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1.
J Food Sci ; 85(7): 2216-2226, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32579753

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is closely related to metabolic syndrome. We investigated the effect of a Psoralea corylifolia L. (PC) seeds extract (PCE) on NAFLD. PC seeds were extracted using different ethanol concentrations to produce five extracts, and the 70% ethanol PCE, which had the highest phenolic content, was used in subsequent in vitro and in vivo experiments. The inhibitory effect of PCE on hepatic steatosis was estimated using HepG2 cells treated with oleic acid (OA). In addition, an in vivo NAFLD model was established using high-fat diet (HFD)-induced obese C57BL/6 mice. Obesity was induced in mice over 14 weeks. PCE (100 or 200 mg/kg/day) was administered orally to mice after 8 weeks of the 14-week treatment period for 6 weeks. PCE suppressed lipid accumulation in OA-treated HepG2 cells. PCE ameliorated the antioxidant activity suppressions induced by the HFD. In addition, both PCE100 and PCE200 groups reduced lipid accumulation and the expression levels of inflammatory proteins as compared with HFD group. PCE administration significantly attenuated hepatic steatosis in liver tissues by decreasing the expression of lipogenic protein sterol regulatory element binding protein 1-c (SREBP-1c) and its downstream protein fatty acid synthase (FAS) in HFD-fed mice and in OA-treated HepG2 cells. Furthermore, PCE administration increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. These results suggest that PCE could be used as a functional material to prevent or ameliorate NAFLD by inhibiting lipid accumulation in liver. PRACTICAL APPLICATION: Psoralea corylifolia L. is rich in polyphenol and other phytochemicals. In this study, we identified the beneficial effects of Psoralea corylifolia L. extract on hepatic steatosis in oleic-acid-induced HepG2 cells and high-fat diet-fed mice. The result of this study will provide the evidence that a Psoralea corylifolia L. extract has potential use as a functional material for the prevention and amelioration of nonalcoholic fatty liver disease.


Assuntos
Ácidos Graxos não Esterificados/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/administração & dosagem , Psoralea/química , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
2.
Am J Hum Genet ; 107(1): 34-45, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32497488

RESUMO

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.


Assuntos
Artrogripose/genética , Mutação/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica/genética , Humanos , Ceratose/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
3.
Anim Sci J ; 91(1): e13391, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32558027

RESUMO

One hundred Yorkshire × Landrace sows were randomly assigned to one of two dietary treatments (diet ND: 6,000 IU vitamin D3 /d feed; diet 25-D: 200 µg/day 25OHD3 feed). The experiment began on d 90 of gestation and continued until weaning on day 21 of lactation. In sows that received 25OHD3 , the growth rate of the piglets before weaning was significantly accelerated (0.266 kg/day, p < .05). Sow serum was collected after weaning, and those in the 25OHD3 group were found to have significantly higher serum calcium (CA) and phosphorus (PI) levels (p < .05). Interestingly, the oestrus cycle of sows fed 25OHD3 was significantly shortened (p < .05), the oestrus time was concentrated on the fifth day after weaning, and the piglets were born with a higher degree of uniformity (p < .05). Colostrum was collected on the day of delivery, and the colostrum of sows fed 25OHD3 contained higher milk fat content than the control group (p < .05). 25OHD3 supplementation increased the mRNA and protein expression of INSIG1 and SREBP1, which regulate milk fat synthesis, in the mammary gland of lactating sows (p < .05). In conclusion, 25OHD3 supplementation in maternal diets improved reproductive performance, milk fat content and the mRNA and protein levels of genes regulating milk fat synthesis in lactating sows.


Assuntos
25-Hidroxivitamina D 2/administração & dosagem , 25-Hidroxivitamina D 2/farmacologia , Fenômenos Fisiológicos da Nutrição Animal/genética , Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Dieta/veterinária , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lactação/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Reprodução/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Suínos/genética , Suínos/fisiologia , Animais , Cálcio/metabolismo , Estro/efeitos dos fármacos , Feminino , Glicolipídeos/metabolismo , Glicoproteínas/metabolismo , Lactação/fisiologia , Fósforo/metabolismo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
4.
J Food Sci ; 85(6): 1915-1923, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32460375

RESUMO

Polar components (PCs) are produced during the frying of oil, affecting the quality of edible oil and posing a hazard to human health. In this study, C57 mice were fed a high-fat (HF) diet containing purified PCs for nine weeks. Their effects on lipid metabolism and liver function in animals were analyzed. Our results indicated that the contents of total PCs and saturated fatty acid increased from 6.07 ± 0.6% and 58.27 ± 0.35% to 19.17 ± 1.8% and 69.91 ± 0.51%, respectively (P < 0.01). PC intake resulted an 18.56% higher liver index in mice than that in the HF group. The PC group had the highest malondialdehyde (MDA) content (1.94 ± 0.11 nmol/mg protein) and the liver nonalcoholic fatty liver disease (NAFLD) activity score (NAS) was 4, which already showed NAFLD characteristics. In addition, the expression levels of lipid metabolism-related genes, including sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthetase (FAS), peroxisome proliferator-activated receptor-alpha, and peroxisome acyl-CoA oxidase 1, indicated that PC increased hepatic lipid accumulation by upregulating the transcriptional level of fat synthesis genes and further leads to liver damage by affecting mitochondrial function. Our results provided important information about the effects of PCs produced in the frying process of PO on animal health, which is critical for assessing the biosafety of fried products. PRACTICAL APPLICATION: The research will help promote the industrial upgrading of fried foods and help consumers build healthy lifestyles.


Assuntos
Metabolismo dos Lipídeos , Fígado/metabolismo , Óleo de Palmeira/química , Óleo de Palmeira/metabolismo , Animais , Culinária , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/metabolismo , Temperatura Alta , Humanos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Óleo de Palmeira/efeitos adversos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
5.
Am J Physiol Endocrinol Metab ; 319(1): E34-E42, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32228319

RESUMO

Nonalcoholic fatty liver disease (NAFLD) amplifies the risk of various liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, and ultimately hepatocellular carcinoma. Accumulating evidence suggests the involvement of aberrant microRNAs (miRNAs or miRs) in the activation of cellular stress, inflammation, and fibrogenesis in hepatic cells at different stages of NAFLD and liver fibrosis. Here, we explored the potential role of miR-130b-5p in the pathogenesis of NAFLD, including lipid accumulation and insulin resistance, as well as the underlying mechanism. Initially, the expression of miR-130b-5p and insulin-like growth factor binding protein 2 (IGFBP2) was examined in the established high-fat diet-induced NAFLD mouse models. Then, the interaction between miR-130b-5p and IGFBP2 was validated using dual luciferase reporter assay. The effects of miR-130b-5p and IGFBP2 on lipid accumulation and insulin resistance, as well as the AKT pathway-related proteins, were evaluated using gain or loss-of-function approaches. miR-130b-5p was upregulated, and IGFBP2 was downregulated in liver tissues of NAFLD mice. miR-130b-5p targeted IGFBP2 and downregulated its expression. MiR-130b-5p inhibition or IGFBP2 overexpression reduced the expression of SREBP-1, LXRα, ChREBP, stearoyl CoA desaturase 1, acetyl CoA carboxylase 1, and fatty acid synthase, and levels of fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance, while increasing the ratio of p-AKT/AKT in NAFLD mice. Overall, downregulation of miR-130b-5p can prevent hepatic lipid accumulation and insulin resistance in NAFLD by activating IGFBP2-dependent AKT pathway, highlighting the potential use of anti-miR-130b-5p as therapeutic approaches for the prevention and treatment of NAFLD.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fígado/metabolismo , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/genética , Acetil-CoA Carboxilase/genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Glicemia/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Ácido Graxo Sintase Tipo I/genética , Expressão Gênica , Regulação da Expressão Gênica , Insulina/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Receptores X do Fígado/genética , Camundongos , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Estearoil-CoA Dessaturase/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
6.
Yakugaku Zasshi ; 140(3): 383-389, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115557

RESUMO

Caloric restriction (CR) improves whole-body metabolism, suppresses various age-related pathophysiological changes, and extends lifespan. The beneficial actions of CR are regulated in growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signal-dependent and -independent manners. To clarify the GH/IGF-1-independent mechanism, we compared gene expression profiles in white adipose tissue (WAT) between CR and GH/IGF-1 suppression, and found that CR upregulated sterol regulatory element-binding protein 1c (SREBP-1c) regulatory gene expression. To validate the impact of SREBP-1c as a beneficial mediator of CR, we compared the responses to CR between wild-type and SREBP-1c knockout (KO) mice. CR extended lifespan, upregulated gene expression involved in FA biosynthesis, activated mitochondrial biogenesis, and suppressed oxidative stress predominantly in WAT. In contrast, most of these findings were not observed in KO mice. Furthermore, SREBP-1c was implicated in CR-associated mitochondrial activation through upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Sirtuin-3 (SIRT3) regulates mitochondrial quality and is also involved in the beneficial actions of CR. We observed that CR upregulated the mature form of SIRT3 protein and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in WAT. MIPEP cleaved precursor form of SIRT3 to mature form, and activated certain mitochondrial matrix proteins, suggesting that MIPEP might contribute to maintenance of mitochondrial quality during CR via SIRT3 activation. Taken together, CR induces SREBP-1c-dependent metabolic remodeling, including enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α, and improvement of mitochondria quality via Mipep in WAT, resulting in beneficial actions.


Assuntos
Tecido Adiposo Branco/metabolismo , Envelhecimento/metabolismo , Restrição Calórica , Animais , Expressão Gênica , Humanos , Longevidade , Camundongos , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 3/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Regulação para Cima
7.
J Med Food ; 23(3): 215-223, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32191576

RESUMO

Anti-obesity activities of Korean red ginseng saponin fraction (RGS) and/or Glycyrrhiza glabra L. extract (GG) were investigated in 3T3-L1 adipocytes and high-fat diet-induced C57BL/6J obese mice. RGS and GG extracts were mixed at a mass ratio of 3:1 (SG31), 1:1 (SG11), or 1:3 (SG13). SG31 showed the highest anti-obesity activity among the three different mass ratios of RGS and GG extracts. SG31 showed higher inhibition efficiency on triglyceride (TG) accumulation than either single extract in 3T3-L1 adipocytes and without any cytotoxicity. It also decreases the expression of adipogenic and lipogenic genes such as C/EBPα and SREBP-1c (sterol regulatory element-binding protein 1c). In the obese induced mouse model, SG31 significantly reduced white adipose tissue weight and body weight, attenuated dyslipidemia, and decreased serum TG levels. In some indices, the activity of SG31 was even higher compared with Garcinia Cambogia water extract, a positive control. The possible mechanism by which SG31 causes the above results was by activating the AMP-activated protein kinase (AMPK) pathway and stimulating the secretion of adiponectin in adipose tissue to regulate energy metabolism balance, inhibit TG formation, and promote ß-oxidation of fatty acids. Therefore, SG31 may have efficacy as an anti-obesity functional food or raw material if the results can be confirmed in human studies.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/administração & dosagem , Glycyrrhiza/química , Obesidade/tratamento farmacológico , Panax/química , Extratos Vegetais/administração & dosagem , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Fármacos Antiobesidade/análise , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Humanos , Lipogênese/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , PPAR gama/genética , PPAR gama/metabolismo , Extratos Vegetais/análise , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue
8.
Gene ; 741: 144516, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32119914

RESUMO

To study the influence of the PGC-1ß gene on chicken adipocyte proliferation and differentiation, we constructed RNA interference (RNAi) vectors that target the PGC-1ß gene and transfected these vectors into adipocytes. Oil Red O staining and a CCK-8 cell kit were used to determine cell triglyceride accumulation status and cell proliferation after transfection, respectively. The mRNA abundances of PGC-1ß and adipocyte-differentiation-related genes (PPARγ, C/EBPα, SREBP-1c, FAS, and A-FABP) were detected by real-time PCR. The results showed that the mRNA and protein abundances of PGC-1ß in PGC-1ß-shRNA transfected adipocytes were significantly lower than those in the control. Interference decreased cell differentiation, but did not depress the cell proliferation. PGC-1ß interference impeded the triglyceride accumulation, the mRNA expression levels of nuclear receptors PPARγ and SREBP-1c, and fatty acid synthetase (FAS), and both proteins PPARγ and SREBP-1c, and the fatty acids transporting protein A-FABP. Generally, PGC-1ß modulated the cell differentiation and triglyceride accumulation in chicken adipocytes.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Diferenciação Celular/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proliferação de Células/genética , Galinhas/genética , Galinhas/crescimento & desenvolvimento , Ácido Graxo Sintases/genética , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , PPAR gama/genética , RNA Mensageiro , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo , Receptor fas/genética
9.
PLoS One ; 15(2): e0228845, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053662

RESUMO

Sterol regulatory element-binding protein (SREBP), a highly conserved family of membrane-bound transcription factors, is an essential regulator for cellular cholesterol and lipid homeostasis in mammalian cells. Sre1, the homolog of SREBP in the fission yeast Schizosaccharomyces pombe (S. pombe), regulates genes involved in the transcriptional responses to low sterol as well as low oxygen. Previous study reported that casein kinase 1 family member Hhp2 phosphorylated the Sre1 N-terminal transcriptional factor domain (Sre1N) and accelerated Sre1N degradation, and other kinases might exist for regulating the Sre1 function. To gain insight into the mechanisms underlying the Sre1 activity and to identify additional kinases involved in regulation of Sre1 function, we developed a luciferase reporter system to monitor the Sre1 activity through its binding site called SRE2 in living yeast cells. Here we showed that both ergosterol biosynthesis inhibitors and hypoxia-mimic CoCl2 caused a dose-dependent increase in the Sre1 transcription activity, concurrently, these induced transcription activities were almost abolished in Δsre1 cells. Surprisingly, either AMPKα Subunit Ssp2 deletion or Glycogen Synthase Kinases Gsk3/Gsk31 double deletion significantly suppressed ergosterol biosynthesis inhibitors- or CoCl2-induced Sre1 activity. Notably, the Δssp2Δgsk3Δgsk31 mutant showed further decreased Sre1 activity when compared with their single or double deletion. Consistently, the Δssp2Δgsk3Δgsk31 mutant showed more marked temperature sensitivity than any of their single or double deletion. Moreover, the fluorescence of GFP-Sre1N localized at the nucleus in wild-type cells, but significantly weaker nuclear fluorescence of GFP-Sre1N was observed in Δssp2, Δgsk3Δgsk31, Δssp2Δgsk3, Δssp2Δgsk31 or Δssp2Δgsk3Δgsk31 cells. On the other hand, the immunoblot showed a dramatic decrease in GST-Sre1N levels in the Δgsk3Δgsk31 or the Δssp2Δgsk3Δgsk31 cells but not in the Δssp2 cells. Altogether, our findings suggest that Gsk3/Gsk31 may regulate Sre1N degradation, while Ssp2 may regulate not only the degradation of Sre1N but also its translocation to the nucleus.


Assuntos
Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Transporte Biológico , Regulação Fúngica da Expressão Gênica/genética , Glicogênio Sintase/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Quinase 3 da Glicogênio Sintase/fisiologia , Quinases da Glicogênio Sintase/metabolismo , Quinases da Glicogênio Sintase/fisiologia , Oxigênio/metabolismo , Fosforilação , Ligação Proteica , Sequências Reguladoras de Ácido Nucleico/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteínas de Ligação a Elemento Regulador de Esterol/fisiologia , Esteróis , Fatores de Transcrição/metabolismo , Ativação Transcricional
10.
J Agric Food Chem ; 68(5): 1436-1446, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31927917

RESUMO

High fructose intake promotes hepatic lipid accumulation. Pterostilbene, a natural analogue of resveratrol found in diet berries, exhibits a hepatoprotective property. Here, we studied the protection by pterostilbene against fructose-induced hepatic lipid accumulation and explored its possible mechanism. We observed a high expression of microRNA-34a (miR-34a, P < 0.05) and a low expression of its target, sirtuin1 (Sirt1, mRNA: P < 0.01; protein: P < 0.001), with the overactivation of downstream sterol regulatory element-binding protein-1 (SREBP-1) lipogenic pathway (nuclear SREBP-1 protein: P < 0.05; FAS and SCD1 mRNA: P < 0.01), in rat livers, as well as BRL-3A and HepG2 cells, stimulated by fructose. More interestingly, pterostilbene recovered the fructose-disturbed miR-34a expression (0.3-0.5-fold vs fructose control, P < 0.05), Sirt1 protein level (1.2- to 1.5-fold vs fructose control, P < 0.05), and SREBP-1 lipogenic pathway, resulting in significant amelioration of hepatocyte lipid accumulation in animal [hepatic triglyceride and total cholesterol (TG&TC) mg/g·wet tissue: 4.90 ± 0.19, 5.23 ± 0.16, 5.20 ± 0.29 vs fructose control 9.73 ± 1.06, P < 0.001; 3.18 ± 0.30, 3.31 ± 0.39, 3.37 ± 0.47 vs 5.67 ± 0.28, P < 0.001] and cell models (BRL-3A TG&TC mmol/g·protein: 0.123 ± 0.011 vs 0.177 ± 0.004, P < 0.001; 0.169 ± 0.011 vs 0.202 ± 0.008, P < 0.05; HepG2: 0.257 ± 0.005 vs 0.303 ± 0.016, P < 0.05; 0.143 ± 0.004 vs 0.201 ± 0.008, P < 0.001). These results provide the experimental evidence supporting the anti-lipogenic effect of pterostilbene against fructose-induced hepatic lipid accumulation via modulating the miR-34a/Sirt1/SREBP-1 pathway.


Assuntos
Frutose/metabolismo , Fígado/efeitos dos fármacos , MicroRNAs/metabolismo , Sirtuína 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Estilbenos/administração & dosagem , Animais , Colesterol/metabolismo , Frutose/efeitos adversos , Fígado/metabolismo , Masculino , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Sirtuína 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo
11.
Nat Commun ; 11(1): 438, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974378

RESUMO

Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.


Assuntos
Imunoterapia/métodos , Lipídeos/biossíntese , Células T Matadoras Naturais/fisiologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Colesterol/metabolismo , Galactosilceramidas/farmacologia , Regulação da Expressão Gênica , Humanos , Interferon gama/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/patologia , PPAR gama/genética , PPAR gama/metabolismo , Pioglitazona/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Microambiente Tumoral/efeitos dos fármacos
12.
Biomed Res Int ; 2020: 4087928, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998789

RESUMO

Objective: Nonalcoholic fatty liver disease (NAFLD) is among the most common chronic liver diseases. However, the pathogenesis of NAFLD is not still unclear. This study aims at evaluating the role of zinc finger and BTB domain-containing 7A (ZBTB7A) in NAFLD. Methods: Western blotting, real-time reverse transcription PCR (RT-PCR), and immunohistochemistry were submitted to evaluate the level of ZBTB7A in the high fatty diet- (HFD-) induced NAFLD mouse model. In vitro, the expression of ZBTB7A was assessed in oleic acid- (OA-) induced HepG2 cells with western blotting and RT-PCR. The luciferase reporter assay was used to estimate the effect of ZBTB7A on the SREBP1 and NF-κB, and the ChIP assay was subjected to evaluate the direct binding to the SREBP1 promoter. Oil Red staining was used to detect lipid accumulation, and the ELISA was used to verify the levels of TG, T-CHO, and MDA. ZBTB7A was knocked down with siRNA, and RT-PCR was performed to analyze the lipogenesis-, fatty acid transporter-, and oxidation metabolism-related genes expression. The levels of ZBTB7A in primary hepatocyte, Kupffer, and hepatic stellate cells (HSCs) were tested by RT-PCR. Results: The upregulation of ZBTB7A expression was assessed in NAFLD mice, and ZBTB7A expression was positively correlated with TNFα, IL-6, TG, T-CHO, and MDA. ZBTB7A was highly expressed in the hepatocytes. In vitro, OA-induced ZBTB7A expression and ZBTB7A expression were closely associated with SREBP1c. ZBTB7A could activate the promoter activity of SREBP1 and activate NF-κB activity. Interestingly, the direct binding of ZBTB7A in the SREBP1 promoter was acquired in HepG2 cells. Inhibition of ZBTB7A expression could attenuate OA-induced lipid accumulation, inhibit the expression of the lipogenesis-related genes and fatty acid transporter genes, and promote the expression of oxidation metabolism-related genes. Conclusion: ZBTB7A plays a significant role in the development process of NAFLD, and obesity-induced upregulation of ZBTB7A promotes lipid accumulation through activation of SREBP1 and NF-κB. ZBTB7A may be a potential novel target for the therapy of NAFLD.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/biossíntese , Regulação para Cima , Animais , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Células Hep G2 , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Fatores de Transcrição/genética
13.
Int J Mol Sci ; 21(2)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952262

RESUMO

Hyperlipidemia is a chronic disorder that plays an important role in the development of cardiovascular diseases, type II diabetes, atherosclerosis, hypertension, and non-alcoholic fatty liver disease. Hyperlipidemias have created a worldwide health crisis and impose a substantial burden not only on personal health but also on societies and economies. Transcription factors in the sterol regulatory element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. SREBPs regulate lipid homeostasis by controlling the expression of a range of enzymes required for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol, and phospholipids. Thereby, SREBPs have been considered as targets for the treatment of metabolic diseases. The aim of this study was to investigate the beneficial functions and the possible underlying molecular mechanisms of SREBP decoy ODN, which is a novel inhibitor of SREBPs, in high-fat diet (HFD)-fed hyperlipidemic mice. Our studies using HFD-induced hyperlipidemia animal model revealed that SREBB decoy ODN inhibited the increased expression of fatty acid synthetic pathway, such as SREBP-1c, FAS, SCD-1, ACC1, and HMGCR. In addition, SREBP decoy ODN decreased pro-inflammatory cytokines, including TNF-α, IL-1ß, IL-8, and IL-6 expression. These results suggest that SREBP decoy ODN exerts its anti-hyperlipidemia effects in HFD-induced hyperlipidemia mice by regulating their lipid metabolism and inhibiting lipogenesis through inactivation of the SREPB pathway.


Assuntos
Modelos Animais de Doenças , Hiperlipidemias/prevenção & controle , Oligodesoxirribonucleotídeos/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Animais , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/etiologia , Hiperlipidemias/genética , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Masculino , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
14.
Comput Biol Chem ; 84: 107163, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31767507

RESUMO

The present study was to illustrate the agonistic property of arjungenin and arjunic acid towards farnesoid X receptor protein (FXR).The pharmacokinetic properties like molecular interactions, absorption, distribution, metabolism, elimination and toxicity (ADMET) of the ligands were checked through in-silico studies. Protein-ligand docking was carried out using autodock software. Molecular docking analysis confirmed strong binding energy and interaction of arjungenin and arjunic acid with the target protein and the ADMET profiles identified for both compounds were promising.Further in vitro studies were performed in 3T3-L1 adipocyte to verify the agonistic property of arjungenin and arjunic acid. Oil red O staining was done to check differentiation induction. Adiponectin, leptin, triglycerides and total cholesterol levels were quantified. The mRNA expression of FXR, Cyp7a1, PPAR-γ and SREBP-1c were quantified using fluorescent real-time PCR. Cytotoxicity assay was confirmed that up to 150 µM concentration there is no significant cell death on treatment with arjunic acid and arjungenin. Treatment with arjungenin and arjunic acid confirms increased differentiation of the cells with significant (P < 0.05) increase in adiponectin (118.07% and 132.92%) and leptin (133.52% and 149.74%) protein levels compared to the negative control group. After treatment with arjungenin and arjunic acid in 3T3-L1 preadipocytes the mRNA expression of FXR, PPAR-γ and SREBP-1c were significantly (P < 0.01) increased and cyp7a1 was significantly (P < 0.01) decreased when compared with the negative control group. Overall, our results suggest that arjungenin and arjunic acid acts as an FXR agonist and may be useful for rational therapeutic strategies as a novel drug to treat cholesterol mediated metabolic syndrome and insulin resistance.


Assuntos
Receptores Citoplasmáticos e Nucleares/agonistas , Triterpenos/farmacologia , Células 3T3-L1 , Adiponectina/metabolismo , Animais , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Expressão Gênica/efeitos dos fármacos , Leptina/metabolismo , Camundongos , Simulação de Acoplamento Molecular , PPAR gama/genética , PPAR gama/metabolismo , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triterpenos/metabolismo , Triterpenos/farmacocinética , Triterpenos/toxicidade
15.
Mol Cell Biochem ; 463(1-2): 13-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31541353

RESUMO

Insulin stimulates de novo lipid synthesis in the liver and in cultured hepatocytes via its ability to activate sterol regulatory element-binding protein 1c (SREBP-1c). Although PI3K-AKT-mTORC1-p70S6K-signaling kinases are known to drive feed-forward expression of SREBP-1c, the identity of the phosphorylated amino acid residue(s) putatively involved in insulin-stimulated de novo lipogenesis remains elusive. We obtained in silico and mass spectrometry evidence, that was combined with siRNA strategies, to discover that insulin-induced phosphorylation of serine 418, serine 419, and serine 422 in rat SREBP-1c was most likely mediated by p70S6 kinase. Here, for the first time, we show that insulin-induced phosphorylation of these 3 serine residues mainly impinged on the mechanisms of proteostasis of both full-length and mature SREBP-1c in the McArdle-RH7777 hepatoma cells. Consistent with this conclusion, nascent SREBP-1c, substituted with phosphomimetic aspartic acid residues at these 3 sites, was resistant to proteasomal degradation. As a consequence, endoplasmic reticulum to Golgi migration and proteolytic maturation of pSREBP-1c was significantly enhanced which led to increased accumulation of mature nSREBP-1c, even in the absence of insulin. Remarkably, aspartic acid substitutions at S418, S419 and S422 also protected the nascent SREBP-1c from ubiquitin-mediated proteasome degradation thus increasing its steady-state levels and transactivation potential in the nucleus. These complementary effects of p70S6K-mediated phosphorylation on proteostasis of pSREBP-1c were necessary and sufficient to account for insulin's ability to enhance transcription of genes controlling de novo lipogenesis in hepatocytes.


Assuntos
Hepatócitos/metabolismo , Lipídeos/biossíntese , Lipogênese , Proteostase , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Hepatócitos/citologia , Humanos , Lipídeos/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Serina-Treonina Quinases TOR/genética , Transcrição Genética
16.
Toxicol Lett ; 319: 85-94, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730885

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic hepatic disease associated with the excessive accumulation of lipids in the liver. Premenopausal women are protected from the liver metabolic complications of obesity compared with body mass index (BMI)-matched men. This protection may be related to estrogen's ability to limit liver fat accumulation. Aryl hydrocarbon receptor (AhR), a novel regulator of NAFLD, may be an important target for regulating estrogen homeostasis. In present study, we used benzo[a]pyrene (BaP), a classic and potent ligand of AhR, to activate AhR pathway causes overexpression of the estrogen-metabolizing enzyme cytochrome P450 1A1 (CYP1A1) and affects the expression of important genes involved in hepatic lipid regulation. BaP induces CYP1A1 expression through AhR signaling and inhibits the protective effect of 17ß-estradiol (E2) on hepatic steatosis, characterized by triglyceride accumulation, and markers of liver damage are significantly elevated. The expression of adipogenic genes involved in the hepatic lipid metabolism of sterol regulatory element-binding protein-1c (SREBP-1c) was increased compared with that in the control group. Furthermore, the mRNA and protein levels of peroxisome proliferator-activated receptor alpha (PPARα), which is involved in fatty acid oxidation, were significantly reduced. Taken together, our results revealed that the steatotic effect of AhR is likely due to overexpression of the E2 metabolic enzyme CYP1A1, which affects the estrogen signaling pathway, leading to the suppression of fatty acid oxidation, inhibition of the hepatic export of triglycerides, and an increase in peripheral fat mobilization. The results from this study may help establish AhR as a novel therapeutic and preventive target for fatty liver disease.


Assuntos
Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Benzo(a)pireno/farmacologia , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A1/genética , Estradiol/farmacologia , Estrogênios/metabolismo , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/biossíntese , PPAR alfa/genética , Receptores de Hidrocarboneto Arílico/agonistas , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo
17.
J Nat Med ; 74(1): 142-152, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31463669

RESUMO

Cynandione A (CA), isolated from ethyl acetate extract of Cynanchum wilfordii (CW), is a bioactive phytochemical that has been found to be beneficial for the treatment of several diseases. Hepatic de novo lipogenesis is one of the main causes of non-alcoholic fatty liver disease (NAFLD), which is thought to be a hepatic manifestation of certain metabolic syndromes. However, it has not yet been reported if CA has any therapeutic value in these diseases. Here, we investigated whether CA can inhibit hepatic lipogenesis induced by liver X receptor α (LXRα) using an in vitro model. We found that the extract and ethyl acetated layer of CW decreased the mRNA levels of sterol regulatory element-binding protein-1c (SREBP-1c), which plays a crucial role in hepatic lipogenesis. Additionally, we observed that CA could suppress the level of SREBP-1c, which was increased using two commercial LXRα agonists, GW3954 and T0901317. Moreover, the enzymes that act downstream of SREBP-1c were also inhibited by CA treatment. To understand the mechanism underlying this effect, the levels of phosphorylated AMP kinase (pAMPK) were measured after CA treatment. Therefore, CA might increase the pAMPK level by inducing phosphorylation of liver kinase B1 (LKB1), which can then convert AMPK to pAMPK. Taken together, we conclude that CA has an alleviative effect on hepatic lipogenesis through the stimulation of the LKB1/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Compostos de Bifenilo/farmacologia , Cynanchum/química , Lipogênese/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Células Hep G2 , Humanos , Hidrocarbonetos Fluorados/farmacologia , Fígado/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fosforilação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Sulfonamidas/farmacologia
18.
Food Funct ; 11(1): 483-492, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31833514

RESUMO

Obesity, being overweight and deposition of body fat are critically associated with metabolic disorders. The number of adipocytes and their lipid content, and the molecules involved in lipid metabolism are involved in obesity comorbidity. The food, Solanum nigrum L. (SN), has medical benefits in many aspects. In our recent report, SN was shown to reduce hepatic fat accumulation and oxidative stress, thus attenuating liver damage. However, it has not yet been explored whether SN is effective for weight loss and body fat reduction. Hence, we aimed to investigate if SN water extract (SWE) and the derived polyphenols (SNPE) are able to prevent obesity. Mice fed a high fat diet (HFD) and 3T3L1 cells model were used. The in vivo experiments showed SWE decreased serum triacylglyceride, cholesterol, and low-density lipoprotein (LDL)-cholesterol induced by a HFD. SWE promoted hepatic lipolysis by increasing PPARα and CPT-1, and inhibited lipogenesis by decreasing FaS and HMG-CoR. The expression of AMPK was enhanced, but sterol regulatory element binding proteins (SREBPs) were reduced by SWE, especially at 5%. In vitro analysis revealed that SNPE decreased the amount and lipid content of adipocytes. SNPE, especially at 0.5 mg mL-1, promoted lipolysis while inhibiting lipogenesis. In comparison with the doses applied in vivo and in vitro, the effect of SN could be attributed to the composition of the polyphenols. The results showed that SNPE is suggested to be an anti-obesity agent that is able to reduce body weight and body fat, by decreasing the amount and lipid content of adipocytes, and regulating lipid metabolism.


Assuntos
Tecido Adiposo/metabolismo , Fármacos Antiobesidade/administração & dosagem , Peso Corporal/efeitos dos fármacos , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Solanum nigrum/química , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , LDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Humanos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , PPAR alfa/genética , PPAR alfa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
19.
Exp Cell Res ; 387(2): 111753, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837293

RESUMO

PURPOSE: The metabolic syndrome (MetS) is characterized of a cluster of medical disorders. Altered function of adipose tissue has a significant impact on whole-body metabolism and represents a key driver for MetS. In this study, we aim to explore the function of human circular RNA H19 (hsa_circH19) in human adipose-derived stem cells (hADSCs). METHODS: The blood samples from MetS patients and normal subjects were used to determine the expression level of the hsa_circH19. After knock-down of hsa_circH19 in hADSCs, we measured the expression of adipogenic genes. Oil red O, Nile red staining assay and triglyceride assessment were performed to examine the role of hsa_circH19 in hADSCs differentiation. Then, RNA Pull-down and RIP assays were conducted to explore the related RNA binding protein of hsa_circH19. IF was performed to determine the potential molecular regulatory mechanism. RESULTS: After accounting for confounding factors, high levels of hsa_circH19 remained an independent risk factor for MetS. Furthermore, the knockdown of hsa_circH19 significantly increased the expression of adipogenic genes and the formation of lipid droplets. Bioinformatics analyses revealed that has_circH19 shared multiple binding sites with polypyrimidine tract-binding protein 1 (PTBP1) and their interaction was validated by circRNA pull-down and RIP assays. Mechanistically, depletion of hsa_circH19 triggered translocation of sterol-regulatory element binding proteins (SREBP1) from cytoplasm to nucleus in the presence of PTBP1. CONCLUSION: Our experiments suggest that knockdown of hsa_circH19 promotes hADCSs adipogenic differentiation via targeting of PTBP1. In consequence, the expression of hsa_circH19 might correlated to lipid metabolism in adipose tissue from MetS.


Assuntos
Adipogenia/genética , Adipogenia/fisiologia , Tecido Adiposo/fisiologia , Diferenciação Celular/genética , RNA Circular/genética , RNA Longo não Codificante/genética , Adipócitos/fisiologia , Idoso , Feminino , Ribonucleoproteínas Nucleares Heterogêneas , Humanos , Masculino , Células-Tronco Mesenquimais/fisiologia , Pessoa de Meia-Idade , Proteína de Ligação a Regiões Ricas em Polipirimidinas , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
20.
Biomed Pharmacother ; 123: 109791, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31887541

RESUMO

BACKGROUND: SREBP1 is a well-known transcript factor regulating lipogenesis. It has been reported to play an important role in tumor progress in recent years. However, the roles of SREBP1 in differentiated thyroid cancer (DTC) are uncertain. Based on this, we aimed to investigate the expression of SREBP1 and the influence of SREBP1 on DTC patients. METHODS: qRT-PCR and immunohistochemistry were used to detect the expression of SREBPs in DTC tissues and the adjacent normal tissues. The following methods, including the MTS, colony-forming assay, flow cytometry and Hoechst staining were used to detect the biological function of thyroid cancer cells based on SREBP1 interference or not. RESULTS: the expression of SREBP1 was significantly different among DTCs, thyroid nodules and the adjacent normal tissues. Briefly, SREBP1 was upregulated follow with the malignancy, but there was no significant difference of SREBP2 between thyroid nodules and the adjacent normal tissues. Further, the ROC curve showed that SREBP1 has higher diagnostic value than SREBP2. SREBP1 expression was significantly related to the tumor size and lymph node metastasis in DTCs. In vitro, the proliferation of thyroid cancer cells was suppressed obviously after interfered with SREBP1, and the apoptotic cells was increased. Further, SREBP1 expression was also associated with the short-term efficacy of levothyroxine in DTC patients. CONCLUSION: this is the first time to report that SREBP1 is an oncogene and a pro-proliferation factor in thyroid cancer, indicating that SREBP1 may serve as a potential biomarker and therapeutic target in thyroid cancer.


Assuntos
Biomarcadores Tumorais/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Tiroxina/administração & dosagem , Adulto , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento , Adulto Jovem
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