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1.
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
2.
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
3.
Biol Res ; 52(1): 60, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847887

RESUMO

BACKGROUND: Recent studies have confirmed that RASAL1 has an antitumor effect in many cancers, but its functional role and the molecular mechanism underlying in colon cancer has not been investigated. RESULTS: We collected human colon cancer tissues and adjacent non-tumor tissues, human colon cancer cell lines LoVo, CaCo2, SW1116, SW480 and HCT-116, and normal colonic mucosa cell line NCM460. RT-qPCR was used to detect the RASAL1 level in the clinical tissues and cell lines. In LoVo and HCT-116, RASAL1 was artificially overexpressed. Cell viability and proliferation were measured using CCK-8 assays, and cell cycle was detected via PI staining and flow cytometry analysis. RASAL1 significantly inhibited the cell proliferation via inducing cell cycle arrest, suppressed cell cycle associated protein expression, and decreased the lipid content and inhibited the SCD1 expression. Moreover, SCD1 overexpression induced and downregulation repressed cell proliferation by causing cell cycle arrest. Additionally, luciferase reporter assays were performed to confirm the direct binding between SREBP1c, LXRα and SCD1 promoter, we also demonstrated that RASAL1 inhibit SCD1 3'-UTR activity. RASAL1 inhibited tumor growth in xenograft nude mice models and shows inhibitory effect of SCD1 expression in vivo. CONCLUSION: Taken together, we concluded that RASAL1 inhibited colon cancer cell proliferation via modulating SCD1 activity through LXRα/SREBP1c pathway.


Assuntos
Proliferação de Células/fisiologia , Neoplasias do Colo/patologia , Proteínas Ativadoras de GTPase/metabolismo , Receptores X do Fígado/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Proteínas Ativadoras de GTPase/genética , Humanos , Receptores X do Fígado/genética , Camundongos , Estearoil-CoA Dessaturase/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
4.
J Agric Food Chem ; 67(37): 10352-10360, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31503479

RESUMO

The potential for apple peels to mitigate the deleterious effects of a high-fat diet in mice was investigated here. Mice were fed a high-fat diet supplemented with apple powders from three apple varieties or a commercial apple polyphenol. Polyphenols were characterized using colorimetric assays and high-performance liquid chromatography. Mice were tested for standard metabolic parameters. There was a dose response to dietary apple peels, with the higher intake leading to reduced weight gain and adipose tissue mass relative to the lower intake, but none of the treatments were statistically different from the control. The gene expression of liver enzyme stearoyl-CoA desaturase (Scd-1) was correlated with adipose weight, and liver enzyme cytochrome P51 (Cyp51) was downregulated by the apple diets. The feces from a subset of mice were analyzed for polyphenols and for bacteria taxa by next-generation sequencing. The results revealed that the makeup of the fecal microbiota was related to the metabolism of dietary polyphenols.


Assuntos
Biflavonoides/análise , Catequina/análise , Fezes/química , Frutas/metabolismo , Microbioma Gastrointestinal , Malus/metabolismo , Obesidade/dietoterapia , Proantocianidinas/análise , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biflavonoides/metabolismo , Catequina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Frutas/química , Humanos , Masculino , Malus/química , Camundongos , Obesidade/genética , Obesidade/metabolismo , Obesidade/microbiologia , Polifenóis/análise , Polifenóis/metabolismo , Proantocianidinas/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Esterol 14-Desmetilase/genética , Esterol 14-Desmetilase/metabolismo
5.
Lipids Health Dis ; 18(1): 168, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477154

RESUMO

BACKGROUND: The alteration of lipid metabolism in cancer cells is recognized as one of the most important metabolic hallmarks of cancer. Membrane rafts defined as plasma membrane microdomains enriched in cholesterol and sphingolipids serve as platforms for signaling regulation in cancer. The main purpose of this study was to evaluate the effect of the cholesterol metabolite, 4-cholesten-3-one, on lipid metabolism and membrane raft integrity in two breast cancer cell lines, MCF-7 and MDA-MB-231. Its ability to reduce cell viability and migration has also been investigated. METHODS: RT-qPCR was performed to evaluate the expression of enzymes involved in lipogenesis and cholesterol synthesis, and ABCG1 and ABCA1 transporters involved in cholesterol efflux. Its effect on cell viability and migration was studied using the MTT assay, the wound healing assay and the Transwell migration assay, respectively. The effect of 4-cholesten-3-one on membrane rafts integrity was investigated by studying the protein expression of flotillin-2, a membrane raft marker, and raft-enriched EGFR by western blot. RESULTS: Interestingly, we found that 4-cholesten-3-one treatment decreased mRNA expression of different enzymes including ACC1, FASN, SCD1 and HMGCR. We further demonstrated that 4-cholesten-3-one increased the expression of ABCG1 and ABCA1. We also found that 4-cholesten-3-one decreased the viability of MCF-7 and MDA-MB-231 cells. This effect was neutralized after treatment with LXR inverse agonist or after LXRß knockdown by siRNA. As a result, we also demonstrated that 4-cholesten-3-one disrupts membrane rafts and cell migration capacity. CONCLUSION: Our results show that 4-cholesten-3-one exerts promising antitumor activity by altering LXR-dependent lipid metabolism in breast cancer cells without increasing lipogenesis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Colestenonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/genética , Microdomínios da Membrana/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Lipogênese/genética , Receptores X do Fígado/metabolismo , Células MCF-7 , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transdução de Sinais , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Células THP-1
6.
BMC Cancer ; 19(1): 760, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370822

RESUMO

BACKGROUNDS: The role of sphere-forming culture in enriching subpopulations with stem-cell properties in hepatocellular carcinoma (HCC) is unclear. The present study investigates its value in enriching cancer stem cells (CSCs) subpopulations and the mechanism by which HCC CSCs are maintained. METHODS: HCC cell lines and fresh primary tumor cells were cultured in serum-free and ultra-low attachment conditions to allow formation of HCC spheres. In vitro and in vivo experiments were performed to evaluate CSC characteristics. Expression levels of CSC-related genes were assessed by qRT-PCR and the correlation between sphere formation and clinical characteristics was investigated. Finally, gene expression profiling was performed to explore the molecular mechanism underlying HCC CSC maintenance. RESULTS: We found that both cell lines and primary tumor cells formed spheres. HCC spheres possessed the capacity for self-renewal, proliferation, drug resistance, and contained different subpopulations of CSCs. Of interest, 500 sphere-forming Huh7 cells or 200 primary tumor cells could generate tumors in immunodeficient animals. Sphere formation correlated with size, multiple tumors, satellite lesions, and advanced stage. Further investigation identified that the PPARα-SCD1 axis plays an important role in maintenance of the CSC properties of HCC sphere cells by promoting nuclear accumulation of ß-Catenin. Inhibition of SCD1 interfered with sphere formation, down-regulated expression of CSC-related markers, and reduced ß-Catenin nuclear accumulation. CONCLUSIONS: Sphere-forming culture can effectively enrich subpopulations with stem-cell properties, which are maintained through activation of the PPARα-SCD1 axis. Therefore, we suggest that targeting the SCD1-related CSC machinery might provide a novel insight into HCC treatment.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/patologia , Esferoides Celulares/patologia , Estearoil-CoA Dessaturase/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Autorrenovação Celular , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , PPAR alfa/metabolismo , Transdução de Sinais , Estearoil-CoA Dessaturase/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Anim Sci ; 97(10): 4114-4123, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31424542

RESUMO

We hypothesized that oleic acid (OA) in the absence of a thiazolidinedione (i.e., a synthetic peroxisome proliferator-activated receptorγ [PPARγ] agonist) would increase adipogenic gene expression in bovine muscle satellite cells (BSC). The BSC were cultured in differentiation medium containing 10 µM ciglitazone (CI), 100 µM OA, or 100 µM OA plus 10 µM CI (CI-OA). Control (CON) BSC were cultured only in differentiation media (containing 2% horse serum). The presence of myogenin, desmin, and paired box 7 proteins was confirmed in the BSC by immunofluorescence staining, demonstrating that we had isolated myogenic cells. The OA BSC had lesser paired box 3 (Pax3) and myogenic differentiation 1 expression but greater Pax7 and mygogenin (MYOG) expression (P < 0.05), than the CON BSC. The CI BSC had greater Pax3, Pax7, and MYOG expression than CON BSC (P < 0.05), suggesting that CI would promote BSC myogenesis under pro-myogenic conditions (i.e., when cultured with horse serum). However, both the OA and CI treatments upregulated the expression of PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα) and C/EBPß, sterol regulatory element-binding protein 1, lipoprotein lipase, and glycerol-3-phosphate acyltransferase 3 gene expression, as well as media adiponectin concentration (P < 0.05). The CI, OA, and CI-OA treatments also increased triacylglycerol and lipid droplet accumulation, in spite of upregulation (relative to CON BSC) of adenosine monophosphate-activated protein kinase alpha-1, perilipin 2 (PLIN2), and PLIN3 in BSC and downregulation of G protein-coupled protein receptor 43, acyl-CoA synthetase long chain family member 3, and stearoyl-CoA desaturase (P < 0.05). These results indicate that OA in the absence of a synthetic PPARγ agonist can effectively increase adipogenic gene expression in BSC.


Assuntos
Ácido Oleico/administração & dosagem , PPAR gama/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Adipogenia/genética , Adiponectina/análise , Animais , Bovinos , Diferenciação Celular , Células Cultivadas , Meios de Cultura , Regulação para Baixo , Imunofluorescência , Expressão Gênica , Metabolismo dos Lipídeos/genética , Desenvolvimento Muscular/genética , Miogenina/genética , Miogenina/metabolismo , PPAR gama/agonistas , PPAR gama/genética , RNA/análise , RNA/isolamento & purificação , Células Satélites de Músculo Esquelético/citologia , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tiazolidinedionas/farmacologia , Triglicerídeos/análise , Triglicerídeos/metabolismo
8.
Phytomedicine ; 63: 152999, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280138

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Recently, the inhibitory effects of flavone glycosides isolated from Sicyos angulatus extract on hepatic lipid accumulation in vitro were demonstrated. However, the effects of S. angulatus extract and its major flavonoid glycoside on in vivo hepatic steatosis induced by a high-fat diet have not yet been established. HYPOTHESIS/PURPOSE: The aim of this study was to investigate the effects of S. angulatus extract and its major flavonoid glycoside, kaempferol 3-O-[α-l-rhamnopyranosyl-(1→6)]-ß-d-glucopyranosyl-7-O-α-l-rhamnopyranoside, on hepatic steatosis in high-fat diet-fed mice, which serves as a model of NAFLD. In addition, attempts have been made to chemically profile the metabolites involved in the activity of the S. angulatus extract. METHODS: C57BL/6 J mice were divided into vehicle, total extract of S. angulatus (SA; 50, 100 and 200 mg/kg) and major active component (20 mg/kg) groups. The mice were fed a high-fat diet (HFD) with or without S. angulatus extract or its major single compound for 10 weeks. Chemical identification was carried out using ultra-high-pressure liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-qTOF-MS/MS) and then quantified by HPLC-DAD. RESULTS: Administration of S. angulatus extract significantly lowered plasma ALT and AST levels in HFD-fed mice compared to those of the vehicle group. The hepatic lipid content, as evidenced by oil-red O staining and quantification, was significantly lower in the S. angulatus-administered group, and the effect was dose dependent. These beneficial effects of S. angulatus extract were related to the decreased expression of hepatic genes involved in fatty acid (ACC1, FAS and SCD1) and triglyceride (DGAT) synthesis. The expression levels of two key transcription factors regulating lipogenesis, SREBP-1c and PPARγ, were significantly suppressed in the liver by administration of S. angulatus extract with HFD. Treatment of the HFD-fed mice with the major compound isolated from S. angulatus extract resulted in improved liver function along with an anti-steatotic effect similar to the results seen with S. angulatus extract. For the standardization of the S. angulatus extract, 23 compounds were identified based on MS/MS fragmentation and UV spectroscopy. Quantitative analysis of the major compound showed that the major component was present in 15.35 ± 0.01 mg/g of total extract. CONCLUSION: These findings suggest that S. angulatus extract and its major component have the potential to improve liver function and hepatic steatosis in diet-induced obese mice.


Assuntos
Cucurbitaceae/química , Glicosídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Glicosídeos/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Extratos Vegetais/química , Espectrofotometria Ultravioleta , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Espectrometria de Massas em Tandem
9.
Food Funct ; 10(8): 4966-4974, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31343008

RESUMO

trans-Trismethoxy resveratrol (TMR) is a methyl analog of resveratrol. It is found to exhibit enhanced biological effects compared to resveratrol, such as inhibition of cancer cell growth and pro-apoptotic activities. However, the role of TMR in lipid metabolism is not fully understood. In this study, we used Caenorhabditis elegans, an in vivo nematode model which has been widely applied in disease research, including research on obesity, to investigate the effect of TMR on lipid metabolism. Treatment with TMR (100 and 200 µM) for 4 days significantly reduced triglyceride accumulation (14% and 20% reduction over the control, respectively) of C. elegans, without affecting nematode growth, food intake and reproduction. Treatment with TMR significantly downregulated stearoyl-CoA desaturase genes, fat-6 and fat-7, accompanied by a decrease in the desaturation index of fatty acids, the ratio of oleic acid to stearic acid. These results suggest that TMR inhibits fat accumulation by downregulating stearoyl-CoA desaturase in C. elegans.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Gorduras/metabolismo , Ácidos Graxos Dessaturases/metabolismo , Resveratrol/farmacologia , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Ácidos Graxos Dessaturases/genética , Resveratrol/química , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/metabolismo
10.
Phytomedicine ; 63: 152986, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31310912

RESUMO

BACKGROUND: Polygonum cuspidatum has been used in traditional Chinese medicine to treat liver disorders associated with oxidative stress, inflammation and lipid accumulation for centuries in patients. PURPOSE: The aim of this study was to examine whether P. cuspidatum extract (PCE) prevented against fructose-induced liver lipid accumulation via regulating Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. METHOD: PCE was administered orally to male Sprague-Dawley rats given 10% fructose drinking water for 6 weeks at 80 and 160 mg/kg once daily for 11 weeks. RESULTS: PCE significantly alleviated liver lipid accumulation in fructose-fed rats with metabolic syndrome. It also inhibited Keap1, activated Nrf2 antioxidant pathway, resulting in the suppression of oxidative stress, evidenced by reducing hydrogen peroxide (H2O2), malondialdehyde (MDA) and hydroxy radical (OH•) levels, and increasing glutathione (GSH)/oxidized glutathione (GSSG) ratio as well as superoxidase dismutase (SOD) and catalase (CAT) activity in the liver of fructose-fed rats. Additionally, PCE up-regulated peroxisome proliferator activated receptor-α (PPAR-α), and down-regulated sterol regulatory element binging protein 1 (SREBP-1), fatty acid synthetase (FAS) and stearoyl-CoA desaturase-1 (SCD-1) in this animal model, being consistent with its reduction of triglyceride (TG) levels. CONCLUSION: These results demonstrate that PCE reduces oxidative stress, and prevent lipid accumulation in the liver of fructose-fed rats possibly by targeting the Keap1/Nrf2 pathway. PCE may be a promising therapeutic strategy for fructose-associated liver lipid accumulation.


Assuntos
Fallopia japonica/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Animais , Antioxidantes/metabolismo , Frutose/efeitos adversos , Glutationa/metabolismo , Fígado/metabolismo , Masculino , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
11.
J Vet Med Sci ; 81(8): 1080-1085, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31217402

RESUMO

To evaluate the effect of overfeeding on fatty acid distribution and metabolism, especially stearoyl-CoA desaturase-1 (SCD-1) indices, 8 cats in the experimental and control groups (4 per group) were evaluated in this study. The experiments involved feeding the experimental group cats twice their daily energy requirement with a commercial diet for 4 weeks. The control group was fed the estimated daily energy requirement with the same diet. Body weight, feline body mass index, body condition score, several zoometry measurements, and plasma metabolites/hepatic injury markers were measured in all the cats before and after the experiment. In addition, the fatty acid profiles in the liver and subcutaneous adipose tissue were measured after the experiment. After 4 weeks of overfeeding, the experimental group demonstrated significant increases in hepatic C18:1, plasma triglyceride, and nonesterified fatty acid (NEFA) concentrations and in alanine aminotransferase activity. Furthermore, hepatic SCD-1 indices were positively correlated with body weight, feline body mass index, body condition score, and plasma NEFA concentration, although subcutaneous adipose tissue did not demonstrate any increase in SCD-1 indices in this study. The increase in hepatic SCD-1 indices might be enhanced by the inflow of plasma NEFA into the liver, and NEFA toxicity might stimulate C18:1 synthesis by SCD-1.


Assuntos
Gatos/metabolismo , Dieta/veterinária , Ácidos Graxos/metabolismo , Fígado/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Gordura Subcutânea/metabolismo , Animais , Fígado/enzimologia , Masculino , Recomendações Nutricionais , Gordura Subcutânea/enzimologia
12.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207892

RESUMO

AIM: Primary human hepatocytes (PHHs) undergo dedifferentiation upon the two-dimensional (2D) culture, which particularly hinders their utility in long-term in vitro studies. Lipids, as a major class of biomolecules, play crucial roles in cellular energy storage, structure, and signaling. Here, for the first time, we mapped the alterations in the lipid profile of the dedifferentiating PHHs and studied the possible role of lipids in the loss of the phenotype of PHHs. Simultaneously, differentially expressed miRNAs associated with changes in the lipids and fatty acids (FAs) of the dedifferentiating PHHs were investigated. METHODS: PHHs were cultured in monolayer and their phenotype was monitored morphologically, genetically, and biochemically for five days. The lipid and miRNA profile of the PHHs were analyzed by mass spectrometry and Agilent microarray, respectively. In addition, 24 key genes involved in the metabolism of lipids and FAs were investigated by qPCR. RESULTS: The typical morphology of PHHs was lost from day 3 onward. Additionally, ALB and CYP genes were downregulated in the cultured PHHs. Lipidomics revealed a clear increase in the saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) containing lipids, but a decrease in the polyunsaturated fatty acids (PUFA) containing lipids during the dedifferentiation of PHHs. In line with this, FASN, SCD, ELOVL1, ELOVL3, and ELOVL7 were upregulated but ELOVL2 was downregulated in the dedifferentiated PHHs. Furthermore, differentially expressed miRNAs were identified, and the constantly upregulated miR-27a and miR-21, and downregulated miR-30 may have regulated the synthesis, accumulation and secretion of PHH lipids during the dedifferentiation. CONCLUSION: Our results showed major alterations in the molecular lipid species profiles, lipid-metabolizing enzyme expression as wells as miRNA profiles of the PHHs during their prolonged culture, which in concert could play important roles in the PHHs' loss of phenotype. These findings promote the understanding from the dedifferentiation process and could help in developing optimal culture conditions, which better meet the needs of the PHHs and support their original phenotype.


Assuntos
Desdiferenciação Celular , Hepatócitos/citologia , Metabolismo dos Lipídeos , MicroRNAs/genética , Acetiltransferases/genética , Acetiltransferases/metabolismo , Células Cultivadas , Citocromos/genética , Citocromos/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Hepatócitos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Albumina Sérica Humana/genética , Albumina Sérica Humana/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Regulação para Cima
13.
Bull Exp Biol Med ; 167(2): 263-266, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31243677

RESUMO

We studied the expression of genes encoding enzymes of carbohydrate and lipid metabolism ketohexokinase (Khk), glucokinase (Gck), pyruvate kinase (Pklr), acetyl-Co-carboxylase (Acaca), fatty acid synthase (Fasn), stearoyl-CoA desaturase (Scd), and their transcription regulators ChREBP (Mlxipl), SREBP-1c (Srebf1), and PPARα (Ppara) in rat liver. Control group rats received a semisynthetic ration over 20 weeks. Experimental group 1 received a semisynthetic ration and 20% fructose solution instead of drinking water. Experimental group 2 rats received a semisynthetic ration with quercetin (0.1% fodder weight) and 20% fructose solution. Consumption of 20% fructose solution (experimental group 1) led to an increase in Scd expression in comparison with the control and did not affect the expression of other genes. Addition of quercetin to the ration (experimental group 2) led to a decrease in the expression of Khk, Gck, Fasn, Scd, Mlxipl, and Ppara genes in comparison with experimental group 1. The results suggest that quercetin reduced the expression of genes of carbohydrate and lipid metabolism enzymes in the liver of rats receiving high-fructose ration.


Assuntos
Enzimas/genética , Frutose/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Quercetina/farmacologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Metabolismo dos Carboidratos/efeitos dos fármacos , Metabolismo dos Carboidratos/genética , Dieta , Enzimas/metabolismo , Frutoquinases/genética , Frutoquinases/metabolismo , Glucoquinase/genética , Glucoquinase/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Ratos , Ratos Wistar , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
14.
Acta Biochim Biophys Sin (Shanghai) ; 51(6): 615-626, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31139819

RESUMO

Few information of the function of stearoyl-coenzyme A (CoA) desaturase (SCD) in apicomplaxan parasite has been obtained. In this study, we retrieved a putative fatty acyl-CoA desaturase (TGGT1_238950) by a protein alignment with Plasmodium falciparum SCD in ToxoDB. A typical Δ9-desaturase domain was revealed in this protein. The putative desaturase was tagged with HA endogenously in Toxoplasma gondii, and the endoplasmic reticulum localization of the putative desaturase was revealed, which was consistent with the fatty acid desaturases in other organisms. Therefore, the TGGT1_238950 was designated T. gondii SCD. Based on CRISPR/Cas9 gene editing technology, SCD conditional knockout mutants in the T. gondii TATi strain were obtained. The growth in vitro and pathogenicity in mice of the mutants suggested that SCD might be dispensable for tachyzoite growth and proliferation. The SCD-overexpressing line was constructed to further explore SCD function. The portion of palmitoleic acid and oleic acid were increased in SCD-overexpressing parasites, compared with the RH parental strain, indicating that T. gondii indeed is competent for unsaturated fatty acid synthesis. The SCD-overexpressing tachyzoites propagated slower than the parental strain, with a decreased invasion capability and weaker pathogenicity in mice. The TgIF2α phosphorylation and the expression changes of several genes demonstrated that ER stress was triggered in the SCD-overexpressing parasites, which were more apt toward autophagy and apoptosis. The function of unsaturated fatty acid synthesis of TgSCD was consistent with our hypothesis. On the other hand, SCD might also be involved in tachyzoite autophagy and apoptosis.


Assuntos
Proteínas de Protozoários/imunologia , Estearoil-CoA Dessaturase/imunologia , Toxoplasma/enzimologia , Toxoplasmose/imunologia , Animais , Células Cultivadas , Clonagem Molecular , Humanos , Camundongos Endogâmicos BALB C , Mutação , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Análise de Sequência de DNA , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Análise de Sobrevida , Toxoplasma/genética , Toxoplasma/patogenicidade , Toxoplasmose/parasitologia
15.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31142011

RESUMO

Nonalcoholic fatty liver disease is a frequent liver malady, which can progress to cirrhosis, the end-stage liver disease if proper treatment is not applied. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, have been clinically proven to lower serum triglyceride levels. Various physiological activities of omega-3 fatty acids are due to their agonistic actions on G-protein-coupled receptor 40 (GPR40) and GPR120. Lipid droplets (LD) accumulation in hepatocytes confirmed that DHA treatment reduced the number of larger ( >10 µm2) LDs, as well as the total area of LDs. Moreover, DHA lowered protein and mRNA expression levels of lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase and stearoyl-CoA desaturase-1 (SCD-1) in primary hepatocytes incubated with liver X receptor (LXR) agonist T0901317 or high glucose and insulin. DHA also decreased protein expression of nuclear and precursor sterol response-element binding protein (SREBP)-1, a key lipogenesis transcription factor. We further found that exposure of murine primary hepatocytes to DHA for 12 h increased GPR40 and GPR120 mRNA levels. Specific agonists (Compound A for GPR120 and AMG-1638 for GPR40), hepatocytes from GPR120 knock-out mice and GPR40 selective antagonist (GW1100) were used to assess whether DHA's antilipogenic effects are mediated through GPR120 or GPR40. Compound A did not decrease SREBP-1 and FAS protein expression in hepatocytes exposed to T0901317 or high glucose with insulin. Moreover, DHA downregulated lipogenesis enzyme expression in GPR120-null hepatocytes. In contrast, AMG-1638 lowered SREBP-1 and SCD-1 protein levels. Additionally, GW1100, a GPR40 antagonist, reversed the antilipogenic effects of DHA. Collectively, our data demonstrate that DHA downregulates the expression SREBP-1-mediated lipogenic enzymes via GPR40 in primary hepatocytes.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Hepatócitos/metabolismo , Lipogênese , Receptores Acoplados a Proteínas-G/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Células Cultivadas , Ácidos Graxos Ômega-3/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
16.
Pestic Biochem Physiol ; 156: 152-159, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31027575

RESUMO

Sex pheromone biosynthesis in moths relies on the activity of multiple enzymes, including Δ9 desaturase, which plays an important role in catalyzing desaturation at the Δ9 position of the carbon chain. However, the physiological function of moth Δ9 desaturase has not been elucidated in vivo. In this study, we used the CRISPR/Cas9 system to knockout the Δ9 desaturase gene (SlitDes11) of Spodoptera litura to analyze its role in sex pheromone biosynthesis. First, through the direct injection of SlitDes11-single guide RNA (sgRNA)/Cas9 messenger RNA into newly laid eggs, gene editing was induced in around 30% of eggs 24 h after injection and was induced in 20.8% of the resulting adult moths. Second, using a sibling-crossing strategy, insects with mutant SlitDes11 (bearing a premature stop codon) were selected, and homozygous mutants were obtained in the G5 generation. Third, pheromone gland extracts of adult female homozygous SlitDes11 mutants were analyzed using Gas chromatography (GC). The results showed that titers of all three ester sex pheromone components; Z9, E11-14:Ac, Z9,E12-14:Ac, and Z9-14:Ac; were reduced by 62.40%, 78.50%, and 72.50%, respectively. This study provides the first direct evidence for the role of SlitDes11 in sex pheromone biosynthesis in S. litura, and indicates the gene could be as potential target to disrupt sexual communication in S. litura for developing a new pollution-free insecticide.


Assuntos
Proteínas de Insetos/metabolismo , Atrativos Sexuais/metabolismo , Spodoptera/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Sequência de Aminoácidos , Animais , Feminino , Mutação em Linhagem Germinativa , Proteínas de Insetos/química , Proteínas de Insetos/genética , Mariposas/metabolismo , Mutação/genética , RNA Mensageiro , Alinhamento de Sequência
17.
Chem Pharm Bull (Tokyo) ; 67(4): 327-332, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930436

RESUMO

Δ9-Fatty acid desaturase (Δ9-desaturase) is a rate-limiting enzyme of unsaturated fatty acid biosynthesis in animal cells and specifically introduces a cis-double bond at the Δ9-position of acyl-CoA. Since the chemical structure of fatty acids determines the physicochemical properties of cellular membrane and modulates a broad range of cellular functions, double bond introduction into a fatty acid by Δ9-desaturase should be specifically carried out. Reported crystal structures of stearoyl-CoA desaturase (SCD)1, one of the most studied Δ9-desaturases, have revealed the mechanism underlying the determination of substrate preference, as well as the position (Δ9) and conformation (cis) of double bond introduction. The crystal structures of SCD1 have also provided insights into the function of other Δ9-desaturases, including Drosophila homologs. Moreover, the amino-terminal sequences of Δ9-desaturases are shown to have unique roles in protein degradation. In this review, we introduce recent advances in the understanding of the function and regulation of Δ9-desaturase from the standpoint of protein structure.


Assuntos
Ácidos Graxos Dessaturases/química , Sequência de Aminoácidos , Animais , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/biossíntese , Humanos , Estrutura Terciária de Proteína , Alinhamento de Sequência , Estearoil-CoA Dessaturase/química , Estearoil-CoA Dessaturase/metabolismo , Especificidade por Substrato
18.
Ren Fail ; 41(1): 211-219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30943799

RESUMO

AIM: Stearoyl-CoA desaturase (SCD)-1 and elongase-6 (Elovl-6) are associated with fatty acid (FA) synthesis. We evaluated the effect of omega-3 FA on erythrocyte membrane FA contents through SCD-1 and Elovl-6 expression in the liver and kidney of a cyclosporine (CsA)-induced rat model. METHODS: Male Sprague Dawley rats were divided into control, CsA, and CsA treated with omega-3 FA groups. We measured SCD-1 and Elovl-6 expression levels via western blot and immunohistochemistry analysis. RESULTS: Erythrocyte membrane oleic acid content was lower in the CsA with omega-3 FA group compared to the CsA group. Compared to the control group, CsA-induced rats showed elevated SCD-1 expression in the kidney and liver, which omega-3 FA treatment reversed. Elovl-6 expression was increased in the liver, but decreased in the kidney in CsA group compared to control, which omega-3 FA treatment also reversed. CONCLUSIONS: Omega-3 FA supplementation decreased erythrocyte membrane oleic acid content by modulating SCD-1 and Elovl-6 expression in the kidney and liver of CsA-induced rats.


Assuntos
Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Nefropatias/tratamento farmacológico , Ácido Oleico/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Acetiltransferases/metabolismo , Animais , Membrana Celular/metabolismo , Ciclosporina/toxicidade , Modelos Animais de Doenças , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/sangue , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos , Ratos Sprague-Dawley
19.
Nutrients ; 11(3)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884788

RESUMO

Smaller cross-sectional studies and bariatric surgery trials suggest that weight loss may change the expression of genes in adipose tissue that have been implicated in the development of metabolic diseases, but well-powered intervention trials are lacking. In post hoc analyses of data from a 12-week dietary intervention trial initially designed to compare metabolic effects of intermittent vs. continuous calorie restriction, we analyzed the effects of overall weight loss on the subcutaneous adipose tissue (SAT) transcriptome. Changes in the transcriptome were measured by microarray using SAT samples of 138 overweight or obese individuals (age range: 35⁻65 years, BMI range: 25⁻40, non-smokers, non-diabetics). Participants were grouped post hoc according to the degree of their weight loss by quartiles (average weight loss in quartiles 1 to 4: 0%, -3.2%, -5.9%, and -10.7%). Candidate genes showing differential expression with weight loss according to microarray analyses were validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and fold changes (FCs) were calculated to quantify differences in gene expression. A comparison of individuals in the highest vs. the lowest weight loss quartile revealed 681 genes to be differentially expressed (corrected p < 0.05), with 40 showing FCs of at least 0.4. Out of these, expression changes in secreted frizzled-related protein 2 (SFRP2, FC = 0.65, p = 0.006), stearoyl-CoA desaturase (SCD, FC = -1.00, p < 0.001), and hypoxia inducible lipid droplet-associated (HILPDA, FC = -0.45, p = 0.001) with weight loss were confirmed by RT-qPCR. Dietary weight loss induces significant changes in the expression of genes implicated in lipid metabolism (SCD and HILPDA) and WNT-signaling (SFRP2) in SAT.


Assuntos
Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Gordura Subcutânea/metabolismo , Perda de Peso/genética , Adulto , Idoso , Restrição Calórica/métodos , Estudos Transversais , Regulação para Baixo/genética , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Obesidade/dietoterapia , Obesidade/genética , Obesidade/metabolismo , Transcriptoma , Resultado do Tratamento , Via de Sinalização Wnt/genética
20.
J Med Food ; 22(4): 325-336, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30864855

RESUMO

Nonalcoholic fatty liver disease is a progressive disease involving the accumulation of lipid droplets in the liver. In this study, we investigated the anti-hepatosteatosis effects of fermented Cordyceps militaris extract (CME) in AML-12 hepatocytes. Although the levels of adenosine and cordycepin were reduced in the extracts of CM grown on germinated soybean (GSCE) and fermented CM grown on germinated soybean (GSC) by Pediococcus pentosaceus ON188 (ON188E), the expression of fatty acid oxidation (FAO) genes were upregulated only by GSC-ON188E treatment in a dose-dependent manner. In contrast, a lipogenic gene, stearoyl Coenzyme A desaturase 1, was downregulated by ON188E. Formation of intracellular lipid droplets by the addition of oleic acid was reduced by ON188E to levels observed in WY14643-treated cells. When cells were treated with ON188E, sphingosine kinase 2 mainly responsible for hepatic sphingosine 1-phosphate (S1P) synthesis was upregulated and S1P was elevated. Collectively, the fermented GSC extract activates FAO through elevation of S1P synthesis and has potential as a therapeutic for hepatosteatosis.


Assuntos
Cordyceps/química , Ácidos Graxos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Cordyceps/metabolismo , Fermentação , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/genética , Oxirredução/efeitos dos fármacos , Pediococcus pentosaceus/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
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