RESUMO
RATIONALE: In black women, triglycerides are paradoxically normal in the presence of insulin resistance. This relationship may be explained by race-related differences in central adiposity and SCD (stearoyl-CoA desaturase)-1 enzyme activity index. OBJECTIVE: In a cross-sectional study, to compare fasting and postprandial triglyceride-rich lipoprotein particle (TRLP) concentrations and size in black compared with white pre- and postmenopausal women and determine the relationship between TRLP subfractions and whole-body insulin sensitivity, hepatic and visceral fat, and SCD-1 levels. METHODS AND RESULTS: In 122 federally employed women without diabetes mellitus, 73 black (58 African American and 15 African immigrant) and 49 white; age, 44±10 (mean±SD) years; body mass index, 30.0±5.6 kg/m2, we measured lipoprotein subfractions using nuclear magnetic resonance. Hepatic fat was measured by proton magnetic resonance spectroscopy, insulin sensitivity index calculated by minimal modeling from a frequently sampled intravenous glucose test, and red blood cell fatty acid profiles were measured by gas chromatography and were used to estimate SCD-1 indices. Hepatic fat, insulin sensitivity index, and SCD-1 were similar in black women and lower than in whites, regardless of menopausal status. Fasting and postprandial large, medium, and small TRLPs, but not very small TRLPs, were lower in black women. Fasting large, medium, and very small TRLPs negatively correlated with insulin sensitivity index and positively correlated with visceral and hepatic fat and SCD-1 activity in both groups. In multivariate models, visceral fat and SCD-1 were associated with total fasting TRLP concentrations (adjR2, 0.39; P=0.001). Black women had smaller postprandial changes in large (P=0.005) and medium TRLPs (P=0.007). CONCLUSIONS: Lower visceral fat and SCD-1 activity may contribute to the paradoxical association of lower fasting and postprandial TRLP subfractions despite insulin resistance in black compared with white pre- and postmenopausal women. Similar concentrations of very small TRLPs are related to insulin resistance and could be important mediators of cardiometabolic disease risk in women. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01809288.
Assuntos
Adiposidade/etnologia , População Negra , Diabetes Mellitus Tipo 2/etnologia , Resistência à Insulina/etnologia , Lipoproteínas/sangue , Obesidade/etnologia , Estado Pré-Diabético/etnologia , Estearoil-CoA Dessaturase/fisiologia , Triglicerídeos/sangue , População Branca , Adulto , África/etnologia , Negro ou Afro-Americano , Glicemia/metabolismo , Estudos Transversais , Suscetibilidade a Doenças , Emigrantes e Imigrantes , Ingestão de Energia , Jejum/sangue , Feminino , Humanos , Resistência à Insulina/fisiologia , Gordura Intra-Abdominal/anatomia & histologia , Fígado/anatomia & histologia , Menopausa , Pessoa de Meia-Idade , Período Pós-Prandial , Estearoil-CoA Dessaturase/sangueRESUMO
Positive strand RNA viruses, such as dengue virus type 2 (DENV2) expand and structurally alter ER membranes to optimize cellular communication pathways that promote viral replicative needs. These complex rearrangements require significant protein scaffolding as well as changes to the ER chemical composition to support these structures. We have previously shown that the lipid abundance and repertoire of host cells are significantly altered during infection with these viruses. Specifically, enzymes in the lipid biosynthesis pathway such as fatty acid synthase (FAS) are recruited to viral replication sites by interaction with viral proteins and displayed enhanced activities during infection. We have now identified that events downstream of FAS (fatty acid desaturation) are critical for virus replication. In this study we screened enzymes in the unsaturated fatty acid (UFA) biosynthetic pathway and found that the rate-limiting enzyme in monounsaturated fatty acid biosynthesis, stearoyl-CoA desaturase 1 (SCD1), is indispensable for DENV2 replication. The enzymatic activity of SCD1, was required for viral genome replication and particle release, and it was regulated in a time-dependent manner with a stringent requirement early during viral infection. As infection progressed, SCD1 protein expression levels were inversely correlated with the concentration of viral dsRNA in the cell. This modulation of SCD1, coinciding with the stage of viral replication, highlighted its function as a trigger of early infection and an enzyme that controlled alternate lipid requirements during early versus advanced infections. Loss of function of this enzyme disrupted structural alterations of assembled viral particles rendering them non-infectious and immature and defective in viral entry. This study identifies the complex involvement of SCD1 in DENV2 infection and demonstrates that these viruses alter ER lipid composition to increase infectivity of the virus particles.
Assuntos
Vírus da Dengue/patogenicidade , Dengue/diagnóstico , Interações Hospedeiro-Patógeno , Estearoil-CoA Dessaturase/fisiologia , Células A549 , Animais , Biomarcadores , Células Cultivadas , Chlorocebus aethiops , Cricetinae , Dengue/patologia , Dengue/virologia , Diagnóstico Diferencial , Progressão da Doença , Diagnóstico Precoce , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Lipogênese/genética , Masculino , Estearoil-CoA Dessaturase/genética , Células Vero , Vírion/patogenicidade , Virulência , Replicação Viral/genéticaRESUMO
Mechanical regulation is known as an important regulator in cancer progression and malignancy. High shear force has been found to inhibit the cell cycle progression and result in cell death in various cancer cells. Stearoyl-CoA desaturase (SCD)-1, one of the important lipogenic enzymes, has recently been indicated as a potential pharmaceutical target in cancer therapy. In this study, we determined whether the cell fate control of shear force stimulation is through regulating the SCD-1 expression in cancer cells. Human MG63 osteosarcoma cells were used in this study. 2 and 20 dynes/cm2 shear forces were defined as low and high intensities, respectively. A SCD-1 upregulation in human MG63 osteosarcoma cells under 20, but not 2, dynes/cm2 shear force stimulation was shown, and this induction was regulated by Smad1/5 and peroxisome proliferator-activated receptor δ (PPARδ) signaling. Moreover, gene knockdown of PPARδ and SCD-1 in human MG63 osteosarcoma cells attenuated the differentiation inhibition and resulted in much more cell death of high shear force initiation. The present study finds a possible auto-protective role of SCD-1 upregulation in high shear force-damaged human MG63 osteosarcoma cells. However, its detailed regulation in the cancer fate decision of high shear force should be further examined.
Assuntos
Osteossarcoma/metabolismo , Resistência ao Cisalhamento/fisiologia , Estearoil-CoA Dessaturase/metabolismo , Linhagem Celular Tumoral , Humanos , Lipogênese , PPAR delta/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/fisiologia , Estresse Mecânico , Ativação TranscricionalRESUMO
BACKGROUND & AIMS: The enzyme stearoyl-coenzyme A desaturase 1 (SCD or SCD1) produces monounsaturated fatty acids by introducing double bonds into saturated bonds between carbons 9 and 10, with oleic acid as the main product. SCD1 is present in the intestinal epithelium, and fatty acids regulate cell proliferation, so we investigated the effects of SCD1-induced production of oleic acid in enterocytes in mice. METHODS: We generated mice with disruption of Scd1 selectively in the intestinal epithelium (iScd1-/- mice) on a C57BL/6 background; iScd1+/+ mice were used as controls. We also generated iScd1-/-ApcMin/+ mice and studied cancer susceptibility. Mice were fed a chow, oleic acid-deficient, or oleic acid-rich diet. Intestinal tissues were collected and analyzed by histology, reverse transcription quantitative polymerase chain reaction, immunohistochemistry, and mass spectrometry, and tumors were quantified and measured. RESULTS: Compared with control mice, the ileal mucosa of iScd1-/- mice had a lower proportion of palmitoleic (C16:1 n-7) and oleic acids (C18:1 n-9), with accumulation of stearic acid (C18:0); this resulted a reduction of the Δ9 desaturation ratio between monounsaturated (C16:1 n-7 and C18:1 n-9) and saturated (C16:0 and C18:0) fatty acids. Ileal tissues from iScd1-/- mice had increased expression of markers of inflammation activation and crypt proliferative genes compared with control mice. The iScd1-/-ApcMin/+ mice developed more and larger tumors than iScd1+/+ApcMin/+ mice. iScd1-/-ApcMin/+ mice fed the oleic acid-rich diet had reduced intestinal inflammation and significantly lower tumor burden compared with mice fed a chow diet. CONCLUSIONS: In studies of mice, we found intestinal SCD1 to be required for synthesis of oleate in the enterocytes and maintenance of fatty acid homeostasis. Dietary supplementation with oleic acid reduces intestinal inflammation and tumor development in mice.
Assuntos
Gorduras Insaturadas na Dieta/administração & dosagem , Enterite/etiologia , Mucosa Intestinal/enzimologia , Neoplasias Intestinais/etiologia , Ácido Oleico/administração & dosagem , Estearoil-CoA Dessaturase/fisiologia , Animais , Feminino , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oleico/metabolismo , Carga TumoralRESUMO
Membrane-bound Δ9 desaturase perform oxygenated desaturation reactions to insert the first double bonds within fatty acyl chains between C9 and C10 positions of most saturated substrates. Arthrospira platensis, a blue green microalga, is an important source of polyunsaturated fatty acids (PUFA) such as oleic, linoleic and linolenic acids lending benefits and functions in dietetics and therapeutic uses. In this paper, we report homology modeling and docking studies of a Δ9 desaturase from Arthrospira platensis strain. The protein model showed high topology resemblance compared to membrane-bound desaturases with a cytoplasmic core displaying the catalytic site and a transmembrane domain created by four α-helices. The cytoplasmic cap contained the three conserved-histidine boxes typical for all membrane bound desaturases. The protein model was used to perform protein-protein docking and the dimer structure was generated. The two monomers are tightly related with hydrophobic interactions between the transmembrane domain helices. The study highlighted also the potent role of a particular 53 residues sequence located at the N terminal end of the enzyme.
Assuntos
Ácidos Graxos Insaturados/biossíntese , Spirulina/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Sequência de Aminoácidos , Domínio Catalítico , Simulação por Computador , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Lipogênese , Simulação de Acoplamento Molecular , Alinhamento de Sequência/métodos , Estearoil-CoA Dessaturase/fisiologia , Estearoil-CoA Dessaturase/ultraestrutura , Relação Estrutura-AtividadeRESUMO
Stearoyl-CoA desaturase-1 (SCD-1) is the key rate-limiting enzyme to catalyze the conversion of saturated fatty acids to monounsaturated fatty acids. The monounsaturated fatty acids in the catalytic products are important substrates for the formation of triglycerides, cholesteryl esters and phospholipids. Therefore, SCD-1 plays an important regulatory role in the metabolic process of fat. Currently, obesity and non-alcoholic fatty liver disease are widely prevalent worldwide. SCD-1 has gradually become a potential drug target for the treatment of such diseases due to its important regulatory role in fat metabolism. We summarize the recent research progress of SCD-1 in obesity and non-alcoholic fatty liver disease and the developmental status of SCD-1 inhibitors in order to provide new ideas and references related to disease and target drugs.
Assuntos
Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Estearoil-CoA Dessaturase/fisiologia , Ácidos Graxos , Humanos , Metabolismo dos Lipídeos , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, when it is not amenable for aggressive therapies such as surgical resection or liver transplantation. Current therapeutic options achieve clinical responses in only a small percentage of cases. As a consequence, effective approaches for prevention and treatment are greatly needed. Altered lipid metabolism has been recently linked to HCC pathogenesis. The aims of this study were to define the cellular and molecular mechanisms linking stearoyl-CoA desaturase (SCD), the rate-limiting enzyme and an essential regulator of lipid homeostasis in liver cells, to carcinogenesis in HCC. MATERIAL AND METHODS: HCC and normal liver specimens were collected. Human HCC cell lines: HepG2, Hep3B, and PLC/PLF/5 were used for immunoblot, cell viability, proliferation, and apoptosis assays. Small interfering RNAs were used for genetic inhibition, and 10, 12 conjugated linoleic acid was used for pharmacologic SCD inhibition. RESULTS: SCD was strongly expressed in surgically resected HCC (n = 64) and various human HCC cell lines (HepG2, Hep3B, and PLC/PLF/5). The levels of SCD negatively correlated with degree of tumor differentiation (P < 0.01). Treatment of these HCC cell lines with a panel of chemotherapeutic drugs resulted in a time-dependent, phosphatidylinositol 3 kinase- and c-Jun N-terminal kinases1/2-mediated upregulation of SCD expression, which paralleled the degree of resistance to drug-induced apoptosis. Specific genetic or pharmacologic SCD suppression resulted in inhibition of cell proliferation (P < 0.001) and significantly increased sensitivity to chemotherapy-induced apoptosis. CONCLUSIONS: Our data suggest that increased SCD expression plays an important role in HCC development and resistance to chemotherapy-induced apoptosis, and this is in part mediated by phosphatidylinositol 3 kinase/c-Jun N-terminal kinases activation. Specific targeted interruption of this pathway in HCC could be a desirable approach in designing novel therapeutic strategies.
Assuntos
Carcinoma Hepatocelular/enzimologia , Proliferação de Células , Neoplasias Hepáticas/enzimologia , Estearoil-CoA Dessaturase/fisiologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologiaRESUMO
Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a hepatoprotectant in inhibiting apoptosis, inflammation, and hyperlipidemia in mouse models of nonalcoholic steatohepatitis (NASH). We studied the ability of UDCA-LPE to inhibit palmitate (Pal)-induced apoptosis in primary hepatocytes and delineate cytoprotective mechanisms. We showed that lipoprotection by UDCA-LPE was mediated by cAMP and was associated with increases in triglycerides (TGs) and phospholipids (PLs). An inhibitor of cAMP-effector protein kinase A partially reversed the protective effects of UDCA-LPE. Lipidomic analyses of fatty acids and PL composition revealed a shift of lipid metabolism from saturated Pal to monounsaturated and polyunsaturated fatty acids, mainly, oleate, docosapentaenoate, and docosahexaenoate. The latter two ω-3 fatty acids were particularly found in phosphatidylcholine and phosphatidylserine pools. The catalysis of Pal by stearoyl-CoA desaturase-1 (SCD-1) is a known mechanism for the channeling of Pal away from apoptosis. SCD-1 protein was upregulated during UDCA-LPE lipoprotection. SCD-1 knockdown of Pal-treated cells showed further increased apoptosis, and the extent of UDCA-LPE protection was reduced. Thus, the major mechanism of UDCA-LPE lipoprotection involved a metabolic shift from toxic saturated toward cytoprotective unsaturated fatty acids in part via SCD-1. UDCA-LPE may thus be a therapeutic agent for treatment of NASH by altering distinct pools of fatty acids for storage into TGs and PLs, and the latter may protect lipotoxicity at the membrane levels.
Assuntos
Apoptose/efeitos dos fármacos , Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Lisofosfolipídeos/farmacologia , Ácido Ursodesoxicólico/farmacologia , Animais , AMP Cíclico/fisiologia , Citoproteção , Ácidos Graxos/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estearoil-CoA Dessaturase/fisiologiaRESUMO
Milk yield and composition are of great economic importance for the dairy goat industry. The identification of genes associated with phenotypic differences for these traits could allow for the implementation of gene-assisted selection programs in goats. Associations between polymorphisms at 3 candidate genes and milk production traits in Alpine goats farmed in Italy were investigated in the present research. Considered genes were acetyl-coenzyme A carboxylase α (ACACA), the major regulatory enzyme of fatty acid biosynthesis; stearoyl-coenzyme A desaturase (SCD), involved in the biosynthesis of monounsaturated fatty acids in the mammary gland; and lipoprotein lipase (LPL), which plays a central role in plasma triglyceride metabolism. An approach somewhat similar to the granddaughter design for detecting quantitative trait loci in dairy cattle was followed. Effects of genotypes of a sample of 59 Alpine bucks on phenotypes of their 946 daughters raised in 75 flocks were investigated. Data comprised 13,331 daily records for milk yields (L/d), fat and protein yields (kg/d), and fat and protein contents (%) of 2,200 lactations. Population genetics parameters were calculated and associations between milk production traits and 10 single nucleotide polymorphisms (SNP) at the 3 genes were tested. Two markers at the ACACA, 1 for the SCD and 1 at the LPL locus, deviated significantly from the Hardy-Weinberg equilibrium, with an observed heterozygosity lower than expected. Flock, age of the goat, kidding season, and stage of lactation affected all traits considered, except fat percentage. Three SNP were found to be significantly associated with milk production traits. The SNP located on the ACACA gene showed an effect on milk yield, with daughters of TT bucks having an average test-day milk yield of about 0.3 to 0.25 L/d lower than the other 2 genotypes. The marker on the LPL locus was highly associated with milk yield, with the largest values for CC daughters (about 0.50L more than GG). The TGT deletion located on the untranslated region of the SCD gene showed significant effects on average milk and protein yields. The homozygote-deleted genotype had values about 0.5 L/d and 16 g/d lower for milk and protein daily yield, respectively, compared with the TGT/TGT genotype. Differences between genotypes were quite constant across most of the lactation. Associations found in the present study, which should be tested in a larger sample, especially for those markers that show rare genotypes, may offer useful indications for the genetic improvement of dairy traits in goats.
Assuntos
Acetil-CoA Carboxilase/genética , Cabras/genética , Lactação/genética , Lipase Lipoproteica/genética , Estearoil-CoA Dessaturase/genética , Acetil-CoA Carboxilase/fisiologia , Alelos , Animais , Gorduras/análise , Feminino , Estudos de Associação Genética/veterinária , Genótipo , Cabras/metabolismo , Cabras/fisiologia , Lactação/fisiologia , Lipase Lipoproteica/fisiologia , Masculino , Leite/química , Proteínas do Leite/análise , Polimorfismo de Nucleotídeo Único/genética , Estearoil-CoA Dessaturase/fisiologiaRESUMO
Induction of endoplasmic reticulum (ER) stress and apoptosis by elevated exogenous saturated fatty acids (FAs) plays a role in the pathogenesis of ß-cell dysfunction and loss of islet mass in type 2 diabetes. Regulation of monounsaturated FA (MUFA) synthesis through FA desaturases and elongases may alter the susceptibility of ß-cells to saturated FA-induced ER stress and apoptosis. Herein, stearoyl-CoA desaturase (SCD)1 and SCD2 mRNA expression were shown to be induced in islets from prediabetic hyperinsulinemic Zucker diabetic fatty (ZDF) rats, whereas SCD1, SCD2, and fatty acid elongase 6 (Elovl6) mRNA levels were markedly reduced in diabetic ZDF rat islets. Knockdown of SCD in INS-1 ß-cells decreased desaturation of palmitate to MUFA, lowered FA partitioning into complex neutral lipids, and increased palmitate-induced ER stress and apoptosis. Overexpression of SCD2 increased desaturation of palmitate to MUFA and attenuated palmitate-induced ER stress and apoptosis. Knockdown of Elovl6 limited palmitate elongation to stearate, increasing palmitoleate production and attenuating palmitate-induced ER stress and apoptosis, whereas overexpression of Elovl6 increased palmitate elongation to stearate and palmitate-induced ER stress and apoptosis. Overall, these data support the hypothesis that enhanced MUFA synthesis via upregulation of SCD2 activity can protect ß-cells from elevated saturated FAs, as occurs in prediabetic states. Overt type 2 diabetes is associated with diminished islet expression of SCD and Elovl6, and this can disrupt desaturation of saturated FAs to MUFAs, rendering ß-cells more susceptible to saturated FA-induced ER stress and apoptosis.
Assuntos
Acetiltransferases/fisiologia , Apoptose/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ácido Palmítico/farmacologia , Estearoil-CoA Dessaturase/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Acetiltransferases/antagonistas & inibidores , Acetiltransferases/genética , Acetiltransferases/metabolismo , Animais , Apoptose/genética , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Retículo Endoplasmático/metabolismo , Elongases de Ácidos Graxos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Técnicas de Silenciamento de Genes , Células Secretoras de Insulina/metabolismo , Masculino , Estado Pré-Diabético/genética , Estado Pré-Diabético/metabolismo , Estado Pré-Diabético/patologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Zucker , Estearoil-CoA Dessaturase/antagonistas & inibidores , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Estresse Fisiológico/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/genéticaRESUMO
Host lipid metabolism and viral responses are intimately connected. However, the process by which the acquired immune systems adapts lipid metabolism to meet demands, and whether or not the metabolic rewiring confers a selective advantage to host immunity, remains unclear. Here we show that viral infection attenuates the expression of genes related to lipid metabolism in murine CD4+ T cells, which in turn increases the expression of antiviral genes. Inhibition of the fatty acid synthesis pathway substantially increases the basal expression of antiviral genes via the spontaneous production of type I interferon (IFN). Using a combination of CRISPR/Cas9-mediated genome editing technology and a global lipidomics analysis, we found that the decrease in monounsaturated fatty acid caused by genetic deletion of Scd2 in mice was crucial for the induction of an antiviral response through activation of the cGAS-STING pathway. These findings demonstrate the important relationship between fatty acid biosynthesis and type I IFN responses that enhances the antiviral response.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Ácidos Graxos Monoinsaturados/metabolismo , Interferon Tipo I/farmacologia , Proteínas de Membrana/fisiologia , Nucleotidiltransferases/fisiologia , Estearoil-CoA Dessaturase/fisiologia , Viroses/imunologia , Animais , Interações Hospedeiro-Patógeno , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais , Viroses/metabolismoRESUMO
Immune cells can metabolize glucose, amino acids, and fatty acids (FAs) to generate energy. The roles of different FA species and their impacts on humoral immunity remain poorly understood. Here, we report that proliferating B cells require monounsaturated FAs (MUFAs) to maintain mitochondrial metabolism and mTOR activity and to prevent excessive autophagy and endoplasmic reticulum (ER) stress. Furthermore, B cell-extrinsic stearoyl-CoA desaturase (SCD) activity generates MUFA to support early B cell development and germinal center (GC) formation in vivo during immunization and influenza infection. Thus, SCD-mediated MUFA production is critical for humoral immunity.
Assuntos
Linfócitos B/fisiologia , Ácidos Graxos Monoinsaturados/imunologia , Ácidos Graxos Monoinsaturados/metabolismo , Imunidade Humoral , Mitocôndrias/fisiologia , Estearoil-CoA Dessaturase/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Autofagia , Estresse do Retículo Endoplasmático , Técnicas de Inativação de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/imunologia , Serina-Treonina Quinases TOR/imunologiaRESUMO
As part of a shift toward macromolecule production to support continuous cell proliferation, cancer cells coordinate the activation of lipid biosynthesis and the signaling networks that stimulate this process. A ubiquitous metabolic event in cancer is the constitutive activation of the fatty acid biosynthetic pathway, which produces saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) to sustain the increasing demand of new membrane phospholipids with appropriate acyl composition. In cancer cells, the tandem activation of the fatty acid biosynthetic enzymes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) leads to increased synthesis of SFA and their further conversion into MUFA by stearoyl-CoA desaturase (SCD) 1. The roles of adenosine triphosphate citrate lyase, ACC and FAS in the pathogenesis of cancer have been a subject of extensive investigation. However, despite early experimental and epidemiological observations reporting elevated levels of MUFA in cancer cells and tissues, the involvement of SCD1 in the mechanisms of carcinogenesis remains surprisingly understudied. Over the past few years, a more detailed picture of the functional relevance of SCD1 in cell proliferation, survival and transformation to cancer has begun to emerge. The present review addresses the mounting evidence that argues for a key role of SCD1 in the coordination of the intertwined pathways of lipid biosynthesis, energy sensing and the transduction signals that influence mitogenesis and tumorigenesis, as well as the potential value of this enzyme as a target for novel pharmacological approaches in cancer interventions.
Assuntos
Apoptose , Proliferação de Células , Transformação Celular Neoplásica , Neoplasias/enzimologia , Neoplasias/patologia , Estearoil-CoA Dessaturase/fisiologia , Animais , HumanosRESUMO
Obesity is currently a worldwide epidemic and public health burden that increases the risk for developing insulin resistance and several chronic diseases such as diabetes, cardiovascular diseases and non-alcoholic fatty liver disease. The multifactorial causes of obesity include several genetic, dietary and lifestyle variables that together result in an imbalance between energy intake and energy expenditure. Dietary approaches to limit fat intake are commonly prescribed to achieve the hypocaloric conditions necessary for weight loss. But dietary fat restriction is often accompanied by increased carbohydrate intake, which can dramatically increase endogenous fatty acid synthesis depending upon carbohydrate composition. Since both dietary and endogenously synthesized fatty acids contribute to the whole-body fatty acid pool, obesity can therefore result from excessive fat or carbohydrate consumption. Stearoyl-Coenzyme A desaturase-1 (SCD1) is a delta-9 fatty acid desaturase that converts saturated fatty acids into monounsaturated fatty acids (MUFA) and this activity is elevated by dietary carbohydrate. Mice lacking Scd1 are protected from obesity and insulin resistance and are characterized by decreased fatty acid synthesis and increased fatty acid oxidation. In this review, we address the association of high-carbohydrate diets with increased SCD activity and summarize the current literature on the subject of SCD1 and body weight regulation.
Assuntos
Carboidratos da Dieta/administração & dosagem , Obesidade/enzimologia , Estearoil-CoA Dessaturase/fisiologia , Animais , HumanosRESUMO
BACKGROUND: Stearoyl-CoA desaturase 1 (SCD1) is an ER resident enzyme introducing a double-bond in saturated fatty acids. Global knockout of SCD1 in mouse increases fatty acid oxidation and insulin sensitivity which makes the animal resistant to diet-induced obesity. Inhibition of SCD1 has therefore been proposed as a potential therapy of the metabolic syndrome. Much of the work has focused on insulin target tissue and very little is known about how reduced levels of SCD1 would affect the insulin-producing ß-cell, however. The aim of the present study was therefore to investigate how reduced levels of SCD1 affect the ß-cell. RESULTS: Insulin-secreting MIN6 cells with reduced levels of SCD1 were established by siRNA mediated knockdown. When fatty acid oxidation was measured, no difference between cells with reduced levels of SCD1 and mock-transfected cells were found. Also, reducing levels of SCD1 did not affect insulin secretion in response to glucose. To investigate how SCD1 knockdown affected cellular mechanisms, differentially regulated proteins were identified by a proteomic approach. Cells with reduced levels of SCD1 had higher levels of ER chaperones and components of the proteasome. The higher amounts did not protect the ß-cell from palmitate-induced ER stress and apoptosis. Instead, rise in levels of p-eIF2α and CHOP after palmitate exposure was 2-fold higher in cells with reduced levels of SCD1 compared to mock-transfected cells. Accordingly, apoptosis rose to higher levels after exposure to palmitate in cells with reduced levels of SCD1 compared to mock-transfected cells. CONCLUSIONS: In conclusion, reduced levels of SCD1 augment palmitate-induced ER stress and apoptosis in the ß-cell, which is an important caveat when considering targeting this enzyme as a treatment of the metabolic syndrome.
Assuntos
Células Secretoras de Insulina/metabolismo , Ácido Palmítico/toxicidade , Estearoil-CoA Dessaturase/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Ácidos Graxos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Terapia Genética , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Síndrome Metabólica/terapia , Camundongos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Estearoil-CoA Dessaturase/genética , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismoRESUMO
Cancer cells are characterized by metabolic alterations. Thereinto, Stearoyl-CoA Desaturase 1 (SCD1), an enzymatic node located in the conversion of saturated fatty acids into monounsaturated fatty acids (MUFAs), has been reported to accelerate the tumorigenesis of multiple cancers. However, its role in the metabolic process of gastric cancer remains largely unexplored. In this study, by in vitro, in vivo and in silico assessments, our results revealed that SCD1 exhibited the ability to promote tumor growth, migration and anti-ferroptosis of gastric cancer. The underlying mechanism might involve the alteration of cancer stemness and modulation of cell cycle-related proteins. Moreover, based on our findings, high expression of SCD1 might predict poor prognosis in gastric cancer patients. Our study provided new insights into the potential of SCD1 as a biomarker as well as a therapeutic target in the treatment of gastric cancer.
Assuntos
Ferroptose , Estearoil-CoA Dessaturase/fisiologia , Neoplasias Gástricas/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Células Tumorais CultivadasRESUMO
Esophageal cancer is one of the most common cancer with limited therapeutic strategies, thus it is important to develop more effective strategies to against it. Sulforaphene (SFE), an isothiocyanate isolated from radish seeds, was proved to inhibit esophageal cancer progression in the current study. Flow cytometric analysis showed SFE induced cell apoptosis and cycle arrest in G2/M phase. Also, scrape motility and transwell assays presented SFE reduced esophageal cancer cell metastasis. Microarray results showed the influence of SFE on esophageal cancer cells was related with stearoyl-CoA desaturase (SCD), cadherin 3 (CDH3), mitogen-activated protein kinase kinase 3 (MAP2K3) and growth arrest and DNA damage inducible beta (GADD45B). SCD and CDH3 could promote esophageal cancer metastasis via activating the Wnt pathway, while the latter one was involved in a positive feedback loop, GADD45B-MAP2K3-p38-p53, to suppress esophageal cancer growth. GADD45B was known to be the target gene of p53, and we proved in this study, it could increase the phosphorylation level of MAP2K3 in esophageal cancer cells, activating p38 and p53 in turn. SFE treatment elevated MAP2K3 and GADD45B expression and further stimulated this feedback loop to better exert antitumor effect. In summary, these results demonstrated that SFE had the potential for developing as a chemotherapeutic agent because of its inhibitory effects on esophageal cancer metastasis and proliferation.
Assuntos
Caderinas/metabolismo , Isotiocianatos/farmacologia , Estearoil-CoA Dessaturase/metabolismo , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caderinas/fisiologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Isotiocianatos/metabolismo , MAP Quinase Quinase 3/genética , MAP Quinase Quinase 3/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Nus , Estearoil-CoA Dessaturase/fisiologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
A key and highly regulated enzyme that is required for the biosynthesis of monounsaturated fatty acids is stearoyl-CoA desaturase (SCD), which catalyzes the D(9)-cis desaturation of a range of fatty acyl-CoA substrates. The preferred substrates are palmitoyl- and stearoyl-CoA, which are converted into palmitoleoyl- and oleoyl-CoA respectively. Oleate is the most abundant monounsaturated fatty acid in dietary fat and is therefore readily available. Studies of mice that have a naturally occurring mutation in the SCD-1 gene isoform as well as a mouse model with a targeted disruption of the SCD gene (SCD-1(-/-)) have revealed the role of de novo synthesized oleate and thus the physiological importance of SCD-1 expression. SCD-1 deficiency results in reduced body adiposity, increased insulin sensitivity, and resistance to diet-induced obesity. The expression of several genes of lipid oxidation are upregulated, whereas lipid synthesis genes are downregulated. SCD-1 was also found to be a component of the novel metabolic response to the hormone leptin. Therefore, SCD-1 appears to be an important metabolic control point, and inhibition of its expression could be of benefit for the treatment of obesity, diabetes, and other metabolic diseases. In this article, we summarize the recent and timely advances concerning the important role of SCD in the biochemistry and physiology of lipid metabolism.
Assuntos
Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/fisiologia , Animais , Metabolismo dos Carboidratos/genética , Metabolismo dos Carboidratos/fisiologia , Humanos , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Estearoil-CoA Dessaturase/genéticaRESUMO
Mono-2-ethylhexyl phthalate (MEHP) is a major bioactive metabolite in the widely used industrial plasticizer diethylhexyl phthalate (DEHP) that has been found to be toxic to the liver. The aim of this study is to determine whether MEHP exposure can change the expression of fatty acid metabolism-related genes in HepG2 cells, which might be related to non-alcoholic fatty liver disease (NAFLD). The results revealed that exposure to MEHP promoted lipid accumulation in HepG2 cells. The levels of intracellular triglycerides in the hepatocytes increased after exposure to 0.8-100 µM MEHP for 24 h and 48 h. The genetic expressions of SREBP-1c, ChREBP, ACC1, FASN, and SCD significantly increased at 6 h after exposure to MEHP. At 24 h, the expression of the SREBP-1c and ChREBP genes remained increased, while the expression of the FASN and SCD genes decreased. At 48 h, the expression of SREBP-1c, ChREBP, ACC1, FASN, and SCD decreased. Furthermore, the levels of proteins including ACC1, FASN, SCD, and ChREBP (except SREBP-1c) increased at 24 h. These findings suggest that MEHP exposure can promote fatty acid synthesis in hepatocytes by regulating the expression of relevant genes and proteins, contributing to NAFLD.
Assuntos
Dietilexilftalato/análogos & derivados , Metabolismo dos Lipídeos/efeitos dos fármacos , Acetil-CoA Carboxilase/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/fisiologia , Dietilexilftalato/toxicidade , Ácido Graxo Sintase Tipo I/fisiologia , Células Hep G2 , Humanos , Estearoil-CoA Dessaturase/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia , Triglicerídeos/metabolismoRESUMO
The prevalence of obesity and related metabolic disorders increases rapidly in western societies. A proper choice of foods may now prevent or delay many of the health consequences related to these disorders. In this respect, replacing dietary saturated fatty acids (SFAs) by cis-monounsaturated fatty acids (cis-MUFAs) has beneficial effects. In addition to diet-derived cis-MUFAs, the human body can also generate cis-MUFAsfrom SFAs through the action of stearoyl-CoA desaturases (SCDs). SCDs may play an adverse role in obesity and obesity-related insulin resistance. Here, we review the current knowledge on the molecular aspects and the role of SCD1 in obesity and the metabolic syndrome (MS). In mice, many studies have suggested a negative role for SCD1 in the development of obesity and insulin resistance. In humans, however, evidence is less convincing. If anything, increased, rather than decreased, levels of SCD1 mRNA levels are negatively associated with MS-related diseases such as insulin resistance. However, an unequivocal conclusion is currently not possible as the number of human studies is limited. Therefore, more human studies are needed at the molecular as well as at the physiological level to understand the true role of SCD1 during the development of obesity and the MS.