3): 1453-1460, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31805015

RESUMO

BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.


Assuntos
Resistência à Insulina , Lipogênese , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Glicemia/metabolismo , Feminino , Humanos , Insulina/sangue , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Palmítico/metabolismo , Triglicerídeos/metabolismo
18.
Diabetes ; 69(3): 300-312, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31806624

RESUMO

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using 2H2O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of 13C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Glucose/metabolismo , Lipase/genética , Ácido Palmítico/metabolismo , Ácidos Esteáricos/metabolismo , Triglicerídeos/metabolismo , Animais , Isótopos de Carbono , Temperatura Baixa , Óxido de Deutério , Ácidos Graxos/metabolismo , Lipase/metabolismo , Lipogênese/genética , Lipólise , Metabolômica , Camundongos , Camundongos Knockout
19.
Cancer Immunol Immunother ; 69(1): 115-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31802182

RESUMO

Pro-inflammatory cytokines are crucial mediators of cancer development, representing potential targets for cancer therapy. The molecular mechanism of a vital pro-inflammatory cytokine, IL-17A, in cancer progression and its potential use in therapy through influencing fatty acid (FA) metabolism, especially FA uptake of cancer cells, remains unknown. In the present study, we used IL-17A and ovarian cancer (OvCa), a representative of both obesity-related and inflammation-related cancers, to explore the interactions among IL-17A, cancer cells and adipocytes (which can provide FAs). We found that in the presence of palmitic acid (PA), IL-17A could directly increase the cellular uptake of PA, leading to the proliferation of OvCa cells via the IL-17A/IL-17RA/p-STAT3/FABP4 axis rather than via CD36. Moreover, in vivo experiments using an orthotopic implantation model in IL-17A-deficient mice demonstrated that endogenous IL-17A could fuel OvCa growth and metastasis with increased expression of FABP4 and p-STAT3. Furthermore, analysis of clinical specimens supported the above findings. Our data not only provide useful insights into the clinical intervention of the growth and metastasis of the tumors (such as OvCa) that are prone to growth and metastasis in an adipocyte-rich microenvironment (ARM) but also provides new insights into the roles of IL-17A in tumor progression and immunomodulatory therapy of OvCa.


Assuntos
Adipócitos/imunologia , Interleucina-17/metabolismo , Neoplasias Ovarianas/imunologia , Ácido Palmítico/metabolismo , Adipócitos/metabolismo , Animais , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ovário/patologia , Fosforilação , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Microambiente Tumoral/imunologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-31740387

RESUMO

Adverse effects of aging can be delayed with life-style interventions. We examined how exercise training (ET) alone or combined with omega-3 polyunsaturated fatty acid (PUFA) affects serum and adipose tissue (AT) lipidome in older women. Fifty-five sedentary older women were included in the physical activity program and given either sunflower (Placebo) or wax esters-rich (Calanus) oil capsules for 4 months. Serum and subcutaneous abdominal AT samples were acquired while maximum rates of oxygen consumption (VO2 max), insulin sensitivity (hyperinsulinemic-euglycemic clamps) and comprehensive lipidome profiles were determined before and after the study. ET increased VO2 max in both groups. Lipidomics profiling revealed unusual serum triacylglycerols and phospholipids with ether-bound alkyls in the Calanus group, while ET generally induced shorter-chain triacylglycerols in AT, suggesting increased de novo lipogenesis. The latter was positively associated with whole-body insulin sensitivity. Unexpectedly, insulin-sensitizing lipokines from the family of branched palmitic acid esters of hydroxy stearic acid (PAHSAs) were elevated in both serum and AT after ET, while PAHSAs-containing triacylglycerols were detected in AT. ET stimulated beneficial changes in AT, including PAHSAs synthesis. Although the added value of omega-3 PUFA supplementation was not proven, our discovery can help understand the nature of the metabolic benefits of exercise.


Assuntos
Tecido Adiposo/metabolismo , Exercício Físico/fisiologia , Ácidos Graxos Ômega-3/administração & dosagem , Insulina/metabolismo , Síndrome Metabólica/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Terapia Combinada , Suplementos Nutricionais , Ésteres/metabolismo , Feminino , Humanos , Lipidômica , Lipogênese/fisiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Ácido Palmítico/metabolismo , Ácidos Esteáricos/metabolismo , Resultado do Tratamento
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