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1.
Diabetologia ; 66(5): 931-954, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36759348

RESUMO

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development. METHODS: Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology. RESULTS: Alb-Cre;Tcf7l2f/f essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions. CONCLUSIONS/INTERPRETATION: In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL. DATA AVAILABILITY: RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449 ).


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Lipogênese/genética , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Hepatócitos/metabolismo , Dieta Hiperlipídica , Triglicerídeos/metabolismo , Glucose/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(51): 32433-32442, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33288688

RESUMO

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.


Assuntos
Ácidos Graxos Insaturados/biossíntese , Ferroptose/fisiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ácido Araquidônico/genética , Ácido Araquidônico/metabolismo , Ácido Araquidônico/farmacologia , Carbolinas/farmacologia , Linhagem Celular Tumoral , Metilação de DNA , Dessaturase de Ácido Graxo Delta-5 , Elementos Facilitadores Genéticos , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/genética , Ácidos Graxos Insaturados/metabolismo , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Regiões Promotoras Genéticas , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia
3.
PLoS Biol ; 17(7): e3000367, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31323018

RESUMO

Human papillomaviruses (HPVs) are causative agents of various diseases associated with cellular hyperproliferation, including cervical cancer, one of the most prevalent tumors in women. E7 is one of the two HPV-encoded oncoproteins and directs recruitment and subsequent degradation of tumor-suppressive proteins such as retinoblastoma protein (pRb) via its LxCxE motif. E7 also triggers tumorigenesis in a pRb-independent pathway through its C-terminal domain, which has yet been largely undetermined, with a lack of structural information in a complex form with a host protein. Herein, we present the crystal structure of the E7 C-terminal domain of HPV18 belonging to the high-risk HPV genotypes bound to the catalytic domain of human nonreceptor-type protein tyrosine phosphatase 14 (PTPN14). They interact directly and potently with each other, with a dissociation constant of 18.2 nM. Ensuing structural analysis revealed the molecular basis of the PTPN14-binding specificity of E7 over other protein tyrosine phosphatases and also led to the identification of PTPN21 as a direct interacting partner of E7. Disruption of HPV18 E7 binding to PTPN14 by structure-based mutagenesis impaired E7's ability to promote keratinocyte proliferation and migration. Likewise, E7 binding-defective PTPN14 was resistant for degradation via proteasome, and it was much more effective than wild-type PTPN14 in attenuating the activity of downstream effectors of Hippo signaling and negatively regulating cell proliferation, migration, and invasion when examined in HPV18-positive HeLa cells. These results therefore demonstrated the significance and therapeutic potential of the intermolecular interaction between HPV E7 and host PTPN14 in HPV-mediated cell transformation and tumorigenesis.


Assuntos
Transformação Celular Neoplásica , Proteínas de Ligação a DNA/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Neoplasias do Colo do Útero/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Feminino , Células HEK293 , Células HeLa , Humanos , Modelos Moleculares , Proteínas Oncogênicas Virais/química , Proteínas Oncogênicas Virais/genética , Ligação Proteica , Domínios Proteicos , Proteínas Tirosina Fosfatases não Receptoras/química , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteína do Retinoblastoma/química , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Homologia de Sequência de Aminoácidos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
4.
J Biol Chem ; 295(39): 13677-13690, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32759168

RESUMO

Astrocytes perform multiple essential functions in the developing and mature brain, including regulation of synapse formation, control of neurotransmitter release and uptake, and maintenance of extracellular ion balance. As a result, astrocytes have been implicated in the progression of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. Despite these critical functions, the study of human astrocytes can be difficult because standard differentiation protocols are time-consuming and technically challenging, but a differentiation protocol recently developed in our laboratory enables the efficient derivation of astrocytes from human embryonic stem cells. We used this protocol along with microarrays, luciferase assays, electrophoretic mobility shift assays, and ChIP assays to explore the genes involved in astrocyte differentiation. We demonstrate that paired-like homeodomain transcription factor 1 (PITX1) is critical for astrocyte differentiation. PITX1 overexpression induced early differentiation of astrocytes, and its knockdown blocked astrocyte differentiation. PITX1 overexpression also increased and PITX1 knockdown decreased expression of sex-determining region Y box 9 (SOX9), known initiator of gliogenesis, during early astrocyte differentiation. Moreover, we determined that PITX1 activates the SOX9 promoter through a unique binding motif. Taken together, these findings indicate that PITX1 drives astrocyte differentiation by sustaining activation of the SOX9 promoter.


Assuntos
Astrócitos/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Fatores de Transcrição SOX9/metabolismo , Diferenciação Celular , Células Cultivadas , Humanos , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição SOX9/genética
5.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925827

RESUMO

Liver disease is the spectrum of liver damage ranging from simple steatosis called as nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). Clinically, NAFLD and type 2 diabetes coexist. Type 2 diabetes contributes to biological processes driving the severity of NAFLD, the primary cause for development of chronic liver diseases. In the last 20 years, the rate of non-viral NAFLD/NASH-derived HCC has been increasing rapidly. As there are currently no suitable drugs for treatment of NAFLD and NASH, a class of thiazolidinediones (TZDs) drugs for the treatment of type 2 diabetes is sometimes used to improve liver failure despite the risk of side effects. Therefore, diagnosis, prevention, and treatment of the development and progression of NAFLD and NASH are important issues. In this review, we will discuss the pathogenesis of NAFLD/NASH and NAFLD/NASH-derived HCC and the current promising pharmacological therapies of NAFLD/NASH. Further, we will provide insights into "adipose-derived adipokines" and "liver-derived hepatokines" as diagnostic and therapeutic targets from NAFLD to HCC.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , Adipocinas/metabolismo , Carcinoma Hepatocelular/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Progressão da Doença , Humanos , Fígado/metabolismo , Cirrose Hepática/fisiopatologia , Falência Hepática , Neoplasias Hepáticas/fisiopatologia , Síndrome Metabólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo
6.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946468

RESUMO

Mitochondria are the major source of intercellular bioenergy in the form of ATP. They are necessary for cell survival and play many essential roles such as maintaining calcium homeostasis, body temperature, regulation of metabolism and apoptosis. Mitochondrial dysfunction has been observed in variety of diseases such as cardiovascular disease, aging, type 2 diabetes, cancer and degenerative brain disease. In other words, the interpretation and regulation of mitochondrial signals has the potential to be applied as a treatment for various diseases caused by mitochondrial disorders. In recent years, mitochondrial transplantation has increasingly been a topic of interest as an innovative strategy for the treatment of mitochondrial diseases by augmentation and replacement of mitochondria. In this review, we focus on diseases that are associated with mitochondrial dysfunction and highlight studies related to the rescue of tissue-specific mitochondrial disorders. We firmly believe that mitochondrial transplantation is an optimistic therapeutic approach in finding a potentially valuable treatment for a variety of mitochondrial diseases.


Assuntos
Mitocôndrias/transplante , Doenças Mitocondriais/terapia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/terapia , Humanos , Hepatopatias/metabolismo , Hepatopatias/patologia , Hepatopatias/terapia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Dinâmica Mitocondrial , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/terapia
7.
Pharmacol Res ; 139: 325-336, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30472463

RESUMO

Adipogenesis involved in hypertrophy and hyperplasia of adipocytes is responsible for expanding the mass of adipose tissues in obese individuals. Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) are two principal transcription factors induced by delicate signaling pathways, including signal transducer and activator of transcription 5 (STAT5), in adipogenesis. Here, we demonstrated a novel role of ginkgetin, a biflavone from Ginkgo biloba leaves, as a STAT5 inhibitor that blocks the differentiation of preadipocytes into adipocytes. During the differentiation of 3T3-L1 cells, ginkgetin treatment during the first 2 days markedly inhibited the formation of lipid-bearing adipocytes. PPARγ and C/EBPα expression was decreased in 3T3-L1 cells during adipogenesis following ginkgetin treatment, whereas no change was observed in C/EBPß or C/EBPδ expression. Inhibition of PPARγ and C/EBPα expression by ginkgetin occurred through the prevention of STAT5 activation during the initiation phase of adipogenesis. In addition, ginkgetin-mediated the inhibition of adipogenesis was recapitulated in the differentiation of primary preadipocytes. Lastly, we confirmed the inhibitory effects of ginkgetin on the hypertrophy of white adipose tissues from high-fat diet-fed mice. These results indicate that ginkgetin is a potential anti-adipogenesis and anti-obesity drug.


Assuntos
Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , Células 3T3-L1 , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Dieta Hiperlipídica , Ginkgo biloba , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo , Folhas de Planta , Transdução de Sinais/efeitos dos fármacos
8.
J Nanobiotechnology ; 17(1): 24, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30722792

RESUMO

BACKGROUND: Silica nanoparticles (SiNPs) are widely used for biosensing and diagnostics, and for the targeted delivery of therapeutic agents. Safety concerns about the biomedical and clinical applications of SiNPs have been raised, necessitating analysis of the effects of their intrinsic properties, such as sizes, shapes, and surface physicochemical characteristics, on human health to minimize risk in biomedical applications. In particular, SiNP size-associated toxicological effects, and the underlying molecular mechanisms in the vascular endothelium remain unclear. This study aimed to elucidate the detailed mechanisms underlying the cellular response to exposure to trace amounts of SiNPs and to determine applicable size criteria for biomedical application. METHODS: To clarify whether these SiNP-mediated cytotoxicity due to induction of apoptosis or necrosis, human ECs were treated with SiNPs of four different non-overlapping sizes under low serum-containing condition, stained with annexin V and propidium iodide (PI), and subjected to flow cytometric analysis (FACS). Two types of cell death mechanisms were assessed in terms of production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress induction, and autophagy activity. RESULTS: Spherical SiNPs had a diameter of 21.8 nm; this was further increased to 31.4, 42.9, and 56.7 nm. Hence, we investigated these effects in human endothelial cells (ECs) treated with these nanoparticles under overlap- or agglomerate-free conditions. The 20-nm SiNPs, but not SiNPs of other sizes, significantly induced apoptosis and necrosis. Surprisingly, the two types of cell death occurred independently and through different mechanisms. Apoptotic cell death resulted from ROS-mediated ER stress. Furthermore, autophagy-mediated necrotic cell death was induced through the PI3K/AKT/eNOS signaling axis. Together, the present results indicate that SiNPs within a diameter of < 20-nm pose greater risks to cells in terms of cytotoxic effects. CONCLUSION: These data provide novel insights into the size-dependence of the cytotoxic effects of silica nanoparticles and the underlying molecular mechanisms. The findings are expected to inform the applicable size range of SiNPs to ensure their safety in biomedical and clinical applications.


Assuntos
Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Nanopartículas/toxicidade , Necrose/patologia , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício , Autofagia/efeitos dos fármacos , Células Cultivadas , Meios de Cultura , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Nanopartículas/química , Necrose/metabolismo , Tamanho da Partícula , Fosfatidilinositol 3-Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Dióxido de Silício/toxicidade
9.
Int J Mol Sci ; 20(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590292

RESUMO

: Mitochondria play a key role in maintaining energy homeostasis in metabolic tissues, including adipose tissues. The two main types of adipose tissues are the white adipose tissue (WAT) and the brown adipose tissue (BAT). WAT primarily stores excess energy, whereas BAT is predominantly responsible for energy expenditure by non-shivering thermogenesis through the mitochondria. WAT in response to appropriate stimuli such as cold exposure and ß-adrenergic agonist undergoes browning wherein it acts as BAT, which is characterized by the presence of a higher number of mitochondria. Mitochondrial dysfunction in adipocytes has been reported to have strong correlation with metabolic diseases, including obesity and type 2 diabetes. Dysfunction of mitochondria results in detrimental effects on adipocyte differentiation, lipid metabolism, insulin sensitivity, oxidative capacity, and thermogenesis, which consequently lead to metabolic diseases. Recent studies have shown that mitochondrial function can be improved by using thiazolidinedione, mitochondria-targeted antioxidants, and dietary natural compounds; by performing exercise; and by controlling caloric restriction, thereby maintaining the metabolic homeostasis by inducing adaptive thermogenesis of BAT and browning of WAT. In this review, we focus on and summarize the molecular regulation involved in the improvement of mitochondrial function in adipose tissues so that strategies can be developed to treat metabolic diseases.


Assuntos
Tecido Adiposo/metabolismo , Doenças Metabólicas/metabolismo , Mitocôndrias/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Restrição Calórica , Metabolismo Energético , Humanos , Doenças Metabólicas/dietoterapia , Doenças Metabólicas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos
10.
Biochem Biophys Res Commun ; 469(3): 552-8, 2016 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-26692489

RESUMO

Abnormal adipocyte differentiation is implicated in the development of metabolic disorders such as obesity and type II diabetes. Thus, an in-depth understanding of the molecular mechanisms associated with adipocyte differentiation is the first step in overcoming obesity and its related metabolic diseases. Here, we examined the role of c-Jun as a transcription factor in adipocyte differentiation. c-Jun overexpression in murine 3T3-L1 preadipocytes significantly inhibited adipocyte differentiation. In addition, the expression level of KLF15, an upstream effector of the key adipogenic factors C/EBPα and PPARγ, was decreased upon the ectopic expression of c-Jun. We found that c-Jun inhibited basal and glucocorticoid receptor (GR)-induced promoter activities of KLF15. c-Jun directly bound near the glucocorticoid response element (GRE) sites in the KLF15 promoter and inhibited adjacent promoter occupancies of GR. Furthermore, the restoration of KLF15 expression in 3T3-L1 cells with the stable ectopic expression of c-Jun partially rescued adipocyte differentiation. Our results demonstrate that c-Jun can suppress adipocyte differentiation through the down-regulation of KLF15 at the transcriptional level. This study proposes a novel mechanism by which c-Jun regulates adipocyte differentiation.


Assuntos
Células 3T3-L1/citologia , Células 3T3-L1/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fatores de Transcrição/metabolismo , Adipogenia/fisiologia , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Fatores de Transcrição Kruppel-Like , Camundongos
11.
Int J Mol Sci ; 18(1)2016 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-28025491

RESUMO

Obesity and type II diabetes are characterized by insulin resistance in peripheral tissues. A high caloric intake combined with a sedentary lifestyle is the leading cause of these conditions. Whole-body insulin resistance and its improvement are the result of the combined actions of each insulin-sensitive organ. Among the fundamental molecular mechanisms by which each organ is able to communicate and engage in cross-talk are cytokines or peptides which stem from secretory organs. Recently, it was reported that several cytokines or peptides are secreted from muscle (myokines), adipose tissue (adipokines) and liver (hepatokines) in response to certain nutrition and/or physical activity conditions. Cytokines exert autocrine, paracrine or endocrine effects for the maintenance of energy homeostasis. The present review is focused on the relationship and cross-talk amongst muscle, adipose tissue and the liver as secretory organs in metabolic diseases.


Assuntos
Adaptação Fisiológica , Adipocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Adipocinas/genética , Tecido Adiposo/metabolismo , Animais , Humanos , Fígado/metabolismo , Músculos/metabolismo
12.
Biochem Biophys Res Commun ; 467(2): 211-7, 2015 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-26449462

RESUMO

Understanding the molecular networks that regulate adipogenesis is crucial for gaining insight into obesity and identifying medicinal targets thereof is necessary for pharmacological interventions. However, the identity and molecular actions of activators that promote the early development of adipocytes are still largely unknown. Here, we demonstrate a novel role for phosphoprotein phosphatase 1CB (PPP1CB) as a potent adipogenic activator that promotes adipocyte differentiation. PPP1CB expression increased in vitro during the early phase of 3T3-L1 adipogenesis and in the murine model of high-fat diet-induced obesity. Depletion of PPP1CB dramatically suppressed the differentiation of 3T3-L1 cells into mature adipocytes, with a concomitant change in adipocyte marker genes and significantly inhibited clonal expansion. We also showed that knockdown of PPP1CB caused a significant decrease in C/EBPδ expression, which in turn resulted in attenuation of PPARγ, C/EBPα, adiponectin, and aP2. In addition, we elucidated the functional significance of PPP1CB by linking p38 activation to C/EBPδ expression in early adipogenesis. Overall, our findings demonstrate a novel function of PPP1CB in promoting adipogenesis and suggest that PPP1CB may be a promising therapeutic target for treatment of obesity and obesity-related diseases.


Assuntos
Adipócitos/enzimologia , Adipogenia/genética , Gorduras na Dieta/administração & dosagem , Obesidade/genética , Proteína Fosfatase 1/metabolismo , Células 3T3-L1 , Adipócitos/patologia , Adiponectina/genética , Adiponectina/metabolismo , Animais , Proteína delta de Ligação ao Facilitador CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular , Dieta Hiperlipídica , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/enzimologia , Obesidade/etiologia , Obesidade/patologia , Proteína Fosfatase 1/antagonistas & inibidores , Proteína Fosfatase 1/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Nanotechnology ; 26(43): 435101, 2015 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-26437254

RESUMO

Nanoparticles are of great interest due to their wide variety of biomedical and bioengineering applications. However, they affect cellular differentiation and/or intracellular signaling when applied and exposed to target organisms or cells. The brown adipocyte is a cell type important in energy homeostasis and thus closely related to obesity. In this study, we assessed the effects of silica nanoparticles (SNPs) on brown adipocyte differentiation. The results clearly showed that brown adipocyte differentiation was significantly repressed by exposure to SNPs. The brown adipocyte-specific genes as well as mitochondrial content were also markedly reduced. Additionally, SNPs led to suppressed p38 phosphorylation during brown adipocyte differentiation. These effects depend on the size of SNPs. Taken together, these results lead us to suggest that SNP has anti-brown adipogenic effect in a size-dependent manner via regulation of p38 phosphorylation.


Assuntos
Nanopartículas/química , Dióxido de Silício/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células 3T3-L1 , Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Adipócitos Marrons/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Canais Iônicos/genética , Canais Iônicos/metabolismo , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , PPAR gama/genética , PPAR gama/metabolismo , Tamanho da Partícula , Fosforilação/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1
14.
Int J Mol Sci ; 16(3): 4581-99, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25734986

RESUMO

Obesity is a chronic disease that is associated with significantly increased levels of risk of a number of metabolic disorders. Despite these enhanced health risks, the worldwide prevalence of obesity has increased dramatically over the past few decades. Obesity is caused by the accumulation of an abnormal amount of body fat in adipose tissue, which is composed mostly of adipocytes. Thus, a deeper understanding of the regulation mechanism of adipose tissue and/or adipocytes can provide a clue for overcoming obesity-related metabolic diseases. In this review, we describe recent advances in the study of adipose tissue and/or adipocytes, focusing on proteomic approaches. In addition, we suggest future research directions for proteomic studies which may lead to novel treatments of obesity and obesity-related diseases.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Animais , Humanos , Metabolismo dos Lipídeos , Obesidade/metabolismo , Isoformas de Proteínas/metabolismo
15.
Mol Biol Rep ; 41(5): 3499-507, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24615502

RESUMO

Breast cancer is the most common type of cancer in women in many areas and is increasing found in developing countries, where the majority of cases are diagnosed in late stages. Retinoic acids, through their associated nuclear receptors, exert intoxicating effects on cell growth, differentiation and apoptosis, and hold significant promise in relation to cancer therapy and chemoprevention. To enhance our understanding of the molecular mechanisms associated with retinoic acids in the breast cancer cell line MCF-7 in a time-dependent manner, we conducted a proteomic analysis of MCF-7 cells using the 2-DE couple with high-throughput mass spectrometry and bioinformatics tools. In the 2-DE patterns of MCF-7 cells treated with retinoic acid in a time-dependent manner, 35 protein spots were found to be differentially expressed. These were 17 increased, 4 decreased, and 14 unevenly expressed protein spots, all of which were analyzed using LTQ-FTICR mass spectrometry. Furthermore, five candidate proteins, up-regulated, were validated by western blotting. These were nucleoredoxin, latexin, aminomethyltransferase, translationally controlled one tumor protein, and rab GDP dissociation inhibitor ß. These observations represent novel findings leading to new insight into the exact mechanism behind the effect of retinoic acids in MCF-7 cells while also identifying possible therapeutic targets for breast cancer diagnosis and novel drug development paths for the treatment of this disease.


Assuntos
Neoplasias da Mama/metabolismo , Proteoma , Proteômica , Tretinoína/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional/métodos , Feminino , Humanos , Células MCF-7 , Proteômica/métodos , Reprodutibilidade dos Testes
16.
Environ Int ; 185: 108522, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38401434

RESUMO

The rapidly increasing prevalence of obesity and overweight, especially in children and adolescents, has become a serious societal issue. Although various genetic and environmental risk factors for pediatric obesity and overweight have been identified, the problem has not been solved. In this study, we examined whether environmental nanoplastic (NP) pollutants can act as environmental obesogens using mouse models exposed to NPs derived from polystyrene and polypropylene, which are abundant in the environment. We found abnormal weight gain in the progeny until 6 weeks of age following the oral administration of NPs to the mother during gestation and lactation. Through a series of experiments involving multi-omic analyses, we have demonstrated that NP-induced weight gain is caused by alterations in the lipid composition (lysophosphatidylcholine/phosphatidylcholine ratio) of maternal breast milk and he gut microbiota distribution of the progeny. These data indicate that environmental NPs can act as obesogens in childhood.


Assuntos
Microbiota , Obesidade Infantil , Masculino , Criança , Feminino , Animais , Camundongos , Humanos , Adolescente , Sobrepeso/epidemiologia , Microplásticos , Aumento de Peso , Leite Humano , Mães , Lipídeos , Ingestão de Alimentos
17.
Biochem Biophys Res Commun ; 441(1): 77-82, 2013 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-24134846

RESUMO

Previously, we identified proteins showing a differential acetylation pattern during adipogenic differentiation. Here, we examined the role of malate dehydrogenase 2 (MDH2) acetylation in the adipogenesis of 3T3-L1 preadipocytes. The acetylation level of MDH2 showed a dramatic increase during adipogenesis. The overexpression of wild-type MDH2 induced the significant acceleration of adipogenic differentiation. On the other hand, the acetylation-block mutant MDH2 showed significantly reduced adipogenic differentiation compared to the wild type. MDH2 acetylation enhances its enzymatic activity and consequently intracellular NADPH level. These results suggest that the acetylation of MDH2 was affected by the cellular energy state and subsequently regulated adipogenic differentiation.


Assuntos
Adipogenia , Diferenciação Celular , Malato Desidrogenase/metabolismo , Células 3T3-L1 , Acetilação/efeitos dos fármacos , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/enzimologia , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Glucose/farmacologia , Camundongos , Mutação/genética , NADP/metabolismo
18.
Biochem Biophys Res Commun ; 434(3): 455-9, 2013 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-23583383

RESUMO

Although retinoic acid (RA) is well known to inhibit the differentiation of 3T3-L1 cells into adipocytes both in vivo and in vitro, its molecular mechanism is not fully understood. In this report, we investigate the inhibitory mechanism of adipocyte differentiation by RA in 3T3-L1 cells. Because both RA and Wnt are known to inhibit adipogenesis at a common step involving the inhibition of PPAR-γ expression, we focused on the crosstalk between these two signaling pathways. We found that RA treatment resulted in a dramatic inhibition of adipogenesis, especially at an early phase of differentiation, and led to increased ß-catenin protein expression. Moreover, RA enhances the transcriptional activity of ß-catenin as well as Wnt gene expression during adipogenesis. Taken together, the present study demonstrated that Wnt/ß-catenin signaling may be associated with the RA-induced suppression of adipogenesis and may cooperatively inhibit adipocyte differentiation.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Transdução de Sinais , Tretinoína/farmacologia , Proteínas Wnt/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Sequência de Bases , Diferenciação Celular , Cromanos/farmacologia , Primers do DNA , Camundongos , PPAR gama/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Tiazolidinedionas/farmacologia , Troglitazona , beta Catenina/metabolismo
19.
BMB Rep ; 56(9): 488-495, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37679296

RESUMO

Mitochondrial transplantation is a promising therapeutic approach for the treatment of mitochondrial diseases caused by mutations in mitochondrial DNA, as well as several metabolic and neurological disorders. Animal studies have shown that mitochondrial transplantation can improve cellular energy metabolism, restore mitochondrial function, and prevent cell death. However, challenges need to be addressed, such as the delivery of functional mitochondria to the correct cells in the body, and the long-term stability and function of the transplanted mitochondria. Researchers are exploring new methods for mitochondrial transplantation, including the use of nanoparticles or CRISPR gene editing. Mechanisms underlying the integration and function of transplanted mitochondria are complex and not fully understood, but research has revealed some key factors that play a role. While the safety and efficacy of mitochondrial transplantation have been investigated in animal models and human trials, more research is needed to optimize delivery methods and evaluate long-term safety and efficacy. Clinical trials using mitochondrial transplantation have shown mixed results, highlighting the need for further research in this area. In conclusion, although mitochondrial transplantation holds significant potential for the treatment of various diseases, more work is needed to overcome challenges and evaluate its safety and efficacy in human trials. [BMB Reports 2023; 56(9): 488-495].


Assuntos
DNA Mitocondrial , Mitocôndrias , Animais , Humanos , DNA Mitocondrial/genética , Morte Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Metabolismo Energético
20.
Cell Biosci ; 13(1): 116, 2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-37370191

RESUMO

BACKGROUND: Hepatic liver disease, including primary sclerosing cholangitis (PSC), is a serious extraintestinal manifestations of colonic inflammation. Cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CrebH) is a transcription factor expressed mostly in the liver and small intestine. However, CrebH's roles in the gut-liver axis remain unknown. METHODS: Inflammatory bowel disease (IBD) and PSC disease models were established in wild-type and CrebH-/- mice treated with dextran sulfate sodium, dinitrobenzene sulfonic acid, and diethoxycarbonyl dihydrocollidine diet, respectively. RNA sequencing were conducted to investigate differential gene expression. Exosomes were isolated from plasma and culture media. miRNA expression profiling was performed using the NanoString nCounter Mouse miRNA Panel. Effects of miR-29a-3p on adhesion molecule expression were investigated in bEnd.3 brain endothelial cells. RESULTS: CrebH-/- mice exhibited accelerated liver injury without substantial differences in the gut after administration of dextran sulfate sodium (DSS), and had similar features to PSC, including enlarged bile ducts, enhanced inflammation, and aberrant MAdCAM-1 expression. Furthermore, RNA-sequencing analysis showed that differentially expressed genes in the liver of CrebH-/- mice after DSS overlapped significantly with genes changed in PSC-liver. Analysis of plasma exosome miRNA isolated from WT and CrebH-/- mice indicates that CrebH can contribute to the exosomal miRNA profile. We also identified miR-29a-3p as an effective mediator for MAdCAM-1 expression. Administration of plasma exosome from CrebH-/- mice led to prominent inflammatory signals in the liver of WT mice with inflammatory bowel disease (IBD). CONCLUSIONS: CrebH deficiency led to increased susceptibility to IBD-induced liver diseases via enhanced expression of adhesion molecules and concomitant infiltration of T lymphocytes. Exosomes can contribute to the progression of IBD-induced liver injury in CrebH-/- mice. These study provide novel insights into the role of CrebH in IBD-induced liver injury.

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