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1.
J Agric Food Chem ; 67(44): 12208-12218, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31608624

RESUMO

To explore the role of apple polyphenol extract (APE) in ameliorating hepatic steatosis and the potential mechanisms involved, we conducted this study. Thirty-three male C57BL/6 mice were randomly divided into three groups: high-fat diet (HFD) with aseptic water ig. (CON), HFD with 125 or 500 mg/(kg·bw·day) APE ig., namely 100 or 400 mg/(kg·bw·day) apple polyphenols (LAP or HAP) for 12 weeks. Compared with the CON group, the APE treatment significantly decreased the body weight gain and increased the ratio of serum albumin/globulin. High dose of APE treatment significantly decreased the liver weight, reduced the hepatic contents of triglyceride and cholesterol, and improved the histopathological features of hepatic steatosis, accompanied by significantly upregulated protein expressions of LKB1, phosphorylated-AMPK, phosphorylated-ACC, and SIRT1, downregulated mTOR, p70 s6k, and HMGCR in the liver, increased mRNA expressions of Ampk and Cyp27a1, and reduced expressions of Srebp-1c, Fas, and Hmgcr. Our data provided new evidence supporting the preventive role of 500 mg/(kg·bw·day) APE treatment in the HFD-induced hepatic steatosis in C57BL/6 mice via the LKB1/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Clorogênico/administração & dosagem , Fígado Gorduroso/tratamento farmacológico , Flavonoides/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Taninos/administração & dosagem , Proteínas Quinases Ativadas por AMP/genética , Animais , Colesterol , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/genética , Triglicerídeos/metabolismo
2.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1869-1875, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342715

RESUMO

To study the effects of ellagic acid(EA)on inflammation and oxidative stress in mice with fatty liver disease induced by AKT gene transfection,the 20 female FVB mice were randomly divided into normal control group,model group and ellagic acid administration group(150,300 mg·kg~(-1)·d~(-1))(n=5).EA experimental groups and model group were using a high pressure into the tail vein transfection plasmid AKT.The next day,EA was started to administered continuously for 5 weeks after the AKT gene transfection,while the model group and the normal control group were given the same amount of saline.After the administration,the liver tissue and serum of mice were taken.HE and oil red O staining were using to observe the histopathological changes in liver;liver function to detect the serum and liver tissue as well as MDA and SOD levels;real-time quantitative PCR(RT-qPCR)was used to measure the mR-NA expression of NF-κB and TNF-α;Western blot and immunohistochemistry were used to measure the expression of NF-κB,TNF-αand COX-2 in liver tissue.RESULTS:: show that after AKT gene transfection,the model group had significant increase in the serum levels of AST,ALT,elevated the levels of MDA and decreased the levels of SOD in serum and liver tissue,aggravated histopathology degeneration and Liver inflammation,and significantly higher expression of NF-κB,TNF-α,IL-6,COX-2 and other inflammatory-related factors in liver tissue.EA administration group significant reductions in the serum levels of AST,ALT,and improved in hepatocyte fatty degeneration and liver inflammation,lower the levels of MDA and increased the levels of SOD in serum and liver tissue,and significant reductions in the expression of NF-κB,TNF-α,IL-6 and COX-2 in liver tissue.These results suggest that EA has obvious anti-inflammatory effect and inhibits oxidative stress and EA has a significant therapeutic effecton AKT gene inducing fatty liver,and the mechanism possibly by inhibiting inflammatory factors of NF-κB,TNF-α,IL-6,COX-2 and anti-oxidative stress-related.


Assuntos
Ácido Elágico/farmacologia , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/genética , Animais , Fígado Gorduroso/genética , Feminino , Camundongos , Distribuição Aleatória , Transfecção
3.
Arch Virol ; 164(10): 2559-2563, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321587

RESUMO

Polymorphisms in the microsomal triglyceride transfer protein (MTTP) gene were genotyped in individuals who were chronically infected with hepatitis C virus (HCV). In the 236 patients, the frequencies of risk alleles of the -164T/C (rs1800804), -400A/T (rs1800803) and H297Q (rs2306985) polymorphisms were 0.30, 0.41 and 0.50, respectively. A significant association between the risk alleles of the -164T/C and -400A/T polymorphisms combined with HCV genotype 3 infection and the occurrence of steatosis was detected (p = 0.004 and p = 0.032), suggesting that a combination of host and viral factors can potentially be used to predict hepatic steatosis.


Assuntos
Proteínas de Transporte/genética , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Predisposição Genética para Doença , Hepacivirus/classificação , Hepatite C Crônica/complicações , Hepatite C Crônica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Genótipo , Técnicas de Genotipagem , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Histocitoquímica , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem
4.
J Food Sci ; 84(7): 1900-1908, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31183867

RESUMO

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


Assuntos
Fígado Gorduroso/dietoterapia , Metabolismo dos Lipídeos , Estresse Oxidativo , Óleo de Brassica napus/química , Óleo de Brassica napus/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Colesterol/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/análise , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Humanos , Resistência à Insulina , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , PPAR alfa/genética , PPAR alfa/metabolismo , Fosfolipídeos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
5.
J Dairy Sci ; 102(8): 7536-7547, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178189

RESUMO

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


Assuntos
Doenças dos Bovinos/metabolismo , Bovinos/metabolismo , Fígado Gorduroso/veterinária , GTP Fosfo-Hidrolases/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Animais , Bovinos/genética , Doenças dos Bovinos/enzimologia , Doenças dos Bovinos/genética , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , GTP Fosfo-Hidrolases/genética , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Mitocôndrias/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
6.
Nat Commun ; 10(1): 2375, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147543

RESUMO

Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins and is involved in many physiological processes. Obesity, as a worldwide healthcare problem, has attracted more and more attention. To investigate the role of adipose HuR, we generate adipose-specific HuR knockout (HuRAKO) mice. As compared with control mice, HuRAKO mice show obesity when induced with a high-fat diet, along with insulin resistance, glucose intolerance, hypercholesterolemia and increased inflammation in adipose tissue. The obesity of HuRAKO mice is attributed to adipocyte hypertrophy in white adipose tissue due to decreased expression of adipose triglyceride lipase (ATGL). HuR positively regulates ATGL expression by promoting the mRNA stability and translation of ATGL. Consistently, the expression of HuR in adipose tissue is reduced in obese humans. This study suggests that adipose HuR may be a critical regulator of ATGL expression and lipolysis and thereby controls obesity and metabolic syndrome.


Assuntos
Tecido Adiposo Branco/metabolismo , Proteína Semelhante a ELAV 1/genética , Intolerância à Glucose/genética , Hipercolesterolemia/genética , Resistência à Insulina/genética , Lipase/genética , Obesidade/genética , Adipócitos/patologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/imunologia , Animais , Crescimento Celular , Dieta Hiperlipídica , Proteína Semelhante a ELAV 1/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Intolerância à Glucose/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Hipertrofia , Inflamação/imunologia , Lipase/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Biossíntese de Proteínas , Estabilidade de RNA/genética , Gordura Subcutânea/metabolismo
7.
BMC Genomics ; 20(1): 372, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088359

RESUMO

BACKGROUND: Dysregulation of adipogenesis causes metabolic diseases, like obesity and fatty liver. Migratory birds such as geese have a high tolerance of massive energy intake and exhibit little pathological development. Domesticated goose breeds, derivatives of the wild greyleg goose (Anser anser) or swan goose (Anser cygnoides), have high tolerance of energy intake resembling their ancestor species. Thus, goose is potentially a model species to study mechanisms associated with adipogenesis. RESULTS: Phenotypically, goose liver exhibited higher fat accumulation than adipose tissues during fattening (liver increased by 3.35 fold than 1.65 fold in adipose), showing a priority of fat accumulation in liver. We found the number of differentially expressed genes in liver (13.97%) was nearly twice the number of that in adipose (6.60%). These differentially expressed genes in liver function in several important lipid metabolism pathways, immune response, regulation of cancer, while in adipose, terms closely related to protein binding, gluconeogenesis were enriched. Typically, genes like MDH2 and SCD, which have key roles in glycolysis and fatty acids metabolism, had higher fold change in liver than in adipose tissues. Three hundred two differentially expressed long noncoding RNAs involved in regulation of metabolism in liver were also identified. For example, lncRNA XLOC_292762, which was 5.7 kb downstream of FERMT2, a gene involved phosphatidylinositol-3,4,5-trisphosphate binding, was significantly down-regulated after the high-intake feeding period. Further investigation of documented obesity-related orthologous genes in goose suggested that understanding the evolutionary split from mammals in adipogenesis will make goose fatty liver a better resource for future research. CONCLUSIONS: Our research reveals that goose uses liver as the major tissue to regulate a distinct lipid synthesis and degradation flux and the dynamic expression network analyses showed numerous layers of positive responses to both massive energy intake and possible pathological development. Our results offer insights into goose adipogenesis and provide a new perspective for research in human metabolic dysregulation.


Assuntos
Tecido Adiposo/química , Fígado Gorduroso/veterinária , Gansos/genética , Perfilação da Expressão Gênica/veterinária , Fígado/química , Adipogenia , Animais , Dieta Hiperlipídica/efeitos adversos , Dieta Hiperlipídica/veterinária , Metabolismo Energético , Evolução Molecular , Fígado Gorduroso/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Gluconeogênese , Metabolismo dos Lipídeos , Masculino , RNA Longo não Codificante/genética
8.
Int J Mol Sci ; 20(10)2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31126043

RESUMO

Phytochemicals are known to benefit human health by modulating various cellular processes, including cell proliferation, apoptosis, and inflammation. Due to the potential use of phytochemicals as therapeutic agents against human diseases such as cancer, studies are ongoing to elucidate the molecular mechanisms by which phytochemicals affect cellular functions. It has recently been shown that phytochemicals may regulate the expression of microRNAs (miRNAs). MiRNAs are responsible for the fine-tuning of gene expression by controlling the expression of their target mRNAs in both normal and pathological cells. This review summarizes the recent findings regarding phytochemicals that modulate miRNA expression and promote human health by exerting anticancer, photoprotective, and anti-hepatosteatosis effects. Identifying miRNAs modulated by phytochemicals and understanding the regulatory mechanisms mediated by their target mRNAs will facilitate the efforts to maximize the therapeutic benefits of phytochemicals.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , MicroRNAs/genética , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Promoção da Saúde , Humanos , Neoplasias/genética , Neoplasias/prevenção & controle , Compostos Fitoquímicos/farmacologia , Substâncias Protetoras/farmacologia
9.
Artif Cells Nanomed Biotechnol ; 47(1): 1782-1787, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062612

RESUMO

Hepatic steatosis is one of the most important features of the pathogenesis for non-alcoholic fatty liver disease. Fat deposition in liver cells can influence hepatic lipogenesis along with other metabolic pathways and further lead to the irreversible liver cirrhosis and injury. However, the underlying mechanism of steatosis remains largely unexplored. Our previous study revealed that AQP7 played an important role in liver steatosis. In this study, we determined that the transcriptional level of AQP7 was up-regulated by estrogen receptor alpha (ERα) upon 17ß-estradiol (E2) and oleic acids treated HepG2 cells. Furthermore, we identified long non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) as a potential hallmark which was down-regulated in ERα silencing HepG2 cells by RNA-Seq. Finally, we validated that the 3' terminal nucleotides of NEAT1 were contributed for the interaction with ERα to facilitate AQP7 transcription to suppress liver steatosis. Overall, our study gave evidence that NEAT1 played an important role in the activation of ERα to regulate AQP7-mediated hepatic steatosis.


Assuntos
Aquaporinas/genética , Receptor alfa de Estrogênio/metabolismo , Fígado Gorduroso/genética , Regulação da Expressão Gênica/genética , RNA Longo não Codificante/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Células Hep G2 , Humanos , RNA Longo não Codificante/metabolismo , Transcrição Genética/genética
10.
J Agric Food Chem ; 67(21): 5957-5967, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31066268

RESUMO

d- chiro-Inositol (DCI) is a biologically active component found in tartary buckwheat, which can reduce hyperglycemia and ameliorate insulin resistance. However, the mechanism underlying the antidiabetic effects of DCI remains largely unclear. This study investigated the effects and underlying molecular mechanisms of DCI on hepatic gluconeogenesis in mice fed a high fat diet and saturated palmitic acid-treated hepatocytes. DCI attenuated free fatty acid uptake by the liver via lipid trafficking inhibition, reduced diacylglycerol deposition, and hepatic PKCε translocation. Thus, DCI could improve insulin sensitivity by suppressing hepatic gluconeogenesis. Subsequent analyses revealed that DCI decreased hepatic glucose output and the expression levels of PEPCK and G6 Pase in insulin resistant mice through PKCε-IRS/PI3K/AKT signaling pathway. Likewise, such effects of DCI were confirmed in HepG2 cells with palmitate-induced insulin resistance. These findings indicate a novel pathway by which DCI prevents hepatic gluconeogenesis, reduces lipid deposition, and ameliorates insulin resistance via regulation of PKCε-PI3K/AKT axis.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Inositol/administração & dosagem , Resistência à Insulina , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Quinase C-épsilon/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/genética , Proteína Quinase C-épsilon/genética , Proteínas Proto-Oncogênicas c-akt/genética
11.
Lipids Health Dis ; 18(1): 87, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954078

RESUMO

BACKGROUND: The homeostasis of lipid droplets (LDs) plays a crucial role in maintaining the physical metabolic processes in cells, and is regulated by many LD-associated proteins, including perilipin 5 (Plin5) in liver. As the putative sites of hepatitis C virus (HCV) virion assembly, LDs are vital to viral infection. In addition, the hepatic LD metabolism can be disturbed by non-structural HCV proteins, such as NS5A, but the details are still inexplicit. METHODS: HCV NS5A was overexpressed in the livers and hepatocytes of wild-type and Plin5-null mice. BODIPY 493/503 and oil red O staining were used to detect the lipid content in mouse livers and hepatocytes. The levels of lipids, lipid peroxidation and inflammation biomarkers were further determined. Immunofluorescence assay and co-immunoprecipitation assay were performed to investigate the relationship of Plin5 and NS5A. RESULTS: One week after adenovirus injection, livers expressing NS5A showed more inflammatory cell aggregation and more severe hepatic injuries in Plin5-null mice than in control mice, which was consistent with the increased serum levels of IL-2 and TNF-α (P < 0.05) observed in Plin5-null mice. Moreover, Plin5 deficiency in the liver and hepatocytes aggravated the elevation of MDA and 4-HNE levels induced by NS5A expression (P < 0.01). The triglyceride (TG) content was increased approximately 25% by NS5A expression in the wild-type liver and hepatocytes but was unchanged in the Plin5-null liver and hepatocytes. More importantly, Plin5 deficiency in the liver and hepatocytes exacerbated the elevation of non-esterified fatty acids (NEFAs) stimulated by NS5A expression (P < 0.05 and 0.01 respectively). Using triacsin C to block acyl-CoA biosynthesis, we found that Plin5 deficiency aggravated the NS5A-induced lipolysis of TG. In contrast, Plin5 overexpression in HepG2 cells ameliorated the NS5A-induced lipolysis and lipotoxic injuries. Immunofluorescent staining demonstrated that NS5A expression stimulated the targeting of Plin5 to the surface of the LDs in hepatocytes without altering the protein levels of Plin5. By co-IP, we found that the N-terminal domain (aa 32-128) of Plin5 was pivotal for its binding with NS5A. CONCLUSIONS: Our data highlight a protective role of Plin5 against hepatic lipotoxic injuries induced by HCV NS5A, which is helpful for understanding the steatosis and injuries in liver during HCV infection.


Assuntos
Fígado Gorduroso/genética , Hepatite C/genética , Fígado/metabolismo , Perilipina-5/genética , Proteínas não Estruturais Virais/genética , Acil Coenzima A/antagonistas & inibidores , Acil Coenzima A/biossíntese , Adenoviridae/genética , Animais , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Fígado Gorduroso/terapia , Regulação Viral da Expressão Gênica/genética , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/metabolismo , Hepatite C/patologia , Hepatite C/virologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Metabolismo dos Lipídeos/genética , Lipólise/genética , Fígado/lesões , Fígado/patologia , Fígado/virologia , Camundongos , Triazenos/administração & dosagem , Triglicerídeos/genética , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/genética
12.
Gene ; 700: 139-148, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898698

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is always characterized by hepatic steatosis and insulin resistance. Dysregulated long noncoding RNAs regulate pathogenesis of NAFLD. However, the role of Mirt2 (long noncoding RNA myocardial infraction associated transcript 2) in NAFLD remains unclear. This original study aims to investigate the role of Mirt2 in hepatic steatosis and insulin resistance. Mirt2 was decreased in the livers of high-fat diet (HFD) mice, Ob/Ob, Db/Db, and fasting mice. Hepatic Mirt2 restoration attenuated hyperglycemia, insulin resistance and steatosis in the livers of obese mice, and Mirt2 inhibition promoted fasting hyperglycemia and lipid droplets accumulation in normal mouse livers. Furthermore, overexpression of Mirt2 resulted in suppression of miR-34a-5p, whereas knockdown of Mirt2 exerted opposite effects in the livers. Then, miR-34a-5p was a positive regulator of NAFLD by targeting USP10, which serves as a negative regulator of NAFLD. Overexpression of Mirt2 made miR-34a-5p mimic fail to reduce luciferase activity of USP10 3'-UTR, and this regulation was also demonstrated by Western blot. Similarly, overexpression of miR-34a-5p significantly let Mirt2 lost the ability to elevate USP10 protein level. Thus, Mirt2 can function as the sponge of miR-34a-5p. Moreover, Mirt2-mediated upregulation of USP10 protein expression can be reversed by silencing USP10. USP10 inhibition could abolish Mirt2 overexpression-induced suppression of glucose production and lipogenesis in hepatocytes. In conclusion, the decrease of Mirt2 expression contributed to hepatic insulin resistance and steatosis in obese mice, and Mirt2/miR-34a-5p/USP10 was involved in NAFLD development. Overexpression of Mirt2 might be a promising strategy for treatment of NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/genética , MicroRNAs/genética , Obesidade/genética , RNA Longo não Codificante/genética , Ubiquitina Tiolesterase/genética , Regiões 3' não Traduzidas , Animais , Linhagem Celular , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Humanos , Resistência à Insulina , Masculino , Camundongos , Regulação para Cima
13.
Methods Mol Biol ; 1951: 179-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30825153

RESUMO

Chromatin immunoprecipitation (ChIP) assays allow for the study of protein-DNA interactions in physiological contexts. Briefly, ChIPs consist of the purification and enrichment of a protein of interest together with its associated chromatin and its later identification. Hence, this technique proves to be particularly useful when assessing novel target genes for nuclear receptors. In the field of metabolic liver diseases, the validation of putative nuclear receptor targets is key for furthering the development of nuclear receptor modulators as therapeutic compounds. In this chapter, the protocol described has been optimized for ChIP on mouse fatty (steatotic) livers. Thanks to the use of a "two-step" (double) cross-linking method, this protocol can also be used for the study of other proteins with weaker interactions or that are present in large complexes, such as cofactors.


Assuntos
Imunoprecipitação da Cromatina , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Sítios de Ligação , Imunoprecipitação da Cromatina/métodos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Ligação Proteica
14.
Int J Mol Sci ; 20(3)2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30717414

RESUMO

Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (>1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to long-term HDL-based therapies in independent studies and might raise concerns regarding the use of hApoA-I-mediated therapy in obese humans.


Assuntos
Apolipoproteína A-I/genética , Colesterol/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Expressão Gênica , Macrófagos/metabolismo , Animais , Transporte Biológico , Peso Corporal , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Perfilação da Expressão Gênica , Humanos , Camundongos
15.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(4): 522-531, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30630053

RESUMO

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. Overexpression of ApoD in mouse neural tissue induces the development of a non-inflammatory hepatic steatosis in 12-month-old transgenic animals. Previous data indicates that accumulation of arachidonic acid, ApoD's preferential ligand, and overactivation of PPARγ are likely the driving forces in the development of the pathology. However, the lack of inflammation under those conditions is surprising. Hence, we further investigated the apparent repression of inflammation during hepatic steatosis development in aging transgenic animals. The earliest modulation of lipid metabolism and inflammation occurred at 6 months with a transient overexpression of L-PGDS and concomitant overproduction of 15d-PGJ2, a PPARγ agonist. Hepatic lipid accumulation was detectable as soon as 9 months. Inflammatory polarization balance varied in time, with a robust anti-inflammatory profile at 6 months coinciding with 15d-PGJ2 overproduction. Omega-3 and omega-6 fatty acids were preferentially stored in the liver of 12-month-old transgenic mice and resulted in a higher omega-3/omega-6 ratio compared to wild type mice of the same age. Thus, inflammation seems to be controlled by several mechanisms in the liver of transgenic mice: first by an increase in 15d-PGJ2 production and later by a beneficial omega-3/omega-6 ratio. PPARγ seems to play important roles in these processes. The accumulation of several omega fatty acids species in the transgenic mouse liver suggests that ApoD might bind to a broader range of fatty acids than previously thought.


Assuntos
Apolipoproteínas D/genética , Ácidos Graxos Insaturados/metabolismo , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Prostaglandinas/metabolismo , Animais , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Fígado Gorduroso/genética , Masculino , Camundongos , Camundongos Transgênicos , PPAR gama/metabolismo , Prostaglandina D2/análogos & derivados , Prostaglandina D2/metabolismo
16.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(4): 489-499, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30639733

RESUMO

Olfactory receptors are primarily expressed in nasal olfactory epithelium, but these receptors are also ectopically expressed in diverse tissues. In this study, we investigated the biological functions of Olfr43, a mouse homolog of human OR1A1, in cultured hepatocytes and mice to assess its functionality in lipid metabolism. Olfr43 was expressed in mouse hepatocytes, and Olfr43 activation by a known ligand, (-)-carvone, stimulated cAMP response element-binding protein (CREB) activity. In ligand-receptor binding studies using site-directed mutagenesis, (-)-carvone binding required two residues, M257 and Y258, in Olfr43. In the mouse study, oral administration of (-)-carvone for 5 weeks in high-fat diet-fed mice improved energy metabolism, including reductions in hepatic steatosis and adiposity, and improved glucose and insulin tolerance. In mouse livers and cultured mouse hepatocytes, Olfr43 activation simulated the CREB-hairy and enhancer of split 1 (HES1)-peroxisome proliferator-activated receptor (PPAR)-γ signaling axis, leading to a reduction in hepatic triglyceride accumulation in the mouse liver. Thus, long-term administration of (-)-carvone reduces hepatic steatosis. The knockdown of Olfr43 gene expression in cultured hepatocytes negated these effects of (-)-carvone. In conclusion, an ectopic olfactory receptor, hepatic Olfr43, regulates energy metabolism via the CREB-HES1-PPARγ signaling axis.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Hepatócitos/citologia , Monoterpenos/administração & dosagem , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Adiposidade/efeitos dos fármacos , Administração Oral , Animais , Linhagem Celular , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Metabolismo Energético , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Monoterpenos/farmacologia , Mutagênese Sítio-Dirigida , PPAR gama/metabolismo , Receptores Odorantes/química , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição HES-1/metabolismo
17.
Toxicol Appl Pharmacol ; 365: 51-60, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30625338

RESUMO

Hepatocellular carcinoma (HCC) is a lethal malignancy with few effective options for therapeutic treatment in its advanced stages. Metformin, a first-line oral agent used in the treatment of type 2 diabetes, exhibits efficacy in metabolic reprogramming fueling changes in cell growth and proliferation for multiple cancer types, including HCC. However, the molecular mechanism by which metformin delays hepatocarcinogenesis in individuals with hepatic steatosis remains rare. Here, we investigate the preventive efficacy of metformin in a rapid AKT/c-Met-triggered HCC mouse model featuring excessive levels of steatosis. Hematoxylin and eosin staining, Oil Red O staining and immunoblotting were applied for mechanistic investigations. Pharmacological and biochemical strategies were employed to illuminate molecular evidence for HCC cell lines. The results show that metformin obstructs the malignant transformation of hepatocytes in AKT/c-Met mice. Mechanistically, metformin reduces the expression of phospho-ERK (Thr202/Tyr204) and two forms of proto-oncogenes, Cyclin D1 and c-Myc, in AKT/c-Met mice. Moreover, metformin ameliorates FASN-mediated aberrant lipogenesis and HK2/PKM2-driven ATP generation in vivo. Furthermore, metformin represses the expression of FASN and HK-2 by targeting c-Myc in an AMPK-dependent manner in vitro. In addition, metformin is effective at inhibiting PKM2 expression in the presence of an AMPK inhibitor compound C, suggesting that its functioning in PKM2 is AMPK-independent. Our study experimentally validates a novel molecular mechanism by which metformin alleviates enhanced lipogenesis and high energy metabolism during hepatocarcinogenesis, indicating that metformin may serve as an agent for the prevention of HCC in patients with nonalcoholic fatty liver diseases.


Assuntos
Trifosfato de Adenosina/metabolismo , Anticarcinógenos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Transformação Celular Neoplásica/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Fígado/efeitos dos fármacos , Metformina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Hexoquinase/metabolismo , Humanos , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-met/genética , Piruvato Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
BMC Genomics ; 20(1): 13, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616512

RESUMO

BACKGROUND: Duck species are known to have different susceptibility to fatty liver production in response to overfeeding. In order to better describe mechanisms involved in the development of hepatic steatosis and differences between species, transcriptome analyses were conducted on RNAs extracted from the livers of Pekin and Muscovy duck species and of their reciprocal hybrids, Mule and Hinny ducks fed ad libitum or overfed to identify differentially expressed genes and associated functions. RESULTS: After extraction from the liver of ducks from the four genetic types, RNAs were sequenced and sequencing data were analyzed. Hierarchic clustering and principal component analyses of genes expression levels indicated that differences between individuals lie primarily in feeding effect, differences between genetic types being less important. However, Muscovy ducks fed ad libitum and overfed were clustered together. Interestingly, Hinny and Mule hybrid ducks could not be differentiated from each other, according to feeding. Many genes with expression differences between overfed and ad libitum fed ducks were identified in each genetic type. Functional annotation analyses of these differentially expressed genes highlighted some expected functions (carbohydrate and lipid metabolisms) but also some unexpected ones (cell proliferation and immunity). CONCLUSIONS: These analyses evidence differences in response to overfeeding between different genetic types and help to better characterize functions involved in hepatic steatosis in ducks.


Assuntos
Patos/genética , Fígado Gorduroso/genética , Doenças das Aves Domésticas/genética , Análise de Sequência de RNA/métodos , Ração Animal , Animais , Patos/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo
19.
Poult Sci ; 98(5): 2201-2210, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608557

RESUMO

In mammals, the AMP-activated protein kinase (AMPK) pathways in the central and peripheral tissues coordinately integrate inputs from multiple sources to regulate energy balance. To investigate the effects of the fatty liver hemorrhagic syndrome (FLHS) caused by high-energy, low-protein diets and to explore the potential role of AMPK in the energy homeostasis of FLHS, 60 laying hens were equally divided into 2 groups: control group (basal diet) and experimental group (high-energy, low-protein diet). Liver tissues were subjected to histopathological analysis. Liver tissues were also collected on the 100th day to determine the levels of total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-Ch), low-density lipoprotein cholesterol (LDL-Ch), aspartate aminotransferase, and alanine aminotransferase in plasma. Additionally, the mRNA expression levels of AMPK signaling pathway related genes in liver were determined by quantitative RT-PCR. The results showed that histopathological lesions presented different degrees of lipid vacuolization in hepatocytes. In combination with hematoxylin and eosin and oil red O staining, the experimental group was divided into mild group and severe group. In the severe group, contents of TG and LDL-Ch were extremely significantly increased (P < 0.01) compared to the control group, and HDL-Ch content was extremely significantly decreased (P < 0.01). The serine-threonine kinase 11 and AMPKα1 mRNA expression levels were downregulated, while acetyl-CoA carboxylase, fatty acid synthase, hepatocyte nuclear factor-4α, 3-hydroxy-3-methyl glutaryl coenzyme A reductase and carnitine palmitoyltransferase-I mRNA expression levels were upregulated by a high-energy and low-protein diet. Taken together, these findings suggest that a functional AMPK signaling pathway exists in chickens and AMPK may alter the energy balance in the FLHS induced by high-energy, low-protein diets.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Galinhas , Dieta com Restrição de Proteínas/veterinária , Fígado Gorduroso/veterinária , Hemorragia/veterinária , Doenças das Aves Domésticas/genética , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/metabolismo , Ração Animal/análise , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Fígado Gorduroso/genética , Feminino , Hemorragia/genética
20.
Oncogene ; 38(16): 3033-3046, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30575815

RESUMO

Metabolic syndrome (MS) is becoming the leading risk factor for hepatocellular carcinoma (HCC). HCC development related to MS may occur in advanced or non-advanced liver fibrosis, suggesting specific molecular pathways. Among these pathways, basal inflammatory state and adipokines production are involved. The aim of this study was to evaluate the role of fatty acid-binding protein 4 (FABP4). In this study, we demonstrate the specific overexpression of FABP4 in human HCC samples from patients with MS compared to other risk factors for chronic liver disease with FABP4 expression restricted to peritumoral endothelial cells. In vitro, glucose, insulin, VEGFA and hypoxia upregulated endothelial FABP4, which was reversed by metformin through mTOR pathway inhibition. FABP4 exerts oncogenic effects on hepatoma cell lines by upregulating the angiogenesis gene signature and pathways involved in the cell cycle, leading to increased cell proliferation and migration, and downregulating HIF1 pathway; effects were reversed in the presence of a specific FABP4 inhibitor (BMS309403). We showed the role of microvesicles as FABP4 vectors between endothelial and tumor cells. In vivo, BMS309403 significantly reduces tumor growth in heterotopic and orthotopic xenografted mice model. In conclusion, this study demonstrates the emerging oncogenic role of liver endothelial cells through FABP4 in HCC related to MS, and highlights new anti-neoplastic mechanism of metformin.


Assuntos
Carcinoma Hepatocelular/genética , Células Endoteliais/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Fígado Gorduroso/genética , Neoplasias Hepáticas/genética , Síndrome Metabólica/genética , Células 3T3-L1 , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Células Hep G2 , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transdução de Sinais/genética , Regulação para Cima/genética , Fator A de Crescimento do Endotélio Vascular/genética
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