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1.
Food Sci Nutr ; 7(7): 2374-2380, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31367366

RESUMO

This study aimed to isolate starch and evaluate its chemical and structural characteristics from six Chinese hulless barley (HB) cultivars. Starch isolated from naked barley displays A-type crystalline packing and a regular granular shape. We measured peak viscosity values ranging from 237 to 264 cP, trough viscosity values from 305 to 380 cP, breakdown values from 390 to 535 cP, final viscosities from 357 to 523 cP, setback values from 245 to 354 cP and 383 to 460 cP, peak times from 5.53 to 5.73 min, and pasting temperatures from 93.10 to 94.65°C by RVA. Transition temperatures (T 0, T p, and T c), gelatinization temperature ranges (ΔT r), and enthalpies of gelatinization (ΔH) were measured on a differential scanning calorimeter analyzer (DSC) and ranged from 57.81 to 61.25°C, 64.36 to 67.57°C, 82.03 to 84.70°C, and 21.52 to 26.89°C and 7.14 to 10.66 J/g, respectively. The varying chemical and structural characteristics of HB starch isolated from different cultivars suggested the potential for broader applications of the cereal.

2.
Theranostics ; 9(12): 3501-3514, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281493

RESUMO

Identification of proper agents to increase or activate UCP1+ cells in adipose tissues remains a potent therapeutic strategy to combat obesity. Screening systems for UCP1 activators have been previously established and allow for unbiased discovery of effective compound(s). Methods: A previously established Ucp1-2A-GFP reporter system was applied to a chemical library containing 33 phosphatase inhibitors. Compounds that can significantly activate UCP1 expression were further tested in vivo in mouse adipose tissues. Possible underlying mechanism was explored via RNA profiling, CMAP analysis, CRISPR targeting as well as inhibitor treatments. Results: We identified BML-260, a known potent inhibitor of the dual-specific phosphatase JSP-1, that significantly increased UCP1 expression in both brown and white adipocytes. BML-260 treatment also activated oxidative phosphorylation genes, increased mitochondrial activity as well as heat generation in vitro and in vivo. Mechanistic studies revealed that effect of BML-260 on adipocytes was partly through activated CREB, STAT3 and PPAR signaling pathways, and was unexpectedly JSP-1 independent. Conclusion: The rhodanine derivate BML-260 was previously identified to be a JSP-1 inhibitor, and thus was proposed to treat inflammatory and proliferative disorders associated with dysfunctional JNK signaling. This work provides evidences that BML-260 can also exert a JSP-1-independent effect in activating UCP1 and thermogenesis in adipocytes, and be potentially applied to treat obesity.

3.
Cell Rep ; 26(4): 884-892.e4, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30673611

RESUMO

DNA variants in the SLC16A11 coding region were identified to be strongly associated with type 2 diabetes (T2DM) in a Mexican population. Previous studies suggested that these variants disrupt SLC16A11 function and therefore proposed to revive SLC16A11 levels or activity to achieve therapeutic benefit. However, with knockout mouse models, here we show that Slc16a11 depletion has no significant metabolic defects. Further studies demonstrate that reconstitution of the mutant, but not the wild-type Slc16a11, in the liver of knockout mice causes more triglyceride accumulation and induction of insulin resistance via upregulation of lipin 1, suggesting gaining of aberrant functions of the mutant protein that affects lipid metabolism. Our findings offer a different explanation to the function of these diabetic variants, challenging the concept of enhancing SLC16A11 function to treat T2DM. The contradictory results by our and previous studies suggest that how the SLC16A11 locus contributes to human metabolism warrants further investigation.

4.
Oncotarget ; 8(19): 31612-31625, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28404942

RESUMO

Ascorbic acid, ß-glycerophosphate, and dexamethasone have been used in osteogenesis differentiation medium for in vitro cell culture, nothing is known for delivering these three bioactive compounds in vivo. In this study, we synthesized a novel bioactive scaffold by combining these three compounds with a lysine diisocyanate-based polyurethane. These bioactive compounds were released from the scaffold during the degradation process. The cell culture showed that the sponge-like structure in the scaffold was critical in providing a large surface area to support cell growth and all degradation products of the polymer were non-toxic. This bioactive scaffold enhanced the bone regeneration as evidenced by increasing the expression of three bone-related genes including collagen type I, Runx-2 and osteocalcin in rabbit bone marrow stem cells (BMSCs) in vitro and in vivo. The osteogenesis differentiation of BMSCs cultured in this bioactive scaffold was similar to that in osteogenesis differentiation medium and more extensive in this bioactive scaffold compared to the scaffold without these three bioactive compounds. These results indicated that the scaffold containing three bioactive compounds was a good osteogenesis differentiation promoter to enhance the osteogenesis differentiation and new bone formation in vivo.


Assuntos
Ácido Ascórbico/administração & dosagem , Regeneração Óssea , Dexametasona/administração & dosagem , Glicerofosfatos/administração & dosagem , Osteogênese/efeitos dos fármacos , Tecidos Suporte , Animais , Materiais Biocompatíveis , Diferenciação Celular , Células Cultivadas , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Polímeros , Coelhos , Ratos , Engenharia Tecidual , Tecidos Suporte/química
5.
J Cell Physiol ; 232(12): 3396-3408, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28059444

RESUMO

Tumor necrosis factor α (TNF-α)-induced osteoclast formation have been demonstrated to play an important role in the pathogenesis of estrogen deficiency-mediated bone loss, but the exact mechanisms by which TNF-α enhanced osteoclast differentiation were not fully elucidated. The class III semaphorins members were critical to regulate bone homeostasis. Here, we identified a novel mechanism whereby TNF-α increasing Semaphorin3D expression contributes to estrogen deficiency-induced osteoporosis. In this study, we found that Semaphorin3D expression was upregulated by TNF-α during the process of RANKL-induced osteoclast differentiation. Inhibition of Semaphorin3D in pre-osteoclasts could attenuate the stimulatory effects of TNF-α on osteoclast proliferation and differentiation. Mechanistically, blocking of the Jun N-terminal kinase (JNK) signaling markedly rescued TNF-α-induced Semaphorin3D expression, suggesting that JNK signaling was involved in the regulation of Semaphorin3D expression by TNF-α. In addition, silencing of Semaphorin3D in vivo could alleviate estrogen deficiency-induced osteoporosis. Our results revealed a novel function for Semaphorin3D and suggested that increased Semaphorin3D may contribute to enhanced bone loss by increased TNF-α in estrogen deficiency-induced osteoporosis. Thus, Semaphorin3D may provide a potential therapeutic target for the treatment of estrogen-deficiency induced osteoporosis.


Assuntos
Estrogênios/metabolismo , Osteoclastos/metabolismo , Osteogênese , Osteoporose/metabolismo , Semaforinas/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Estrogênios/deficiência , Feminino , MAP Quinase Quinase 4/metabolismo , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Ovariectomia , Ligante RANK/metabolismo
6.
Mol Cell Endocrinol ; 439: 133-140, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-27815211

RESUMO

Glycogen and triglyceride are two major forms of energy storage in the body and provide the fuel during different phases of food deprivation. However, how glycogen metabolism is linked to fat deposition in adipose tissue has not been clearly characterized. We generated a mouse model with whole-body deletion of PPP1R3G, a glycogen-targeting subunit of protein phosphatase-1 required for glycogen synthesis. Upon feeding with high-fat diet, the body weight and fat composition are significantly reduced in the PPP1R3G-/- mice compared to the wild type controls. The metabolic rate of the mice as measured by O2 consumption and CO2 production is accelerated by PPP1R3G deletion. The high-fat diet-induced liver steatosis is also slightly relieved by PPP1R3G deletion. The glycogen level in adipose tissue is reduced by PPP1R3G deletion. In 3T3L1 cells, overexpression of PPP1R3G leads to increases of both glycogen and triglyceride levels. In conclusion, our study indicates that glycogen is actively involved in fat accumulation in adipose tissue and obesity development upon high-fat diet. Our study also suggests that PPP1R3G is an important player that links glycogen metabolism to lipid metabolism in vivo.


Assuntos
Deleção de Genes , Glicogênio/metabolismo , Obesidade/metabolismo , Proteína Fosfatase 1/deficiência , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Metabolismo Basal , Glicemia/metabolismo , Dieta Hiperlipídica , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/sangue , Obesidade/complicações , Obesidade/patologia , Período Pós-Prandial , Proteína Fosfatase 1/metabolismo , Triglicerídeos/metabolismo
7.
RNA ; 23(1): 1-5, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27742910

RESUMO

Multiplex genome engineering in vivo with CRISPR/Cas9 shows great promise as a potential therapeutic approach. The ability to incorporate multiple single guide RNA (sgRNA) cassettes together with Cas9 gene expression in one AAV vector could greatly enhance the efficiency. In a recent Method article, Mefferd and coworkers indicated that small tRNA promoters could be used to drive sgRNA expression to facilitate the construction of a more effective AAV vector. In contrast, we found that when targeting endogenous genomic loci, CRISPR/Cas9 with tRNA promoter-driven sgRNA expression showed much reduced genome editing activity, compared with significant cleavage with U6 promoter-driven sgRNA expression. Though the underlying mechanisms are still under investigation, our study suggests that the CRISPR/Cas9 system with tRNA promoter-driven sgRNA expression needs to be reevaluated before it can be used for therapeutic genome editing.


Assuntos
Exorribonucleases/genética , Edição de Genes/métodos , Regiões Promotoras Genéticas , RNA Guia/genética , RNA de Transferência/genética , Sistemas CRISPR-Cas , Expressão Gênica
10.
Stem Cells Int ; 2016: 8283257, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27703485

RESUMO

Objective. Nucleus pulposus (NP) and annulus fibrosus (AF) are two main components of intervertebral disc (IVD). We aimed to figure out whether NP and AF also contain stem cells and whether these stem cells share common properties with chondrocytes and/or fibroblasts in their phenotypes or whether they are completely different types of cells with different characteristics. Design. The disk cells were isolated from AF and NP tissues of the same lumbar spine of the rabbits. The properties of these disk cells were characterized by their morphology, population doubling time (PDT), stem cell marker expression, and multidifferentiation potential using tissue culture techniques, immunocytochemistry, and RT-PCR. Results. Both disk cells formed colonies in culture and expressed stem cell markers, nucleostemin, Oct-4, SSEA-4, and Stro-1, at early passages. However, after 5 passages, AFSCs became elongated and NPSCs appeared senescent. Conclusion. This study indicated that IVD contains stem cells and the characteristics of AFSCs and NPSCs are intrinsically different. The findings of this study may provide basic scientific data for understanding the properties of IVD cells and the mechanisms of lower back pain.

11.
Arterioscler Thromb Vasc Biol ; 36(5): 783-6, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26941020

RESUMO

OBJECTIVE: Although early proof-of-concept studies of somatic in vivo genome editing of the mouse ortholog of proprotein convertase subtilisin/kexin type 9 (Pcsk9) in mice have established its therapeutic potential for the prevention of cardiovascular disease, the unique nature of genome-editing technology-permanent alteration of genomic DNA sequences-mandates that it be tested in vivo against human genes in normal human cells with human genomes to give reliable preclinical insights into the efficacy (on-target mutagenesis) and safety (lack of off-target mutagenesis) of genome-editing therapy before it can be used in patients. APPROACH AND RESULTS: We used a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) 9 genome-editing system to target the human PCSK9 gene in chimeric liver-humanized mice bearing human hepatocytes. We demonstrated high on-target mutagenesis (approaching 50%), greatly reduced blood levels of human PCSK9 protein, and minimal off-target mutagenesis. CONCLUSIONS: This work yields important information on the efficacy and safety of CRISPR-Cas9 therapy targeting the human PCSK9 gene in human hepatocytes in vivo, and it establishes humanized mice as a useful platform for the preclinical assessment of applications of somatic in vivo genome editing.


Assuntos
Proteínas Associadas a CRISPR/genética , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Edição de Genes/métodos , Marcação de Genes/métodos , Hepatócitos/enzimologia , Pró-Proteína Convertase 9/genética , Animais , Proteínas Associadas a CRISPR/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Genótipo , Hepatócitos/transplante , Humanos , Hidrolases/deficiência , Hidrolases/genética , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Pró-Proteína Convertase 9/biossíntese , Pró-Proteína Convertase 9/sangue
12.
EMBO J ; 35(5): 496-514, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26834238

RESUMO

The Beclin1-VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation. However, the underlying molecular mechanism that coordinates the timely activation of VPS34 complex is poorly understood. Here, we identify that PAQR3 governs the preferential formation and activation of ATG14L-linked VPS34 complex for autophagy initiation via two levels of regulation. Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. Deletion of PAQR3 leads to reduction of exercise-induced autophagy in mice, accompanied by a certain degree of disaggregation of ATG14L-associated VPS34 complex. Together, this study uncovers that PAQR3 can not only enhance the capacity of pro-autophagy class III PI3K due to its scaffold function, but also integrate AMPK signal to activation of ATG14L-linked VPS34 complex upon glucose starvation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Relacionadas à Autofagia , Proteína Beclina-1 , Glucose/deficiência , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fígado/metabolismo , Masculino , Camundongos Knockout , Músculo Esquelético/metabolismo , Corrida/fisiologia , Transdução de Sinais
13.
Bone ; 84: 78-87, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26723579

RESUMO

The proinflammatory cytokines, especially tumor necrosis factor alpha (TNF-α), have been shown to inhibit osteogenic differentiation of mesenchymal stem cells (MSCs) and bone formation in estrogen-deficiency-induced osteoporosis, but the mechanisms of TNF-α impaired bone formation remain poorly understood. Semaphorins have been shown to regulate cell growth, cell migration, and cell differentiation in a variety of tissues, including bone tissue. Here, we identified a novel mechanism whereby TNF-α, suppressing Semaphorin3B expression contributes to estrogen-deficiency-induced osteoporosis. In this study, we found that TNF-α could decrease Semaphorin3B expression in osteogenic differentiation of MSCs. Overexpression of Semaphorin3B in MSCs attenuated the inhibitory effects of TNF-α on MSCs proliferation and osteoblastic differentiation. Mechanistically, activation of the Wnt/ß-catenin signaling markedly rescued TNF-α-inhibited Semaphorin3B expression, suggesting that Wnt/ß-catenin signaling was involved in the regulation of Semaphorin3B expression by TNF-α. Taken together, our results revealed a novel function for Semaphorin3B and suggested that suppressed Semaphorin3B may contribute to impaired bone formation by elevated TNF-α in estrogen-deficiency-induced osteoporosis. This study may indicate a therapeutic target gene of Semaphorin3B for osteoporosis.


Assuntos
Diferenciação Celular , Estrogênios/deficiência , Células-Tronco Mesenquimais/citologia , Osteogênese , Osteoporose/etiologia , Semaforinas/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Via de Sinalização Wnt , Animais , Proliferação de Células , Feminino , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Osteoporose/metabolismo , Ovariectomia , Semaforinas/metabolismo
14.
Int J Oncol ; 48(1): 215-24, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26530697

RESUMO

Chronic inflammation is a well-known etiological factor for colorectal cancer (CRC) and cancer cells are known to preferentially metabolize glucose through aerobic glycolysis. However, the connection between chronic inflammation and aerobic glycolysis in the development of CRC is largely unexplored. The present study investigated whether interleukin-6 (IL-6), a pro-inflammatory cytokine, promotes the development of CRC by regulating the aerobic glycolysis and the underlying molecular mechanisms. In colitis-associated CRC mouse, anti-IL-6 receptor antibody treatment reduced the incidence of CRC and decreased the expression of key genes in aerobic glycolysis, whereas the plasma concentrations of glucose and lactate were not affected. Consistently, IL-6 treatment stimulated aerobic glycolysis, upregulated key genes in aerobic glycolysis and promoted cell proliferation and migration in SW480 and SW1116 CRC cells. 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) was the most downregulated gene by anti-IL-6 receptor antibody in colorectal adenoma tissues. Further analysis in human samples revealed overexpression of PFKFB3 in colorectal adenoma and adenocarcinoma tissues, which was also associated with lymph node metastasis, intravascular cancer embolus and TNM stage. In addition, the effect of IL-6 on CRC cells can be abolished by knocking down PRKFB3 through siRNA transfection. Our data suggest that chronic inflammation promotes the development of CRC by stimulating aerobic glycolysis and IL-6 is functioning, at least partly, through regulating PFKFB3 at early stage of CRC.


Assuntos
Proliferação de Células/genética , Neoplasias Colorretais/genética , Interleucina-6/genética , Fosfofrutoquinase-2/biossíntese , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Interleucina-6/metabolismo , Camundongos , Estadiamento de Neoplasias , Fosfofrutoquinase-2/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncol Lett ; 12(6): 4665-4670, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28105173

RESUMO

Interleukin-6 (IL-6) is a well-known etiological factor of colitis-associated colorectal cancer (CAC) and has a significant role in CAC progression. In addition, hypoxia-inducible factor 1α (HIF-1α) serves a primary role in the progression of CAC. However, the association between IL-6 and HIF-1α during the progression of CAC remains unclear. To investigate this association, the present study induced CAC in a mouse model using azoxymethane and dextran sulfate sodium. In addition, an anti-IL-6 receptor antibody was used to inhibit IL-6. In this model, anti-IL-6 receptor antibody treatment significantly inhibited the development of CAC and the expression of HIF-1α, in colorectal adenomas and adenocarcinomas. In patients with CAC, the HIF-1α gene was demonstrated to be overexpressed in tumor tissue compared with adjacent non-malignant tissue. Furthermore, HIF-1α mRNA expression was positively correlated with serum IL-6 concentration. The results of the present study suggest that IL-6 promotes CAC progression, in the early stage of the disease, through HIF-1α regulation.

16.
Yi Chuan ; 37(11): 1167-73, 2015 11.
Artigo em Chinês | MEDLINE | ID: mdl-26582531

RESUMO

The RNA-guided CRISPR (clustered regularly interspaced short palindromic repeat)-associated Cas9 nuclease has offered a new platform for genome editing with high efficiency. Here, we report the use of CRISPR/Cas9 technology to target a specific genomic region in human pluripotent stem cells. We show that CRISPR/Cas9 can be used to disrupt a gene by introducing frameshift mutations to gene coding region; to knock in specific sequences (e.g. FLAG tag DNA sequence) to targeted genomic locus via homology directed repair; to induce large genomic deletion through dual-guide multiplex. Our results demonstrate the versatile application of CRISPR/Cas9 in stem cell genome editing, which can be widely utilized for functional studies of genes or genome loci in human pluripotent stem cells.


Assuntos
Sistemas CRISPR-Cas/genética , Genoma Humano/genética , Células-Tronco Pluripotentes/metabolismo , Edição de RNA , Mutação da Fase de Leitura , Humanos , RNA Guia/genética
17.
Yi Chuan ; 37(10): 983-91, 2015 10.
Artigo em Inglês | MEDLINE | ID: mdl-26496750

RESUMO

Precision medicine emerges as a new approach that takes into account individual variability. The successful conduct of precision medicine requires the use of precise disease models. Human pluripotent stem cells (hPSCs), as well as adult stem cells, can be differentiated into a variety of human somatic cell types that can be used for research and drug screening. The development of genome editing technology over the past few years, especially the CRISPR/Cas system, has made it feasible to precisely and efficiently edit the genetic background. Therefore, disease modeling by using a combination of human stem cells and genome editing technology has offered a new platform to generate " personalized " disease models, which allow the study of the contribution of individual genetic variabilities to disease progression and the development of precise treatments. In this review, recent advances in the use of genome editing in human stem cells and the generation of stem cell models for rare diseases and cancers are discussed.


Assuntos
Sistemas CRISPR-Cas , Doença/genética , Engenharia Genética/métodos , Genoma Humano/genética , Medicina de Precisão/métodos , Células-Tronco/metabolismo , Humanos , Modelos Genéticos , Neoplasias/genética , Neoplasias/patologia , Medicina de Precisão/tendências , Doenças Raras/genética , Doenças Raras/patologia
18.
J Lipid Res ; 56(7): 1329-39, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26022806

RESUMO

Alcoholic liver disease (ALD) is a major health problem worldwide and hepatic steatosis is an early response to alcohol consumption. Fat and glycogen are two major forms of energy storage in the liver; however, whether glycogen metabolism in the liver impacts alcohol-induced steatosis has been elusive. In this study, we used a mouse model with overexpression of PPP1R3G in the liver to dissect the potential role of glycogen on alcohol-induced fatty liver formation. PPP1R3G is a regulatory subunit of protein phosphatase 1 and stimulates glycogenesis in the liver. Chronic and binge ethanol (EtOH) feeding reduced glycogen level in the mouse liver and such inhibitory effect of EtOH was reversed by PPP1R3G overexpression. In addition, PPP1R3G overexpression abrogated EtOH-induced elevation of serum levels of alanine aminotransferase and aspartate aminotransferase, increase in liver triglyceride concentration, and lipid deposition in the liver. EtOH-stimulated sterol regulatory element-binding protein (SREBP)-1c, a master regulator of lipogenesis, was also reduced by PPP1R3G overexpression in vivo. In AML-12 mouse hepatocytes, PPP1R3G overexpression could relieve EtOH-induced lipid accumulation and SREBP-1c stimulation. In conclusion, our data indicate that glycogen metabolism is closely linked to EtOH-induced liver injury and fatty liver formation.


Assuntos
Etanol/toxicidade , Fígado Gorduroso Alcoólico/metabolismo , Glicogênio/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Animais , Linhagem Celular , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/genética , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Proteína Fosfatase 1/genética
19.
Front Biosci (Landmark Ed) ; 19: 1418-24, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24896361

RESUMO

Hepatic fibrosis is caused by an imbalance between production and dissolution of extracellular matrix after chronic and inflmmatory injury, when hepatic stellate cells are stimulated to proliferate and secret extracellular matrix. The most common causes of liver fibrosis are chronic viral hepatitis B and C. Cirrhosis is the most advanced stage of fibrosis, which usually develop into hepatocellular carcinoma (HCC). microRNAs participate the pathogenesis of hepatic fibrosis and cirrhosis or even the onset of HCC. In this review, we will summarize the role of miRNA in the pathogenesis of viral hepatitis fibrosis, non-alcoholic steatohepatitis fibrosis, primary biliary cirrhosis and HCC onset, especially in the regulation of stellate cells.


Assuntos
Células Estreladas do Fígado/metabolismo , Hepatite Viral Humana/genética , Cirrose Hepática/genética , MicroRNAs/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Hepacivirus/fisiologia , Células Estreladas do Fígado/virologia , Vírus da Hepatite B/fisiologia , Hepatite Viral Humana/virologia , Interações Hospedeiro-Patógeno , Humanos , Cirrose Hepática/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia
20.
Mol Endocrinol ; 28(1): 116-26, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24264575

RESUMO

Liver glycogen metabolism plays an important role in glucose homeostasis. Glycogen synthesis is mainly regulated by glycogen synthase that is dephosphorylated and activated by protein phosphatase 1 (PP1) in combination with glycogen-targeting subunits or G subunits. There are seven G subunits (PPP1R3A to G) that control glycogenesis in different organs. PPP1R3G is a recently discovered G subunit whose expression is changed along the fasting-feeding cycle and is proposed to play a role in postprandial glucose homeostasis. In this study, we analyzed the physiological function of PPP1R3G using a mouse model with liver-specific overexpression of PPP1R3G. PPP1R3G overexpression increases hepatic glycogen accumulation, stimulates glycogen synthase activity, elevates fasting blood glucose level, and accelerates postprandial blood glucose clearance. In addition, the transgenic mice have a reduced fat composition, together with decreased hepatic triglyceride level. Fasting-induced hepatic steatosis is relieved by PPP1R3G overexpression. In addition, PPP1R3G overexpression is able to elevate glycogenesis in primary hepatocytes. The glycogen-binding domain is indispensable for the physiological activities of PPP1R3G on glucose metabolism and triglyceride accumulation in the liver. Cumulatively, these data indicate that PPP1R3G plays a critical role in postprandial glucose homeostasis and liver triglyceride metabolism via its regulation on hepatic glycogenesis.


Assuntos
Glucose/metabolismo , Homeostase , Metabolismo dos Lipídeos , Glicogênio Hepático/biossíntese , Fígado/metabolismo , Proteína Fosfatase 1/metabolismo , Animais , Sítios de Ligação , Glicemia , Células Cultivadas , Metabolismo Energético , Hepatócitos/metabolismo , Resistência à Insulina , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Cultura Primária de Células , Proteína Fosfatase 1/genética , Triglicerídeos/metabolismo
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