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1.
Biol Res ; 53(1): 50, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109277

RESUMO

BACKGROUND: Acupuncture, a therapy of traditional Chinese medicine, is confirmed to exert the therapeutic action on polycystic ovary syndrome (PCOS). However, the detailed therapeutic mechanisms of acupuncture in PCOS remain ambiguous. In this study, we further investigated whether electroacupuncture (EA) alleviated PCOS-like symptoms in rats via regulating a metabolic regulator, sterol regulatory element binding protein-1 (SREBP1). METHODS: The PCOS-like rat model was built by hypodermic injection with dehydroepiandrosterone (DHEA). The rats were subjected to EA intervention (ST29 and SP6 acupuncture points) for 5 weeks. Primary granulosa cells were isolated from control and PCOS-like rats for evaluating insulin resistance, mitochondrial dysfunction and oxidative stress in vitro. RESULTS: The expression of SREBP1 was increased in PCOS-like rats, which was suppressed by EA treatment. In addition, lentivirus-mediated overexpression of SREBP1 restrained EA treatment-induced improvement in pathological changes, serum hormone levels and insulin resistance in rats. In addition, overexpression of SREBP1 repressed insulin-stimulated phosphorylation of insulin receptor ß (IR) and AKT in primary granulosa cells. Moreover, upregulation of SREBP1 further exacerbated mitochondrial dysfunction and oxidative stress in granulosa cells isolated from PCOS-like rats. Mechanically, EA treatment suppressed SREBP1 expression through inducing the activation of AMP-activated protein kinase (AMPK) signaling pathway in PCOS-like rats. CONCLUSION: EA intervention alleviated PCOS-like symptoms in rats via improving IR, mitochondrial dysfunction and oxidative stress through regulating SREBP1, a lipid metabolism regulator. Our findings illuminate the novel protective mechanisms of EA in the treatment of PCOS.


Assuntos
Eletroacupuntura , Resistência à Insulina , Mitocôndrias/patologia , Estresse Oxidativo , Síndrome do Ovário Policístico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Desidroepiandrosterona , Feminino , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/terapia , Ratos , Ratos Sprague-Dawley
2.
Life Sci ; 259: 118375, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32891612

RESUMO

OBJECTIVE: Short-chain fatty acids were reported to be the precursors of milk fat and can stimulate the de novo synthesis of fatty acids in bovine mammary epithelial cells (bMECs). However, the mechanism has not been elucidated. The purpose of this study was to investigate the effects of sodium butyrate (NaB) on milk fat synthesis in bMECs and explore its potential mechanism. METHODS: Bovine mammary epithelial cells (bMECs) were isolated for subsequent experimental uses. BODIPY staining and triglyceride kit were used to detect the milk fat synthesis in bMECs. Western blotting and RT-PCR assays were performed to detect the expression of related genes in bMECs. Immunoprecipitation was used to detect the acetylation of SREBP1 in bMECs. RESULTS: The results showed that NaB significantly promoted milk fat synthesis, promoted the activity of mechanistic target of rapamycin (mTOR) and S6 kinase (S6K), inhibited the activity of AMP-activated protein kinase (AMPK), and promoted the gene expression of G protein-coupled receptor 41 (GPR41). Knockdown of GPR41 and sterol regulatory element binding protein 1 (SREBP1) and overexpression of sirtuin1 (SIRT1), mTOR inhibitor (rapamycin), and AMPK activator (AICIR) eliminated these effects. These results indicated that NaB increased the nuclear translocation of SREBP1 via the GPR41/AMPK/mTOR/S6K signalling pathway, promoted the acetylation of mature SREBP1a via GPR41/AMPK/SIRT1, and then promoted milk fat synthesis. CONCLUSION: Taken together, these results demonstrated that NaB increased nuclear translocation and acetylation of SREBP1 to promote milk fat synthesis by activating GPR41 and its downstream signalling pathways.


Assuntos
Ácido Butírico/farmacologia , Glicolipídeos/biossíntese , Glicoproteínas/biossíntese , Glândulas Mamárias Animais/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Carbazóis , Bovinos , Células Cultivadas , Feminino , Imunoprecipitação , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Naftalenos , Reação em Cadeia da Polimerase em Tempo Real , Sirtuína 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
3.
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
4.
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
5.
Chem Biol Interact ; 327: 109176, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32534989

RESUMO

Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.


Assuntos
Fígado Gorduroso Alcoólico/etiologia , PPAR alfa/metabolismo , Adiponectina/metabolismo , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Regulação para Baixo , Etanol , Fígado Gorduroso Alcoólico/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/etiologia , Inflamação/metabolismo , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , PPAR alfa/agonistas , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
6.
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
7.
J Pharmacol Sci ; 143(3): 188-198, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414691

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease that causes morbidity associated with metabolic syndrome. NAFLD is a worldwide problem and represents a major cause of liver injury, which can lead to liver cell death. We investigated the effects of nonivamide (pelargonic acid vanillylamide, PAVA; 1 mg/kg) and rosuvastatin (RSV; 10 mg/kg) on hepatic steatosis induced by a high-fat diet (HFD). Male Sprague-Dawley rats were fed a HFD for 16 weeks then received PAVA or RSV for 4 additional weeks. We examined the metabolic parameters, function, fat content, histological alterations, reactive oxygen species production, and apoptotic cell death of the liver, in addition to the expression of the following important molecules: transient receptor potential cation channel subfamily V member 1 (TRPV1) phosphorylation of sterol regulatory element binding protein (pSREBP-1c/SREBP-1c), total and membrane glucose transporter 2 (GLUT2), 4-hydroxynonenal (4-HNE), and cleaved caspase-3. HFD-induced hepatic steatosis was associated with significantly increased morphological disorganization, injury markers, oxidative stress, lipid peroxidation, and apoptosis. However, metabolic dysfunction and hepatic injury were reduced by RSV and PAVA treatment. PAVA regulated lipid deposition, improved insulin resistance, and decreased oxidative stress and apoptotic cell death. Therefore, PAVA represents a promising therapeutic approach for treating metabolic disorders in patients with NAFLD.


Assuntos
Capsaicina/análogos & derivados , Capsicum/química , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Fitoterapia , Aldeídos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Capsaicina/administração & dosagem , Capsaicina/isolamento & purificação , Capsaicina/farmacologia , Caspase 3/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Canais de Cátion TRPV/metabolismo
8.
Nature ; 580(7804): 530-535, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32322062

RESUMO

Cancer cells increase lipogenesis for their proliferation and the activation of sterol regulatory element-binding proteins (SREBPs) has a central role in this process. SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. Regulation of the interaction between INSIG proteins and SCAP by sterol levels is critical for the dissociation of the SCAP-SREBP complex from the endoplasmic reticulum and the activation of SREBPs1,2. However, whether this protein interaction is regulated by a mechanism other than the abundance of sterol-and in particular, whether oncogenic signalling has a role-is unclear. Here we show that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme in gluconeogenesis, at Ser90. Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes, proliferation of tumour cells, and tumorigenesis in mice. In addition, phosphorylation of PCK1 at Ser90, INSIG1 at Ser207 and INSIG2 at Ser151 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC, but also associated with poor HCC prognosis. Our findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Gluconeogênese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipogênese , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Animais , Carcinogênese , Carcinoma Hepatocelular/patologia , Proliferação de Células , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Neoplasias Hepáticas/patologia , Masculino , Proteínas de Membrana/química , Camundongos , Camundongos Nus , Oxisteróis/metabolismo , Fosforilação , Prognóstico , Ligação Proteica , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
9.
J Pharmacol Exp Ther ; 374(1): 142-150, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32341017

RESUMO

Nonalcoholic fatty liver disease is a chronic inflammatory liver disease. It is associated with obesity and type 2 diabetes. Oxycholesterols are metabolites of cholesterol, and several of them can act on the G protein-coupled receptor, G protein-coupled receptor 183 (GPR183)/Epstein-Barr virus-induced gene 2. We found expression of GPR183 in human hepatoma cell lines and in vivo induction of GPR183 expression in mouse livers after high-fat diet feeding. Therefore, the role of oxycholesterols and GPR183 in hepatocytes was studied using a model of hepatic steatosis induced by liver X receptor (LXR) activation. LXR activation by T0901317 resulted in fat accumulation in Hep3B human hepatoma cells. This lipid accumulation was inhibited by 7α,25-dihydroxycholesterol, the most potent agonist of GPR183. The protective effects of 7α,25-dihydroxycholesterol were suppressed by a specific GPR183 antagonist, NIBR189 [(2E)-3-(4-Bromophenyl)-1-[4-4-methoxybenzoyl)-1-piperazinyl]-2-propene-1-one]. T0901317 treatment induced expression of the major transcription factor for lipogenesis, sterol regulatory element-binding protein 1c (SREBP-1c). 7α,25-Dihydroxycholesterol inhibited the induction of SREBP-1c proteins in a GPR183-dependent manner. Using inhibitors specific for intracellular signaling molecules, 7α,25-dihydroxycholesterol-induced suppression of hepatocellular steatosis was shown to be mediated through Gi/o proteins, p38 mitogen-activated protein kinases, phosphoinositide 3-kinase, and AMP-activated protein kinase. In addition, the inhibitory effect of 7α,25-dihydroxycholesterol was validated in HepG2 cells and primary mouse hepatocytes. Therefore, the present report suggests that 7α,25-dihydroxycholesterol-GPR183 signaling may suppress hepatocellular steatosis in the liver. SIGNIFICANCE STATEMENT: Oxycholesterols, which are metabolites of cholesterol, act on the G protein-coupled receptor, G protein-coupled receptor 183 (GPR183)/Epstein-Barr virus-induced gene 2, which is expressed in human hepatoma cell lines, and its expression is induced in vivo in mouse livers after high-fat diet feeding. Activation of GPR183 inhibits fat accumulation in primary mouse hepatocytes and HepG2 cells through Gi/o proteins, p38 mitogen-activated protein kinases, phosphoinositide 3-kinase, and AMP-activated protein kinase.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hidroxicolesteróis/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Hidroxicolesteróis/uso terapêutico , Receptores X do Fígado/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
10.
Invest Ophthalmol Vis Sci ; 61(3): 39, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32196098

RESUMO

Purpose: Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to Graves' orbitopathy (GO). Guggulsterone (GS), a phytosterol found in the resin of the guggul plant, is a well-known treatment for several inflammatory disorders, such as arthritis, obesity, and hyperlipidemia. Here we investigated the effects of GS treatment on GO pathology. Methods: Using primary cultures of orbital fibroblasts from GO patients and non-GO controls, we examined the effects of GS on hyaluronan production and the production of proinflammatory cytokines induced by interleukin (IL)-1ß, using real-time reverse transcription-polymerase chain reaction analysis, western blots, and enzyme-linked immunosorbent assays. Further, adipogenic differentiation was evaluated by quantification of Oil Red O staining and assessment of protein levels of peroxisome proliferator activator gamma (PPARγ), CCAAT-enhancer-binding proteins (C/EBP) α and ß, and sterol regulatory element-binding protein-1 (SREBP-1). Results: Treatment with noncytotoxic concentrations of GS resulted in the dose-dependent inhibition of IL-1ß-induced inflammatory cytokines, including IL-6, IL-8, MCP-1, and COX-2, at both mRNA and protein levels. The hyaluronan level was also significantly suppressed by GS. Moreover, GS significantly decreased the formation of lipid droplets and expression of PPARγ, C/EBP α/ß, and SREBP-1 in a dose-dependent manner. GS pretreatment attenuated the phosphorylation of nuclear factor-kappa B induced by IL-1ß. Conclusions: Our data show significant inhibitory effects of GS on inflammation, production of hyaluronan, and adipogenesis in orbital fibroblasts. To our knowledge, this is the first in vitro preclinical evidence of the therapeutic effect of GS in GO.


Assuntos
Fibroblastos/efeitos dos fármacos , Oftalmopatia de Graves/tratamento farmacológico , Órbita/efeitos dos fármacos , Pregnenodionas/uso terapêutico , Adipogenia/efeitos dos fármacos , Adulto , Idoso , Western Blotting , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular , Células Cultivadas , Commiphora/química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Fibroblastos/metabolismo , Oftalmopatia de Graves/metabolismo , Humanos , Ácido Hialurônico/metabolismo , Masculino , Pessoa de Meia-Idade , Órbita/metabolismo , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Adulto Jovem
11.
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
12.
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
13.
Circ Res ; 126(6): 767-783, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32078435

RESUMO

RATIONALE: Central nervous system has low vascular permeability by organizing tight junction (TJ) and limiting endothelial transcytosis. While TJ has long been considered to be responsible for vascular barrier in central nervous system, suppressed transcytosis in endothelial cells is now emerging as a complementary mechanism. Whether transcytosis regulation is independent of TJ and its dysregulation dominantly causes diseases associated with edema remain elusive. Dll4 signaling is important for various vascular contexts, but its role in the maintenance of vascular barrier in central nervous system remains unknown. OBJECTIVE: To find a TJ-independent regulatory mechanism selective for transcytosis and identify its dysregulation as a cause of pathological leakage. METHODS AND RESULTS: We studied transcytosis in the adult mouse retina with low vascular permeability and employed a hypertension-induced retinal edema model for its pathological implication. Both antibody-based and genetic inactivation of Dll4 or Notch1 induce hyperpermeability by increasing transcytosis without junctional destabilization in arterial endothelial cells, leading to nonhemorrhagic leakage predominantly in the superficial retinal layer. Endothelial Sox17 deletion represses Dll4 in retinal arteries, phenocopying Dll4 blocking-driven vascular leakage. Ang II (angiotensin II)-induced hypertension represses arterial Sox17 and Dll4, followed by transcytosis-driven retinal edema, which is rescued by a gain of Notch activity. Transcriptomic profiling of retinal endothelial cells suggests that Dll4 blocking activates SREBP1 (sterol regulatory element-binding protein 1)-mediated lipogenic transcription and enriches gene sets favorable for caveolae formation. Profiling also predicts the activation of VEGF (vascular endothelial growth factor) signaling by Dll4 blockade. Inhibition of SREBP1 or VEGF-VEGFR2 (VEGF receptor 2) signaling attenuates both Dll4 blockade-driven and hypertension-induced retinal leakage. CONCLUSIONS: In the retina, Sox17-Dll4-SREBP1 signaling axis controls transcytosis independently of TJ in superficial arteries among heterogeneous regulations for the whole vessels. Uncontrolled transcytosis via dysregulated Dll4 underlies pathological leakage in hypertensive retina and could be a therapeutic target for treating hypertension-associated retinal edema.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Barreira Hematorretiniana/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Retinopatia Hipertensiva/metabolismo , Transcitose , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Artérias/metabolismo , Proteínas de Ligação ao Cálcio/genética , Cavéolas/metabolismo , Células Endoteliais/metabolismo , Proteínas HMGB/metabolismo , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fatores de Transcrição SOXF/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Junções Íntimas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
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
15.
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
16.
FASEB J ; 34(1): 865-880, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914686

RESUMO

Intramembrane cleavage of transmembrane proteins is a fundamental cellular process to produce important signals that elicit biological responses. These proteolytic events are known as regulated intramembrane proteolysis (RIP). ATF6 and BBF2H7 are transmembrane basic leucine zipper transcription factors and are subjected to RIP by site-1 protease (S1P) and site-2 protease (S2P) sequentially in response to endoplasmic reticulum (ER) stress. However, the detailed mechanisms responsible for RIP of the transcription factors, including the precise cutting sites, are still unknown. In this study, we demonstrated that S1P cleaves BBF2H7 just before the RXXL S1P recognition motif. Conversely, S2P cut at least three different sites in the membrane (next to Leu380, Met381, and Leu385), indicating that S2P cleaves the substrates at variable sites or via a multistep process. Interestingly, we found BBF2H7-derived small peptide (BSP) fragments located between the S1P and S2P cleavage sites in cells exposed to ER stress. Major type of BSP fragments was composed of 45 amino acid including partial transmembrane and luminal regions and easily aggregates like amyloid ß (Aß) protein. These results advance the understanding of poorly characterized ER stress-dependent RIP. Furthermore, the aggregable peptides produced by ER stress could link to the pathophysiology of neurodegenerative disorders.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Proteólise , Fator 6 Ativador da Transcrição/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Humanos , Fragmentos de Peptídeos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Transcrição Genética/fisiologia
17.
Int J Mol Sci ; 21(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31935815

RESUMO

Non-alcoholic fatty liver disease (NAFLD) and -steatohepatitis (NASH) imply a state of excessive fat built-up in livers with/or without inflammation and have led to serious medical concerns in recent years. Antrodan (Ant), a purified ß-glucan from A. cinnamomea has been shown to exhibit tremendous bioactivity, including hepatoprotective, antihyperlipidemic, antiliver cancer, and anti-inflammatory effects. Considering the already well-known alleviating bioactivity of A. cinnamomea for the alcoholic steatohepatitis (ASH), we propose that Ant can be beneficial to NAFLD, and that the AMPK/Sirt1/PPARγ/SREBP-1c pathways may be involved in such alleviations. To uncover this, we carried out this study with 60 male C57BL/6 mice fed high-fat high-fructose diet (HFD) for 60 days, in order to induce NAFLD/NASH. Mice were then grouped and treated (by oral administration) as: G1: control; G2: HFD (HFD control); G3: Ant, 40 mgkg (Ant control); G4: HFD+Orlistat (10 mg/kg) (as Orlistat control); G5: HFD+Ant L (20 mg/kg); and G6: HFD+Ant H (40 mg/kg) for 45 days. The results indicated Ant at 40 mg/kg effectively suppressed the plasma levels of malondialdehyde, total cholesterol, triglycerides, GOT, GPT, uric acid, glucose, and insulin; upregulated leptin, adiponectin, pAMPK, Sirt1, and down-regulated PPARγ and SREBP-1c. Conclusively, Ant effectively alleviates NAFLD via AMPK/Sirt1/CREBP-1c/PPARγ pathway.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR gama/metabolismo , Extratos Vegetais/uso terapêutico , Proteínas Quinases/metabolismo , Sirtuína 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Administração Oral , Animais , Antrodia/química , Dieta Hiperlipídica/efeitos adversos , Frutose/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/administração & dosagem , Transdução de Sinais
18.
Food Funct ; 11(1): 711-721, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31909773

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide; thus, a dietary supplement that can restrict hepatic fat accumulation is needed. Baicalein, a major component of Scutellaria baicalensis, is used as a dietary supplement in Eastern and Western cultures and can reduce hepatic fat accumulation. However, the detailed mechanism by which baicalein exerts this effect has yet to be elucidated in vivo and in vitro. In this study, we characterized the hepatic fat-lowering activity of baicalein and found that baicalein reduced hepatic fat accumulation by activating AMPK and suppressing SREBP1 cleavage, thus consequently inhibiting the transcriptional activity of SREBP1 and the synthesis of hepatic fat in oleic acid-induced HepG2 cells and high-fat diet-induced non-insulin-resistant mice. Moreover, baicalein improved NAFLD by decreasing TC, increasing HDLC, decreasing LDLC, affecting antioxidant activity, and exerting other effects. Therefore, the mechanism of baicalein with regard to NAFLD prevention and treatment might involve effects on multiple targets and pathways. Our study supports the use of baicalein as a dietary supplement due to its ability to reduce hepatic fat accumulation and to ameliorate NAFLD-related biochemical abnormalities.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antioxidantes/farmacologia , Flavanonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Dieta Hiperlipídica , Flavanonas/administração & dosagem , Células Hep G2/metabolismo , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Oleico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
19.
Int J Mol Sci ; 21(2)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936890

RESUMO

Ergosterol peroxide is a natural compound of the steroid family found in many fungi, and it possesses antioxidant, anti-inflammatory, anticancer and antiviral activities. The anti-obesity activity of several edible and medicinal mushrooms has been reported, but the effect of mushroom-derived ergosterol peroxide on obesity has not been studied. Therefore, we analyzed the effect of ergosterol peroxide on the inhibition of triglyceride synthesis at protein and mRNA levels and differentiation of 3T3-L1 adipocytes. Ergosterol peroxide inhibited lipid droplet synthesis of differentiated 3T3-L1 cells, expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAT/enhancer-binding protein alpha (C/EBPα), the major transcription factors of differentiation, and also the expression of sterol regulatory element-binding protein-1c (SREBP-1c), which promotes the activity of PPARγ, resulting in inhibition of differentiation. It further inhibited the expression of fatty acid synthase (FAS), fatty acid translocase (FAT), and acetyl-coenzyme A carboxylase (ACC), which are lipogenic factors. In addition, it inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) involved in cell proliferation and activation of early differentiation transcription factors in the mitotic clonal expansion (MCE) stage. As a result, ergosterol peroxide significantly inhibited the synthesis of triglycerides and differentiation of 3T3-L1 cells, and is, therefore, a possibile prophylactic and therapeutic agent for obesity and related metabolic diseases.


Assuntos
Adipócitos/metabolismo , Fármacos Antiobesidade/farmacologia , Diferenciação Celular/efeitos dos fármacos , Ergosterol/análogos & derivados , Metabolismo dos Lipídeos/efeitos dos fármacos , Reishi/química , Células 3T3-L1/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adipocinas , Animais , Fármacos Antiobesidade/uso terapêutico , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ergosterol/química , Ergosterol/farmacologia , Ergosterol/uso terapêutico , Lipogênese/efeitos dos fármacos , Camundongos , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos
20.
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
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