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1.
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
2.
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
3.
J Agric Food Chem ; 67(45): 12419-12427, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31610126

RESUMO

The liver X receptors (LXRs) are major regulators of lipogenesis, and their reduced activation by an inhibitor could be a treatment strategy for fatty liver disease. Small molecules originating from dietary food are considered suitable and attractive drug candidates for humans in terms of safety. In this study, an edible plant, Lysimachia vulgaris (LV), used as a traditional and medicinal food in East Asia was evaluated for lipogenesis decreasing effects. Activity-guided fractionation was performed, and the isolated compounds were identified using spectroscopic methods. We conducted in vitro real-time polymerase chain reaction (PCR) and Western blotting as well as histological and biochemical analyses following in vivo treatments. Using a high-fat diet animal model, we confirmed that LV extracts (LVE) decreased lipogenic metabolism and restored liver function to control levels. To identify active components, we conducted activity-guided fractionation and then isolated compounds. Two compounds, loliolide and pinoresinol, were identified in the dichloromethane fraction, and they significantly attenuated the expression levels of lipogenic factors including sterol regulatory element-binding protein (SREBP)-1, stearoyl-CoA desaturase 1 (SCD1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Importantly, loliolide and pinoresinol significantly accelerated the protein degradation of LXRs by enhanced ubiquitination, which inhibited lipogenesis. These results suggest that loliolide and pinoresinol might be potential candidate supplementary treatments for nonalcoholic fatty liver disease (NAFLD) by reducing lipogenesis through increased ubiquitination of LXRs.


Assuntos
Benzofuranos/administração & dosagem , Furanos/administração & dosagem , Lignanas/administração & dosagem , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Primulaceae/química , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Humanos , Fígado/metabolismo , Receptores X do Fígado/genética , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
4.
Rev Assoc Med Bras (1992) ; 65(9): 1144-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618328

RESUMO

OBJECTIVE: In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS: A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS: The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION: The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.


Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Muco do Colo Uterino/efeitos dos fármacos , Clomifeno/farmacologia , Quimioterapia Combinada , Endométrio/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Indução da Ovulação , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto Jovem
5.
BMC Complement Altern Med ; 19(1): 255, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519174

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is characterized by excessive hepatic lipid accumulation. Many studies have suggested that lipid overload is the key initial factor that contributes to hepatic steatosis. Our previous study indicated that diosgenin (DSG) has a beneficial effect on energy metabolism, but the underlying mechanism remains unclear. METHODS: Human normal hepatocytes (LO2 cells) were incubated with palmitic acid to establish the cell model of nonalcoholic fatty liver. The effects of DSG on lipid metabolism, glucose uptake and mitochondrial function were evaluated. Furthermore, the mechanism of DSG on oxidative stress, lipid consumption and lipid synthesis in LO2 cells was investigated. RESULTS: The results indicated that palmitic acid induced obvious lipid accumulation in LO2 cells and that DSG treatment significantly reduced the intracellular lipid content. DSG treatment upregulated expression of lipolysis proteins, including phospho-AMP activated protein kinase (p-AMPK), phospho-acetyl-coA carboxylase (p-ACC) and carnitine acyl transferase 1A (CPT-1A), and inhibited expression of lipid synthesis-related proteins, including sterol regulatory element-binding protein 1c (SREBP-1c) and fatty acid synthase (FAS). Additionally, DSG-treated cells displayed a marked improvement in mitochondrial function, with less production of reactive oxygen species and a higher mitochondrial membrane potential compared with the model group. CONCLUSION: This study suggests that DSG can reduce intracellular lipid accumulation in LO2 cells and that the underlying mechanism may be related to the improving oxidative stress, increasing fatty acid ß-oxidation and decreasing lipid synthesis. The above changes might be mediated by the activation of the AMPK/ACC/CPT-1A pathway and inhibition of the SREBP-1c/FAS pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Diosgenina/farmacologia , Ácido Graxo Sintases/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácido Palmítico/efeitos adversos , Proteínas Quinases Ativadas por AMP/genética , Acetil-CoA Carboxilase/genética , Carnitina O-Acetiltransferase/genética , Carnitina O-Acetiltransferase/metabolismo , Linhagem Celular , Ácido Graxo Sintases/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
6.
BMC Complement Altern Med ; 19(1): 246, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488172

RESUMO

BACKGROUND: Yangkyuksanwha-tang (YST) is an herbal medicine based on Sasang constitutional medicine (SCM) and is widely used in Korean traditional medicine. The aim of the study was to evaluate the effect of YST on obesity in high-fat diet (HFD)-induced obese mice. METHODS: We induced obesity in C57bl/6 J mice using a HFD, and then orally administered 300 mg/kg YST for 6 weeks. We measured body weight, food efficiency, organ and fat weight, serum biochemical parameters, and obesity-related gene expression, and carried out histological analysis at the end of the experimental period. RESULTS: YST significantly reduced the absolute body weight and food efficiency ratio. The serum, aminotransferase, glucose, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels were significantly lower in the YST-treated group than in the control group, whereas the high-density lipoprotein-cholesterol level in the YST-treated group was significantly higher. The YST-treated group also showed a significant reduction in regional fatty tissues and the absolute weight of various organs. We also observed a significantly reduced expression of AP2/FABP4, C/EBP-ß, leptin, and SREBP1c/ADD1 mRNA, and significantly increased expression of UCP-2 and adiponectin mRNA in adipose tissue in the YST-treated group. YST also decreased the lipid droplet size and lipid accumulation in the liver, as well as adipocyte size in epididymal adipose tissue. At the dose tested, YST was non-toxic to the liver and kidneys of the mice. CONCLUSION: The results imply that YST has anti-obesity effects in obesity-induced mice. Although the number of experimental animals was limited and the drug effects concern mice, rather than humans, which have different constitutions, the study has valuable implications with respect to the general effects of YST.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Fármacos Antiobesidade/química , Peso Corporal/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , HDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Humanos , Leptina/genética , Leptina/metabolismo , Masculino , Medicina Tradicional Coreana , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Extratos Vegetais/química , Plantas Medicinais/química , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
7.
J Agric Food Chem ; 67(37): 10513-10520, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31475823

RESUMO

Amino acids can stimulate milk fat synthesis, but the underlying molecular mechanism is still largely unknown. In this study, we studied the regulatory role and corresponding molecular mechanism of cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2) in amino acid-induced milk fat synthesis in mammary epithelial cells. We showed that leucine and methionine stimulated CRTC2 but not p-CRTC2(Ser171) expression and nuclear localization in cow mammary epithelial cells. Knockdown of CRTC2 decreased milk fat synthesis and sterol regulatory element binding protein 1c (SREBP-1c) expression and activation, whereas its overexpression had the opposite effects. Neither knockdown nor overexpression of CRTC2 affected ß-casein synthesis and phosphorylation of the machanistic target of rapamycin (mTOR), suggesting that CRTC2 only regulates milk fat synthesis. CRTC2 knockdown abolished the stimulation of leucine and methionine on SREBP-1c expression and activation. Knockdown or overexpression of CRTC2 did not affect the protein level of cAMP-response element-binding protein (CREB) and its phosphorylation but decreased or increased the binding of p-CREB to the promoter of SREBP-1c gene and its mRNA expression, respectively. Mutation of Ser171 of CRTC2 did not alter the stimulation of CRTC2 on SREBP-1c expression and activation, further suggesting that CRTC2 functions in the nucleus. mTOR inhibition by rapamycin totally blocked the stimulation of leucine and methionine on CRTC2 expression. The expression of CRTC2 was dramatically higher in the mouse mammary gland of lactation period, compared with that of the dry and puberty periods, whereas p-CRTC2(Ser171) was not changed, further supporting that CRTC2 is a key transcription coactivator for milk fat synthesis. These results uncover that CRTC2 is a key transcription coactivator of amino acid-stimulated mTOR-mediated milk fat synthesis in mammary epithelial cells.


Assuntos
Aminoácidos/metabolismo , Bovinos/metabolismo , Células Epiteliais/metabolismo , Gorduras/metabolismo , Glândulas Mamárias Animais/citologia , Leite/metabolismo , Fatores de Transcrição/metabolismo , Animais , Bovinos/genética , Feminino , Glândulas Mamárias Animais/metabolismo , Camundongos , Fosforilação , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética
8.
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
9.
Chem Biol Interact ; 311: 108794, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421115

RESUMO

Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae), with anti-inflammatory and hepatic-protective effects. The present study intended to reveal the effect and mechanism of AA on nonalcoholic fatty liver disease (NAFLD) associated with lipid accumulation by activating Farnesoid X receptor (FXR) and liver X receptors (LXRs) signaling. C57BL/6 mice were received a modified Lieber-DeCarli diet with 71% high-fat (L-D) and treated with AA (20 and 40 mg/kg) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid (PA). When L-D diet-fed mice were treated with AA, loss in body weight, liver index, and liver lipid droplet were observed along with reduced triglyceride (TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1 (SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones (FXR antagonist) or GW3965 (LXR agonist). Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.


Assuntos
Diterpenos/farmacologia , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Dieta Hiperlipídica , Diterpenos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores X do Fígado/agonistas , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , PPAR alfa/metabolismo , Ácido Palmítico/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue
10.
Biol Pharm Bull ; 42(8): 1295-1302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366865

RESUMO

Obesity is characterized by abnormal or excessive fat accumulation, which leads to the development of metabolic syndrome. Because oxidative stress is increased in obesity, antioxidants are regarded as suitable agents for preventing metabolic syndrome. Here, we examined the impact of cranberry, which contains various antioxidants, on metabolic profiles, including that during the progression of non-alcoholic fatty liver disease (NAFLD), in high-fat diet (HFD)-fed C57BL/6 mice. We observed that oxidative stress was diminished in mice that were fed HFD diets supplemented with 1 and 5% cranberry powder as compared with that in HFD-fed control mice. Notably, from 1 week after beginning the diets to the end of the study, the body weight of mice in the cranberry-treatment groups was significantly lower than that of mice in the HFD-fed control group; during the early treatment phase, cranberry suppressed the elevation of serum triglycerides; and adipocytes in the adipose tissues of cranberry-supplemented-HFD-fed mice were smaller than these cells in HFD-fed control mice. Lastly, we examined the effect of cranberry on NAFLD, which is one of the manifestations of metabolic syndrome in the liver. Histological analysis of the liver revealed that lipid-droplet formation and hepatocyte ballooning, which are key NAFLD characteristics, were both drastically decreased in cranberry-supplemented-HFD-fed mice relative to the levels in HFD-fed control mice. Our results suggest that cranberry ameliorates HFD-induced metabolic disturbances, particularly during the early treatment stage, and exhibits considerable potential for preventing the progression of NAFLD.


Assuntos
Antioxidantes/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Preparações de Plantas/uso terapêutico , Vaccinium macrocarpon , Animais , Antioxidantes/farmacologia , Glicemia/análise , Dieta Hiperlipídica , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Preparações de Plantas/farmacologia , Pós , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/sangue
11.
J Exp Clin Cancer Res ; 38(1): 302, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296258

RESUMO

BACKGROUND: Diabetes is recognized to be a risk factor of pancreatic cancer, but the mechanism has not been fully elucidated. Sterol regulatory element binding protein 1 (SREBP1) is an important transcription factor involved in both lipid metabolism and tumor progression. However, the relationship between high glucose microenvironment, SREBP1 and pancreatic cancer remains to be explored. METHODS: Clinical data and surgical specimens were collected. Pancreatic cancer cell lines BxPc-3 and MiaPaCa-2 were cultured in specified medium. Immunohistochemistry (IHC) and western blotting were performed to detect the expression of SREBP1. MTT and colony formation assays were applied to investigate cell proliferation. Immunofluorescence, mRFP-GFP adenoviral vector and transmission electron microscopy were performed to evaluate autophagy. We used streptozotocin (STZ) to establish a high glucose mouse model for the in vivo study. RESULTS: We found that high blood glucose levels were associated with poor prognosis in pancreatic cancer patients. SREBP1 was overexpressed in both pancreatic cancer tissues and pancreatic cancer cell lines. High glucose microenvironment promoted tumor proliferation, suppressed apoptosis and inhibited autophagy level by enhancing SREBP1 expression. In addition, activation of autophagy accelerated SREBP1 expression and suppressed apoptosis. Moreover, high glucose promotes tumor growth in vivo by enhancing SREBP1 expression. CONCLUSION: Our results indicate that SREBP1-autophagy axis plays a crucial role in tumor progression induced by high glucose microenvironment. SREBP1 may represent a novel target for pancreatic cancer prevention and treatment.


Assuntos
Autofagia/genética , Glucose/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto , Idoso , Animais , Apoptose/genética , Glicemia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Expressão Gênica , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
12.
J Agric Food Chem ; 67(32): 8884-8895, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31345029

RESUMO

Leucine is an essential amino acid in the milk production of bovine mammary glands, but the regulatory roles and molecular mechanisms of leucine are still not known well. This study investigated the roles of leucine on milk synthesis and explored the corresponding mechanism in bovine mammary epithelial cells (BMECs). Leucine (0, 0.25, 0.5, 0.75, 1.0, and 1.25 mM) was added to BMECs that were cultured in FBS-free OPTI-MEM medium. Leucine significantly promoted milk protein and milk fat synthesis and also increased phosphorylation of mTOR signaling protein and the protein expression levels of SREBP-1c, with the most significant effects at 0.75 mM concentration. Leucine increased the expression and nuclear localization of DDX59, and loss and gain of gene function experiments further reveal that DDX59 mediates the stimulation of leucine on the mRNA expression variation of mTOR and SREBP-1c genes. PI3K inhibition experiment further detected that leucine upregulated expression of DDX59 and its downstream signaling via PI3K activation. ChIP-qPCR analysis further proved the binding of DDX59 to the promoter regions of mTOR and SREBP-1c. In summary, these data prove that DDX59 positively regulates the mTOR and SREBP-1c signaling pathways leading to synthesis of milk, and leucine regulates these two signaling pathways through the PI3K-DDX59 signaling.


Assuntos
Bovinos/metabolismo , Células Epiteliais/metabolismo , Leucina/metabolismo , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , RNA Helicases/metabolismo , Animais , Bovinos/genética , Feminino , Fosfatidilinositol 3-Quinases/genética , RNA Helicases/genética , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
13.
Food Funct ; 10(8): 4705-4715, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31304501

RESUMO

Lactobacillus reuteri FN041 is a secretory IgA-targeted Lactobacillus strain from human breast milk that has probiotic potential. The aim of this study was to test whether FN041 can alleviate dyslipidaemia and mucosal-barrier damage caused by a high-fat diet (HFD) and whether it can affect diurnal variation of the intestinal microbiota. C57BL/6 mice were fed either a normal chow diet or high-fat diet (HFD) for 7 weeks and were treated with either PBS as a control or L. reuteri FN041 for 4 weeks. Our results showed that FN041 treatment significantly attenuated HFD-induced weight gain (P < 0.01), accumulation of testicular fat, an increase in locomotor activity during the active phase (P < 0.01), triglyceridaemia, hypercholesterolaemia (P < 0.05), liver Fas overexpression, and Srebp1c mRNA expression inhibition. Moreover, FN041 treatment improved intestinal epithelial barrier function and induced a daily oscillation-dependent change in short-chain fatty acid production by the gut microbiota. A deeper understanding of the molecular pathways participating in intestinal barrier and microbiota modifications, and changes to lipid metabolism under the influence of FN041, will have important implications by potentially opening new horizons for the development of relevant foods to prevent metabolic disorders and unrelated intestinal diseases.


Assuntos
Dislipidemias/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Lactobacillus reuteri/fisiologia , Probióticos/administração & dosagem , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/microbiologia , Ácidos Graxos Voláteis/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Ganho de Peso
14.
BMC Cancer ; 19(1): 685, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299935

RESUMO

BACKGROUND: Sterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC). METHODS: Expression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-κB inhibitor SN50 was used to test the relationship of SREBP1, NF-κB pathway and MMP7. RESULTS: We found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-κB-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-κB inhibitor SN50. CONCLUSION: Our results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 7 da Matriz/genética , NF-kappa B/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo
15.
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
16.
J Agric Food Chem ; 67(25): 7005-7015, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31174423

RESUMO

Amino acids can enhance milk fat synthesis in bovine mammary epithelial cells (BMECs), but the molecular mechanism is not well-known. In this study, we explored the regulatory role and molecular mechanism of lysine (Lys) on milk fat synthesis induced by fatty acids (FAs). We show that Lys dose-dependently affects number of cells and milk fat synthesis, and has more stimulatory effects in the presence of FAs. Lys enhances FA-induced sterol regulatory element binding protein 1c (SREBP-1c) expression and maturation in a fatty-acid-binding protein 5 (FABP5)-dependent manner. We further show that the Lys stimulates FABP5 expression via the GPRC6A (GPCR, class C, group 6, subtype A)-PI3K (phosphatidylinositol 3-kinase) signaling. Lys dose-dependently affects GPRC6A expression and localization at the plasma membrane. In summary, our data reveals that Lys enhances FAs-stimulated SREBP-1c expression and maturation leading to milk fat synthesis via the GPRC6A-PI3K-FABP5 signaling in BMECs.


Assuntos
Bovinos/metabolismo , Células Epiteliais/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/biossíntese , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Bovinos/genética , Gorduras/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Lisina , Glândulas Mamárias Animais/citologia , Fosfatidilinositol 3-Quinases/genética , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
17.
J Food Sci ; 84(7): 1900-1908, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31183867

RESUMO

The quality of canola oil is affected by different extraction methods. The effect of cold-pressed canola oil (CPCO) diet and traditional refined bleached deodorized canola oil (RBDCO) diet on lipid accumulation and hepatic steatosis in mice were investigated. The body weight, peroxisome proliferator-activated receptor-α concentration, serum lipid profile, insulin sensitivity, and oxidative stress were increased in mice fed with CPCO diet, which had higher unsaturated fatty acid, tocopherols, phytosterols, and phospholipids but lower saturated fatty acid than RBDCO, after 12 weeks,. Moreover, CPCO significantly increased tocopherols and phytosterols content in liver and reduced liver cholesterol contents and lipid vacuoles accumulation than RBDCO. Also, serum proinflammatory cytokines, 3-hydroxy-3-methylglutary coenzyme A reductase expression level, lipogenic enzymes, and transcriptional factors such as sterol regulatory element-binding proteins 1c, acetyl-CoA carboxylase, and fatty acid synthase in the liver were also markedly downregulated from CPCO diet mice. Overall, CPCO can reduce lipid accumulation and hepatic steatosis by regulating oxidative stress and lipid metabolism in Kun Ming mice compared with RBDCO. PRACTICAL APPLICATION: The results suggested that more bioactive components were contained in cold-pressed canola oil (CPCO) rather than refined bleached deodorized canola oil (RBDCO). CPCO could lower the risk of obesity and hyperlipidemia, reduce lipid accumulation, and prevent hepatic steatosis. It could be considered as a kind of better edible oil than RBDCO.


Assuntos
Fígado Gorduroso/dietoterapia , Metabolismo dos Lipídeos , Estresse Oxidativo , Óleo de Brassica napus/química , Óleo de Brassica napus/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Colesterol/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/análise , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Humanos , Resistência à Insulina , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , PPAR alfa/genética , PPAR alfa/metabolismo , Fosfolipídeos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
18.
J Dairy Sci ; 102(8): 7536-7547, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178189

RESUMO

High blood concentrations of nonesterified fatty acids (NEFA) and altered lipid metabolism are key characteristics of fatty liver in dairy cows. In nonruminants, the mitochondrial membrane protein mitofusin 2 (MFN2) plays important roles in regulating mitochondrial function and intrahepatic lipid metabolism. Whether MFN2 is associated with hepatic lipid metabolism in dairy cows with moderate fatty liver is unknown. Therefore, to investigate changes in MFN2 expression and lipid metabolic status in dairy cows with moderate fatty liver, blood and liver samples were collected from healthy dairy cows (n = 10) and cows with moderate fatty liver (n = 10). To determine the effects of MFN2 on lipid metabolism in vitro, hepatocytes isolated from healthy calves were used for small interfering RNA-mediated silencing of MFN2 or adenovirus-mediated overexpression of MFN2 for 48 h, or treated with 0, 0.6, 1.2, or 2.4 mM NEFA for 12 h. Milk production and plasma glucose concentrations in dairy cows with moderate fatty liver were lower, but concentrations of NEFA and ß-hydroxybutyrate (BHB) were greater in dairy cows with moderate fatty liver. Dairy cows with moderate fatty liver displayed hepatic lipid accumulation and lower abundance of hepatic MFN2, peroxisome proliferator-activated receptor-α (PPARα), and carnitine palmitoyltransferase 1A (CPT1A). However, sterol regulatory element-binding protein 1c (SREBP-1c), acetyl CoA carboxylase 1 (ACACA), fatty acid synthase (FASN), and diacylglycerol acyltransferase 1 (DGAT1) were more abundant in the livers of dairy cows with moderate fatty liver. In vitro, exogenous NEFA treatment upregulated abundance of SREBP-1c, ACACA, FASN, and DGAT1, and downregulated the abundance of PPARα and CPT1A. These changes were associated with greater lipid accumulation in calf hepatocytes, and MFN2 silencing aggravated this effect. In contrast, overexpression of MFN2-ameliorated exogenous NEFA-induced lipid accumulation by downregulating the abundance of SREBP-1c, ACACA, FASN, and DGAT1, and upregulating the abundance of PPARα and CPT1A in calf hepatocytes. Overall, these data suggest that one cause for the negative effect of excessive NEFA on hepatic lipid accumulation is the inhibition of MFN2. As such, these mechanisms partly explain the development of hepatic steatosis in dairy cows.


Assuntos
Doenças dos Bovinos/metabolismo , Bovinos/metabolismo , Fígado Gorduroso/veterinária , GTP Fosfo-Hidrolases/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Animais , Bovinos/genética , Doenças dos Bovinos/enzimologia , Doenças dos Bovinos/genética , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , GTP Fosfo-Hidrolases/genética , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Mitocôndrias/metabolismo , 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.
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
20.
Thromb Haemost ; 119(7): 1058-1071, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31055798

RESUMO

Interaction between the transcription factors, hypoxia-inducible factor (HIF1α and HIF2α) and Sp1, mediates hypoxia-driven expression of FVII gene encoding coagulation factor VII (fVII) in ovarian clear cell carcinoma (CCC) cells. This mechanism is synergistically enhanced in response to serum starvation, a condition possibly associated with tumor hypoxia. This transcriptional response potentially results in venous thromboembolism, a common complication in cancer patients by producing procoagulant extracellular vesicles (EVs). However, which deficient serum factors are responsible for this characteristic transcriptional mechanism is unknown. Here, we report that cholesterol deficiency mediates synergistic FVII expression under serum starvation and hypoxia (SSH) via novel sterol regulatory element binding protein-1 (SREBP1)-driven mechanisms. Unlike conventional mechanisms, SREBP1 indirectly enhances FVII transcription through the induction of a new target, glucocorticoid-induced leucine zipper (GILZ) protein. GILZ expression induced in response to hypoxia by a HIF1α-dependent mechanism activates SREBP1 under SSH, suggesting reciprocal regulation between SREBP1 and GILZ. Furthermore, GILZ binds to the FVII locus. Xenograft tumor samples analyzed by chromatin immunoprecipitation confirmed that HIF1α-aryl hydrocarbon nuclear translocator and GILZ bind to the TSC22D3 (GILZ) and FVII gene loci, respectively, thereby potentially modulating chromatin function to augment FVII transcription. Thus, deficiency of both O2 and cholesterol, followed by interplay between HIFs, Sp1, and SREBP1-GILZ pathways synergistically induce fVII synthesis, resulting in the shedding of procoagulant EVs.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Coagulantes/metabolismo , Fator VII/genética , Hipóxia/metabolismo , Neoplasias Ovarianas/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Colesterol/metabolismo , Montagem e Desmontagem da Cromatina , Fator VII/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Soro/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de Xenoenxerto
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