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1.
Nat Commun ; 12(1): 614, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504762

RESUMO

Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation from those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.


Assuntos
Isocitrato Desidrogenase/genética , Mutação/genética , Organelas/metabolismo , Fosfolipídeos/metabolismo , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Glioblastoma/patologia , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Humanos , Modelos Biológicos , Oligodendroglioma/patologia , Estearoil-CoA Dessaturase/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-32920140

RESUMO

A comprehensive molecular mechanistic role of lutein on adipogenesis is not well understood. The present study focused to evaluate the effect of lutein at the early and late phase of adipocyte differentiation in vitro using a 3T3-L1 cell model. The effect of purified carotenoid on the viability of normal and differentiated 3T3-L1 cells was analyzed by WST-1 assay. Oil Red O and Nile red staining were employed to observe lipid droplets in mature adipocytes. The effect of lutein on gene and protein expression of major transcription factors and adipogenic markers was analyzed by RT-PCR and western blotting, respectively. The role of lutein on mitotic clonal expansion was analyzed by flow cytometry. The results showed a significant reduction (p < 0.05) in the accumulation of lipid droplets in lutein-treated (5 µM) cells. Inhibition in lipid accumulation was associated with down-regulated expression of CEBP-α and PPAR-γ at gene and protein levels. Subsequently, lutein repressed gene expression of FAS, FABP4, and SCD1 in mature adipocytes. Interestingly, it blocks the protein expression of CEBP-α and PPAR-γ in the initial stages of adipocyte differentiation. This early-stage inhibition of adipocyte differentiation is linked with repressed phosphorylation AKT and ERK. Further, upregulated cyclin D and down-regulated CDK4 and CDK2 in lutein treated adipocytes enumerate its role in delaying the cell cycle progression at the G0/G1 phase. Our results emphasize that adipogenesis inhibitory efficacy of lutein is potentiated by halting early phase regulators of adipocyte differentiation, which strengthens the competency of lutein besides its inevitable presence in the human body.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diferenciação Celular/efeitos dos fármacos , Luteína/farmacologia , PPAR gama/genética , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Animais , Proteínas Estimuladoras de Ligação a CCAAT/antagonistas & inibidores , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Ciclina D/genética , Ciclina D/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Dexametasona/farmacologia , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação da Expressão Gênica , Camundongos , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/genética , Transdução de Sinais , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-33049404

RESUMO

A large body of research has demonstrated that human stearoyl-CoA desaturase 1 (SCD1), a universally expressed fatty acid Δ9-desaturase that converts saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA), is a central regulator of metabolic and signaling pathways involved in cell proliferation, differentiation, and survival. Unlike SCD1, stearoyl-CoA desaturase 5 (SCD5), a second SCD isoform found in a variety of vertebrates, including humans, has received considerably less attention but new information on the catalytic properties, regulation and biological functions of this enzyme has begun to emerge. This review will examine the new evidence that supports key metabolic and biological roles for SCD5, as well as the potential implication of this desaturase in the mechanisms of human diseases.


Assuntos
Fissura Palatina/genética , Ácidos Graxos Monoinsaturados/metabolismo , Ácidos Graxos/metabolismo , Neoplasias/genética , Doenças Neurodegenerativas/genética , Estearoil-CoA Dessaturase/genética , Sequência de Aminoácidos , Animais , Sobrevivência Celular , Fissura Palatina/enzimologia , Fissura Palatina/patologia , Regulação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Neoplasias/enzimologia , Neoplasias/patologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/patologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Estearoil-CoA Dessaturase/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-33075494

RESUMO

MicroRNA-221-3p (miR-221-3p) is associated with both metabolic diseases and cancers. However, its role in terminal adipocyte differentiation and lipid metabolism are uncharacterized. miR-221-3p or its inhibitor was transfected into differentiating or mature human adipocytes. Triglyceride (TG) content and adipogenic gene expression were monitored, global lipidome analysis was carried out, and mechanisms underlying the effects of miR-221-3p were investigated. Finally, cross-talk between miR-221-3p expressing adipocytes and MCF-7 breast carcinoma (BC) cells was studied, and miR-221-3p expression in tumor-proximal adipose biopsies from BC patients analyzed. miR-221-3p overexpression inhibited terminal differentiation of adipocytes, as judged from reduced TG storage and gene expression of the adipogenic markers SCD1, GLUT4, FAS, DGAT1/2, AP2, ATGL and AdipoQ, whereas the miR-221-3p inhibitor increased TG storage. Knockdown of the predicted miR-221-3p target, 14-3-3γ, had similar antiadipogenic effects as miR-221-3p overexpression, indicating it as a potential mediator of mir-221-3p function. Importantly, miR-221-3p overexpression inhibited de novo lipogenesis but increased the concentrations of ceramides and sphingomyelins, while reducing diacylglycerols, concomitant with suppression of sphingomyelin phosphodiesterase, ATP citrate lyase, and acid ceramidase. miR-221-3p expression was elevated in tumor proximal adipose tissue from patients with invasive BC. Conditioned medium of miR-221-3p overexpressing adipocytes stimulated the invasion and proliferation of BC cells, while medium of the BC cells enhanced miR-221-3p expression in adipocytes. Elevated miR-221-3p impairs adipocyte lipid storage and differentiation, and modifies their ceramide, sphingomyelin, and diacylglycerol content. These alterations are relevant for metabolic diseases but may also affect cancer progression.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Gotículas Lipídicas/metabolismo , MicroRNAs/genética , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Adipócitos/patologia , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Diferenciação Celular , Proliferação de Células , Ceramidas/classificação , Ceramidas/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Lipase/genética , Lipase/metabolismo , Células MCF-7 , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transdução de Sinais , Esfingolipídeos/classificação , Esfingolipídeos/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/classificação , Triglicerídeos/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
5.
Nat Commun ; 11(1): 4830, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973134

RESUMO

Non-invasively probing metabolites within single live cells is highly desired but challenging. Here we utilize Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. Each cell line represents a different characteristic level of cancer cell de-differentiation. First, with Raman spectroscopy, followed by stimulated Raman scattering (SRS) microscopy and transcriptomics analysis, we identify the fatty acid synthesis pathway as a druggable susceptibility for differentiated melanocytic cells. We then utilize hyperspectral-SRS imaging of intracellular lipid droplets to identify a previously unknown susceptibility of lipid mono-unsaturation within de-differentiated mesenchymal cells with innate resistance to BRAF inhibition. Drugging this target leads to cellular apoptosis accompanied by the formation of phase-separated intracellular membrane domains. The integration of subcellular Raman spectro-microscopy with lipidomics and transcriptomics suggests possible lipid regulatory mechanisms underlying this pharmacological treatment. Our method should provide a general approach in spatially-resolved single cell metabolomics studies.


Assuntos
Melanoma/metabolismo , Metabolômica/métodos , Microscopia/métodos , Análise Espectral Raman/métodos , Apoptose , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Humanos , Gotículas Lipídicas , Metabolismo dos Lipídeos , Lipidômica , Lipídeos , Ácido Oleico , Estearoil-CoA Dessaturase/metabolismo , Transcriptoma
6.
DNA Cell Biol ; 39(9): 1573-1582, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32678986

RESUMO

Many immune cells participate in the pathogenesis of ulcerative colitis (UC), and fatty acid metabolism (FAM) is reported to supporting their cell-specific functions and proliferation, but the underlying mechanism is unclear. This study aimed to investigate the relationship between FAM and inflammation in colon tissues and identify potential therapeutic targets for regulating immune response. A total of 870 different expression genes (DEGs), 304 immunity-related DEGs, and 11 FAM-related DEGs were obtained, gene ontology analysis results showed that immune DEGs were significantly enriched in neutrophil migration, positive regulation of T cell activation. Fifteen types of immune cells were identified in inflamed colon tissues. Five FAM-related DEGs (ACOX1, ACSL4, ELOVL5, FADS2, and SCD) were highly correlated with immunity-related DEGs, and ACSL4, ELOVL5, and FADS2 were significantly upregulated in immune cells, while SCD is downregulated. Five FAM-related DEGs were highly correlated with immune cells. The study promotes the understanding of the pathogenesis of FAM in UC immune cells.


Assuntos
Colite Ulcerativa/genética , Ácidos Graxos/metabolismo , Redes Reguladoras de Genes , Transcriptoma , Acil-CoA Oxidase/genética , Acil-CoA Oxidase/metabolismo , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Colite Ulcerativa/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Linfócitos/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
7.
Anat Sci Int ; 95(4): 489-497, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32361815

RESUMO

Steatohepatitis, fibrosis, and cirrhosis are common pathological features in the progression of hepatic steatosis. In the current work, we investigated the effect of germinated barely on the structure and function of the liver and its regulatory mechanism on SDC1 gene expression in a steatohepatitis rat model. Forty-eight adult male white Wistar rats were randomly divided into four groups: Group I, control; Group II, rats fed a germinated barley diet; Group III, rats fed a high-fat diet (HFD); and Group IV, rats fed both germinated barley (GB) and a high-fat diet for 14 weeks. Biochemical, histopathological, immunohistochemical, and morphometric studies, as well as qRT-PCR, were used to analyze the effect of germinated barley on steatohepatitis. The rats in Group IV had a lower liver index percentage and improved altered lipid profile and liver function tests compared to those in Group III. Supplementation of GB with a HFD ameliorated the histopathological features in the livers of rats fed a HFD, decreased the percentage of CD68-positive macrophages, and lowered the upregulated expression of SDC1. Supplementation of a HFD with GB prohibited the deterioration of liver function, lipid profile, and alteration of liver structure; it also decreased the associated hepatic inflammation and downregulated SDC1 in liver tissue.


Assuntos
Dieta , Regulação para Baixo/efeitos dos fármacos , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Expressão Gênica , Germinação , Hordeum , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Animais , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo dos Lipídeos , Fígado/metabolismo , Macrófagos , Masculino , Ratos Wistar , Sindecana-1
8.
Am J Chin Med ; 48(3): 579-595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329643

RESUMO

Corosolic acid (CA) is the main active component of Lagetstroemia speciosa and has been known to serve as several different pharmacological effects, such as antidiabetic, anti-oxidant, and anticancer effects. In this study, effects of CA on the hepatic lipid accumulation were examined using HepG2 cells and tyloxapol (TY)-induced hyperlipidemia ICR mice. CA significantly inhibited hepatic lipid accumulation via inhibition of SREBPs, and its target genes FAS, SCD1, and HMGCR transcription in HepG2 cells. These effects were mediated through activation of AMPK, and these effects were all abolished in the presence of compound C (CC, an AMPK inhibitor). In addition, CA clearly alleviated serum ALT, AST, TG, TC, low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDL-C) levels, and obviously attenuated TY-induced liver steatosis and inflammation. Moreover, CA significantly upregulated AMPK, ACC, LKB1 phosphorylation, and significantly inhibited lipin1, SREBPs, TNF-α, F4/80, caspase-1 expression, NF-κB translocation, and MAPK activation in TY-induced hyperlipidemia mice. Our results suggest that CA is a potent antihyperlipidemia and antihepatic steatosis agent and the mechanism involved both lipogenesis and cholesterol synthesis and inflammation response inhibition via AMPK/SREBPs and NF-κB/MAPK signaling pathways.


Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Fitoterapia , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Animais , Células Hep G2 , Humanos , Inflamação , Lagerstroemia/química , Camundongos Endogâmicos ICR , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/metabolismo
9.
Int J Mol Sci ; 21(7)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32244800

RESUMO

Fat deposition, which influences pork production, meat quality and growth efficiency, is an economically important trait in pigs. Numerous studies have demonstrated that stearoyl-CoA desaturase (SCD), a key enzyme that catalyzes the conversion of saturated fatty acids into monounsaturated fatty acids, is associated with fatty acid composition in pigs. As SCD was observed to be significantly induced in 3T3-L1 preadipocytes differentiation, we hypothesized that it plays a role in porcine adipocyte differentiation and fat deposition. In this study, we revealed that SCD is highly expressed in adipose tissues from seven-day-old piglets, compared to its expression in tissues from four-month-old adult pigs. Moreover, we found that SCD and lipogenesis-related genes were induced significantly in differentiated porcine adipocytes. Using CRISPR/Cas9 technology, we generated SCD-/- porcine embryonic fibroblasts (PEFs) and found that the loss of SCD led to dramatically decreased transdifferentiation efficiency, as evidenced by the decreased expression of known lipid synthesis-related genes, lower levels of oil red O staining and significantly lower levels of triglyceride content. Our study demonstrates the critical role of SCD expression in porcine adipocyte differentiation and paves the way for identifying it as the promising candidate gene for less fat deposition in pigs.


Assuntos
Adipócitos/enzimologia , Tecido Adiposo/metabolismo , Diferenciação Celular/genética , Genes Essenciais/genética , Estearoil-CoA Dessaturase/genética , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/crescimento & desenvolvimento , Animais , Ácidos Graxos/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Lipogênese/genética , Carne , Camundongos , Estearoil-CoA Dessaturase/metabolismo , Suínos , Triglicerídeos/metabolismo
10.
PLoS One ; 15(3): e0229322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176696

RESUMO

Tetradecylthioacetic acid (TTA) is a synthetic fatty acid with a sulfur substitution in the ß-position. This modification renders TTA unable to undergo complete ß-oxidation and increases its biological activity, including activation of peroxisome proliferator activated receptors (PPARs) with preference for PPARα. This study investigated the effects of TTA on lipid and lipoprotein metabolism in the intestine and liver of mice fed a high fat diet (HFD). Mice receiving HFD supplemented with 0.75% (w/w) TTA had significantly lower body weights compared to mice fed the diet without TTA. Plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with increase in liver TAG. Total cholesterol was unchanged in plasma and liver. However, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA treated mice, accompanied by increased mRNA expression of fatty acid transporter genes. Expression of the cholesterol efflux pump Abca1 was induced in the small intestine, but not in the liver. Scd1 displayed markedly increased mRNA and protein expression in the intestine of the TTA group. It is concluded that TTA treatment of HFD fed mice leads to increased expression of genes involved in uptake and transport of fatty acids and HDL cholesterol in the small intestine with concomitant changes in the plasma profile of smaller lipoproteins.


Assuntos
HDL-Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Lipoproteínas/metabolismo , PPAR alfa/agonistas , Sulfetos/administração & dosagem , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Sulfetos/farmacologia , Triglicerídeos/sangue
11.
Biochem Biophys Res Commun ; 524(3): 716-722, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32035613

RESUMO

MicroRNAs are well acknowledged as key mediators in the development of chronic metabolic diseases, including NAFLD. However, their roles in hepatic lipid metabolism and fatty liver still remain well elucidated. Here, we found that miR-103 represses de novo lipogenesis (DNL) and dampens the development of obesity/diet-induced fatty liver through targeting at Fasn and Scd1 in mouse liver. miR-103, robustly amplified in obese livers, inhibits the expression of Fasn and Scd1 via directly interacting with their mRNA 3' untranslated regions. Upregulated miR-103 sufficiently reduces the expression of Fasn and Scd1 and blocks the lipid accumulation in oleate-incubated hepatocytes. Furthermore, specifically overexpressing miR-103 in mouse liver by adenovirus significantly inhibits hepatic DNL to repress HCD-promoted hepatic lipid contents as well as NAFLD development. Meanwhile, enforced expression of hepatic miR-103 also alleviates obesity-associated fatty liver via reducing Fasn and Scd1 in db/db mice. Together, our study reveals a critical role of miR-103 in lipid homeostasis of liver and pathogenesis of NAFLD.


Assuntos
Ácido Graxo Sintases/metabolismo , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Estearoil-CoA Dessaturase/metabolismo , Animais , Sequência de Bases , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Lipogênese/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Oleico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estearoil-CoA Dessaturase/genética
12.
Sci Rep ; 10(1): 3490, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103057

RESUMO

Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genome-scale metabolic network models have been used successfully to simulate cancer metabolic networks. However, most models use bulk gene expression data of entire tumor biopsies, ignoring spatial heterogeneity in the TME. To account for spatial heterogeneity, we performed spatially-resolved metabolic network modeling of the prostate cancer microenvironment. We discovered novel malignant-cell-specific metabolic vulnerabilities targetable by small molecule compounds. We predicted that inhibiting the fatty acid desaturase SCD1 may selectively kill cancer cells based on our discovery of spatial separation of fatty acid synthesis and desaturation. We also uncovered higher prostaglandin metabolic gene expression in the tumor, relative to the surrounding tissue. Therefore, we predicted that inhibiting the prostaglandin transporter SLCO2A1 may selectively kill cancer cells. Importantly, SCD1 and SLCO2A1 have been previously shown to be potently and selectively inhibited by compounds such as CAY10566 and suramin, respectively. We also uncovered cancer-selective metabolic liabilities in central carbon, amino acid, and lipid metabolism. Our novel cancer-specific predictions provide new opportunities to develop selective drug targets for prostate cancer and other cancers where spatial transcriptomics datasets are available.


Assuntos
Redes e Vias Metabólicas/genética , Neoplasias da Próstata/patologia , Ácido Araquidônico/metabolismo , Cisteína/metabolismo , Bases de Dados Factuais , Humanos , Masculino , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Neoplasias da Próstata/metabolismo , Estearoil-CoA Dessaturase/antagonistas & inibidores , Estearoil-CoA Dessaturase/metabolismo , Ácido Succínico/metabolismo , Suramina/química , Suramina/metabolismo , Microambiente Tumoral
13.
Proc Natl Acad Sci U S A ; 117(5): 2462-2472, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953260

RESUMO

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote "beiging" of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.


Assuntos
Complexo II de Transporte de Elétrons/metabolismo , Gorduras/metabolismo , Obesidade/enzimologia , Estearoil-CoA Dessaturase/genética , Ácido Succínico/metabolismo , Adipócitos Bege/citologia , Adipócitos Bege/metabolismo , Adipogenia , Animais , Metabolismo Energético , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Estearoil-CoA Dessaturase/metabolismo , Termogênese
14.
Nat Commun ; 11(1): 483, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980623

RESUMO

Inflammatory bowel disease is associated with changes in the mucosal barrier, increased intestinal permeability, and increased risk of infections and sepsis, but the underlying mechanisms are incompletely understood. Here, we show how continuous translocation of gut microbial components affects iron homeostasis and facilitates susceptibility to inflammation-associated sepsis. A sub-lethal dose of lipopolysaccharide results in higher mortality in Mucin 2 deficient (Muc2-/-) mice, and is associated with elevated circulatory iron load and increased bacterial translocation. Translocation of gut microbial components attenuates hepatic stearoyl CoA desaturase-1 activity, a key enzyme in hepatic de novo lipogenesis. The resulting reduction of hepatic saturated and unsaturated fatty acid levels compromises plasma membrane fluidity of red blood cells, thereby significantly reducing their life span. Inflammation in Muc2-/- mice alters erythrophagocytosis efficiency of splenic macrophages, resulting in an iron-rich milieu that promotes bacterial growth. Our study thus shows that increased intestinal permeability triggers a cascade of events resulting in increased bacterial growth and risk of sepsis.


Assuntos
Mucosa Intestinal/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Sepse/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Animais , Permeabilidade da Membrana Celular , Citofagocitose , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/microbiologia , Mucosa Intestinal/microbiologia , Ferro/sangue , Lipogênese , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mucina-2/deficiência , Mucina-2/genética , Sepse/etiologia , Sepse/microbiologia
15.
Lipids ; 55(1): 63-72, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31944322

RESUMO

Palmitoleic acid has been classified as an insulin-sensitizing lipokine, but evidence for this from human studies has been inconsistent. We hypothesized that this is related to either the types of samples or conditions under which samples are collected. We measured plasma palmitoleic acid and total free fatty acids (FFA) using ultra-performance liquid chromatography in blood samples collected from 34 adults under a variety of conditions. We collected duplicate samples of adipose (n = 10), FFA (n = 9), and very low density lipoprotein triacylglycerol (VLDL-TAG) (n = 7) to measure the palmitoleic acid as a percentage of total fatty acids. We tested whether the percentage of palmitoleic acid was correlated with insulin resistance, as measured by homeostatic model of insulin resistance (HOMA-IR). Adipose stearoyl-coenzyme A desaturase 1 (SCD-1) protein was measured by capillary Western blotting. FFA-palmitoleic acid percentage increased as a function of total FFA and was greater (p < 0.005) in females than males. Adipose palmitoleic acid percentage was greater in females than males (p < 0.001), as was adipose SCD-1. Palmitoleic acid was greater in femoral fat than in abdominal fat in both females and males (p < 0.001), and correlated positively with HOMA-IR only in females. The test-retest reliability values for percentage palmitoleic acid were 7 ± 10% for adipose, 24 ± 26% for VLDL, and 53 ± 31% for FFA. Because FFA-palmitoleic acid percentage varies as a function of total FFA, investigators should re-evaluate how palmitoleic acid data is presented. The positive relationship between adipose palmitoleic acid and HOMA-IR in females suggests that it is not a potent insulin-sensitizing lipokine in humans.


Assuntos
Ácidos Graxos Monoinsaturados/sangue , Ácidos Graxos não Esterificados/sangue , Lipoproteínas LDL/sangue , Obesidade/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/sangue , Absorciometria de Fóton , Tecido Adiposo/química , Adulto , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Resistência à Insulina , Masculino , Obesidade/sangue , Estudos Prospectivos , Caracteres Sexuais , Adulto Jovem
16.
PLoS One ; 15(1): e0226070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923252

RESUMO

Conjugated linoleic acid (CLA) is known for its multiple benefits including improvement of growth, increasing lean mass, and anti-carcinogenic effects. However, when used in long-term supplementations CLA does not improve semen parameters in boar and bull and reduces fertility in Japanese quails. The content of unsaturated fatty acids in dietary lipids plays a significant role in spermatogenesis owning the high proportion of unsaturated fatty acids in plasma membrane of sperms. Whether CLA plays a role in testicular tissue and epididymal fat is still unknown. Therefore, in this study we hypothesize that long-term supplementation of equal proportion of CLA isomer mix (c9,t11-CLA and t10,c12- CLA) in rabbit bucks might alter male reproductive potentials. Twelve V-Line weaned male rabbits were used in 26 weeks trial, rabbits were individually raised and randomly allocated into three dietary groups. Control group (CON) received a basal diet, a group received 0.5% CLA (CLA 0.5%), and a group received 1% CLA (CLA 1%). Rabbits were euthanized at the end of the trial and several parameters were evaluated related to growth, semen quality, and testicular and epididymal tissue histopathology and transcriptome. The long-term supplementation of CLA increased feed intake by 5% and body weight by 2-3%. CLA 1% decreased sperm progressive motility. In testicular tissue L-carnitine and α-tocopherol were decreased by CLA supplementation. In epididymal fat, CLA tended to decrease concentration of polyunsaturated fatty acids, the expression of SCD5 gene was upregulated by CLA 1% and CASP3 gene was upregulated by CLA 0.5%. Transcription of PPARG was downregulated by CLA. Feeding 1% CLA also decreased testicular epithelial thickness. Long-term supplementation of CLA modestly enhanced male rabbit growth, but negatively impacted male reproduction, especially at high dose of CLA.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Linoleicos Conjugados/farmacologia , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Carnitina/metabolismo , Suplementos Nutricionais , Regulação para Baixo/efeitos dos fármacos , Epididimo/metabolismo , Epididimo/patologia , Ácidos Graxos Insaturados/metabolismo , Masculino , PPAR gama/genética , PPAR gama/metabolismo , Coelhos , Análise do Sêmen , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Transcriptoma/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
17.
Chem Biol Interact ; 316: 108917, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31838050

RESUMO

Stearoyl-CoA desaturase (SCD) generates monounsaturated fatty acids (MUFAs) which contribute to cell growth, survival, differentiation, metabolic regulation and signal transduction. Overexpression of SCD is evident and implicated in metabolic diseases such as diabetes and non-alcoholic fatty liver disease. SCD also stimulates canonical Wnt pathway and YAP activation in support of stemness and tumorigenesis. SCD facilitates metabolic reprogramming in cancer which is mediated, at least in part, by regulation of AKT, AMPK, and NF-kB via MUFAs. Our research has revealed the novel positive loop to amplify Wnt signaling through stabilization of LRP5/6 in both hepatic stellate cells and liver tumor-initiating stem cell-like cells. As such, this loop is pivotal in promoting liver fibrosis and liver tumor development. This review summarizes the mechanisms of SCD-mediated tumor promotion described by recent studies and discusses the future prospect for SCD-mediated signaling crosstalk as a potential therapeutic target for cancer.


Assuntos
Carcinogênese , Estearoil-CoA Dessaturase/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Estearoil-CoA Dessaturase/genética , Via de Sinalização Wnt
18.
Mol Cell ; 77(1): 120-137.e9, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31733993

RESUMO

Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated transcription factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, although how MITF promotes proliferation and suppresses invasion is poorly defined. Here, we show that MITF is a lineage-restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4-mediated feedback loop that maintains de-differentiation. Our results reveal that MITF is a lineage-specific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype switching, and highlight that cell phenotype dictates the response to drugs targeting lipid metabolism.


Assuntos
Adaptação Fisiológica/fisiologia , Ácidos Graxos/metabolismo , Melanoma/metabolismo , Fator de Transcrição Associado à Microftalmia/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação para Baixo/fisiologia , Humanos , Camundongos , Invasividade Neoplásica/patologia , Fenótipo , Transdução de Sinais/fisiologia
19.
Environ Toxicol ; 35(3): 404-413, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31738477

RESUMO

Cadmium (Cd) is one of the major contaminants in aquatic ecosystem. Stearoyl-coenzyme A desaturase 1 (Scd1) has been implicated in adaptive responses to environmental stressors. The objectives of this study are (a) to characterize scd1 mRNA from silver pomfret (Pampus argenteus); (b) to investigate the expression and activity of Scd1 in silver pomfret exposed to Cd; and (c) to investigate how Cd modifies scd1 gene transcription in silver pomfret. Results indicated that Scd1 was generally conserved across fish species and scd1 mRNA level was higher by far in the brain and liver, followed by the kidney and intestine. Exposure to Cd led to significant changes of the expression and activity of Scd1 in in the liver and intestine. The liver mRNA abundance of scd1 was significantly lower in the Cd-treated groups than in the control group. The 10 days treatment with 1 mg/L Cd significantly upregulated the intestinal scd1 mRNA level, an approximately 9-fold higher in the 1 mg/L Cd-treated group as compared with the control group. Accordingly, Scd1 activity indices (18:1n-9/18:0) in the liver were significantly decreased in the 0.5 mg/L group compared with the control group, while Scd1 activity indices in the intestine were significantly increased in the 1 mg/L group compared with the control group. Moreover, overexpression of sterol regulatory element binding transcription factor 1 (Srebp1) and peroxisome proliferator-activated receptor γ (Pparγ )in HEK 293T cells produced a 2-fold increment in the activity of the scd1 promoter. Furthermore, srebp1 had a similar expression pattern to scd1 in the liver and intestine of silver pomfret exposed to Cd. These results indicated that Cd could regulate scd1 expression, possibly through the transcriptional factor Srebp1.


Assuntos
Cádmio/farmacologia , Peixes/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Estearoil-CoA Dessaturase/genética , Transcrição Genética/efeitos dos fármacos , Poluentes Químicos da Água/farmacologia , Animais , Peixes/metabolismo , Células HEK293 , Humanos , Fígado/metabolismo , PPAR gama/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
20.
Food Chem ; 305: 125458, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505416

RESUMO

The purpose of the present study was to elucidate the effects of feeding flaxseed meal (FSM) and turmeric rhizome powder (TRP) supplementation on tissue lipid profile, lipid metabolism, health indices, oxidative stability, and physical properties of broiler chicken meat. The 100 g FSM along with 10.0 g TRP supplementation significantly increased the ω-3 PUFA, particularly ALA, EPA, DPA, and DHA of broiler chicken meat due to the corresponding increase ∆9 and Δ5 + Δ6 desaturase activities. The increased activities of the desaturases resulted in significantly better health indices of the broiler chicken meat. The feeding of 100 g FSM along with 10.0 g TRP supplementation reduced the atherogenic and thrombogenic indices of broiler chicken meat. The 100 g FSM feeding reduced the oxidative stability, water holding capacity, extract release volume of broiler chicken meat and increased drip loss, whereas, 10.0 g TRP supplementation reversed these negative effects of FSM.


Assuntos
Ração Animal/análise , Curcuma/metabolismo , Ácidos Graxos Ômega-3/análise , Linho/metabolismo , Carne/análise , Animais , Antioxidantes/química , Galinhas , Dieta , Ácidos Graxos Ômega-3/metabolismo , Peroxidação de Lipídeos , Oxirredução , Estearoil-CoA Dessaturase/metabolismo
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