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

RESUMO

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


Assuntos
Benzofuranos/administração & dosagem , Furanos/administração & dosagem , Lignanas/administração & dosagem , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Primulaceae/química , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Humanos , Fígado/metabolismo , Receptores X do Fígado/genética , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
2.
Medicine (Baltimore) ; 98(32): e16704, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393374

RESUMO

The human leukocyte antigen (HLA) genes may play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH). The aim of this study was to assess the association of HLA class I and II alleles with NASH and its histological features.Deoxyribonucleic acid (DNA) was extracted from 140 subjects (85 biopsy-proven NAFLD and 55 controls) and genotyped for HLA (-A, -B, -C, -DR1, -DR3, -DQ, and -DP). Liver biopsies were assessed for presence of NASH, degree of fibrosis and inflammation. Multivariate analysis was performed to assess associations between HLA genes and different histologic features of NAFLD.Our data for HLA class I showed that HLA-C*4 was associated with lower risk for histologic NASH and HLA-C*6 was protective against portal fibrosis. Conversely, HLA-B*27 was associated with high-grade hepatic steatosis, while HLA-A*31 was associated with increased risk for advanced fibrosis. Among HLA class II alleles, HLA-DQA1*01 was associated with lower risk for NASH while HLA-DRB1*03 was associated with increased risk for NASH.Our findings indicate that HLA class I and II gene polymorphism may be associated with susceptibility to NASH, fibrosis and other pathologic features and may be involved in the pathogenesis of NAFLD.


Assuntos
Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Alelos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo Genético , Estudos Prospectivos
3.
Zhonghua Gan Zang Bing Za Zhi ; 27(7): 533-540, 2019 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357780

RESUMO

Objective: To analyze non-alcoholic steatohepatitis (NASH)-related differentially expressed genes (DEGs) by bioinformatics methods to find key pathways and potential therapeutic targets for NASH. Methods: GSE61260 chip was downloaded from the public microarray database and liver biopsy samples from 24 NASH cases and 38 healthy controls were included. The Limma software package in R language was used to screen DEGs under the condition of difference multiple > 1.5 and adj. P < 0.05. The clusterProfiler software package was used for GO analysis and KEGG analysis. The STRING online database was used for protein-protein interaction analysis, and the L1000 and DrugBank databases were used for drug prediction. Results: Compared with healthy control group, 857 DEGs were screened out in NASH group including 167 up-regulated genes and 690 down-regulated genes. GO analysis showed that DEGs were mainly involved in inflammation and cholesterol metabolism. KEGG analysis showed that DEGs were mainly enriched in PPAR, non-alcoholic fatty liver disease, oxidative phosphorylation and other signaling pathways. Among them, eight genes of ACSL4, CYP7A1, FABP4, FABP5, lipoprotein lipase, ME1, OLR1 and PLIN1 were enriched in PPAR signaling pathway, and 165 interaction nodes were formed with 47 DEGs-encoded proteins. Lipoprotein lipase interacted with 21 DEGs, and its up-regulated expression had improved lipid metabolism, insulin resistance and anti-inflammatory effects. Four drugs (gemfibrozil, bezafibrate, omega-3 carboxylic acid and glycyrrhizic acid) were screened by L1000 and DrugBank to activate lipoprotein lipase. Presently, these four drugs are clinically used to treat hypertriglyceridemia or to improve inflammation. In this regard, we speculated that the pharmacological effects of these four drugs had improved NASH by activating lipoprotein lipase to promote liver lipid metabolism and alleviate inflammation. Conclusion: PPAR signaling pathway is closely associated to the occurrence and development of NASH, and thereby lipoprotein lipase agonist is a new attempt to treat NASH.


Assuntos
Ativadores de Enzimas/farmacologia , Metabolismo dos Lipídeos , Lipase Lipoproteica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Bezafibrato/farmacologia , Biópsia , Ácidos Carboxílicos/farmacologia , Estudos de Casos e Controles , Biologia Computacional , Genfibrozila/farmacologia , Ácido Glicirrízico/farmacologia , Humanos , Hepatopatia Gordurosa não Alcoólica/enzimologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Depuradores Classe E
4.
BMC Med ; 17(1): 135, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31311600

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. METHODS: First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). RESULTS: Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10- 20). This effect was consistent in both pediatric (p = 9.92 × 10- 6) and adult (p = 9.73 × 10- 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10- 8, beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10- 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10- 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10- 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses. CONCLUSIONS: In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings.


Assuntos
Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Redes Comunitárias/organização & administração , Redes Comunitárias/estatística & dados numéricos , Progressão da Doença , Registros Eletrônicos de Saúde/organização & administração , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/organização & administração , Genômica/estatística & dados numéricos , Humanos , Lipase/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Morbidade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética
5.
Gastroenterology ; 157(3): 777-792.e14, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31078624

RESUMO

BACKGROUND & AIMS: We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH. METHODS: We stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1-/-) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays. RESULTS: HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1-/- mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/- mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1. CONCLUSIONS: Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.


Assuntos
Anticorpos Neutralizantes/farmacologia , Hepatite/prevenção & controle , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-11/antagonistas & inibidores , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Morte Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Subunidade alfa de Receptor de Interleucina-11/genética , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos , Células THP-1
7.
Cell Mol Life Sci ; 76(21): 4341-4354, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31119300

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a metabolic liver disease that is thought to be reversible by changing the diet. To examine the impact of dietary changes on progression and cure of NAFLD, we fed mice a high-fat diet (HFD) or high-fructose diet (HFrD) for 9 weeks, followed by an additional 9 weeks, where mice were given normal chow diet. As predicted, the diet-induced NAFLD elicited changes in glucose tolerance, serum cholesterol, and triglyceride levels in both diet groups. Moreover, the diet-induced NAFLD phenotype was reversed, as measured by the recovery of glucose intolerance and high cholesterol levels when mice were given normal chow diet. However, surprisingly, the elevated serum triglyceride levels persisted. Metagenomic analysis revealed dietary-induced changes of microbiome composition, some of which remained altered even after reversing the diet to normal chow, as illustrated by species of the Odoribacter genus. Genome-wide DNA methylation analysis revealed a "priming effect" through changes in DNA methylation in key liver genes. For example, the lipid-regulating gene Apoa4 remained hypomethylated in both groups even after introduction to normal chow diet. Our results support that dietary change, in part, reverses the NAFLD phenotype. However, some diet-induced effects remain, such as changes in microbiome composition, elevated serum triglyceride levels, and hypomethylation of key liver genes. While the results are correlative in nature, it is tempting to speculate that the dietary-induced changes in microbiome composition may in part contribute to the persistent epigenetic modifications in the liver.


Assuntos
Metilação de DNA , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Metilação de DNA/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Obesidade/genética , Obesidade/metabolismo , Obesidade/microbiologia
8.
Indian J Med Res ; 149(1): 9-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-31115369

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most common cancer in world and third largest cause of cancer-related deaths. The last few decades have witnessed the emergence of non-viral causes of HCC, the most important being non-alcoholic fatty liver disease (NAFLD). NAFLD ranges from simple steatosis in the absence of excessive alcohol intake to non-alcoholic steatohepatitis (NASH) with or without cirrhosis. About 3-15 per cent of the obese patients with NASH progress to cirrhosis and about 4-27 per cent of NASH with cirrhosis patients transform to HCC. It is also known that HCC can develop de novo in patients with NASH without the presence of cirrhosis. Yearly cumulative incidence of NASH-related HCC is low (2.6%) compared to four per cent of viral-HCC. NAFLD has been associated with risk factors such as metabolic syndrome, insulin resistance, altered gut flora and persistent inflammation. Due to alarming rise in metabolic diseases, both in the developing as well as the developed world, it is expected that the incidence of NAFLD/NASH-HCC would rise manifold in future. No definite guidelines have been drawn for surveillance and management of NAFLD/NASH-associated HCC. It is thus important to discuss the entity of HCC in NAFLD at length with special focus on its epidemiology, risk factors, pathophysiology, diagnosis, clinical presentation and prevention.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/prevenção & controle , Humanos , Resistência à Insulina/genética , Cirrose Hepática/complicações , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/prevenção & controle , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fatores de Risco
9.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987167

RESUMO

The purpose of this work was to evaluate the effect of dietary carotenoids from spinach on the inflammation and oxidative stress biomarkers, liver lipid profile, and liver transcriptomic and metabolomics profiles in Sprague-Dawley rats with steatosis induced by a high-fat diet. Two concentrations of spinach powder (2.5 and 5%) were used in two types of diet: high-fat (H) and standard (N). Although rats fed diet H showed an accumulation of fat in hepatocytes, they did not show differences in the values of adiponectin, tumor necrosis factor alpha (TNF-α), and oxygen radical absorption (ORAC) in plasma or of isoprostanes in urine compared with animals fed diet N. The consumption of spinach and the accumulation of α and ß carotenes and lutein in the liver was inversely correlated with serum total cholesterol and glucose and the content of hepatic cholesterol, increasing monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and reducing cholesterol in the livers of rats fed diet H and spinach. In addition, changes in the expression of genes related to the fatty liver condition occurred, and the expression of genes involved in the metabolism of fatty acids and cholesterol increased, mainly through the overexpression of peroxisome proliferator activated receptors (PPARs). Related to liver metabolites, animals fed with diet H showed hypoaminoacidemia, mainly for the glucogenic aminoacids. Although no changes were observed in inflammation and oxidative stress biomarkers, the consumption of spinach modulated the lipid metabolism in liver, which must be taken into consideration during the dietary treatment of steatosis.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Spinacia oleracea/química , Animais , Antioxidantes/metabolismo , Biomarcadores/sangue , Carotenoides/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Comportamento Alimentar , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/sangue , Fígado/patologia , Metaboloma/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/genética , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Análise de Componente Principal , Ratos Sprague-Dawley , Ganho de Peso
10.
Med Sci Monit ; 25: 2293-3004, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31013265

RESUMO

BACKGROUND The occurrence of nonalcoholic fatty liver disease (NAFLD) is closely related to type 2 diabetes, especially in patients with insulin resistance. The purpose of this research was to elucidate the major genes and transcriptional regulation of insulin resistance in the progression of NAFLD. MATERIAL AND METHODS We downloaded the gene expression matrix of GSE89632 from Gene Expression Omnibus. Then the principal component analysis was used to identify whether the samples were clustered. Differentially expressed genes were identified by limma R package. Enrichment analysis and protein­protein interaction network was used to find potential function and screening hub genes. We further used ChIP-seq data from ENCODE to predict the transcriptional regulation of hub genes. Finally, we verified the functions of hub genes with clinical information. RESULTS These hub genes were significantly enriched in "response to insulin", "response to glucose", and "fat cell differentiation". ChIP-seq data showed that EGR1 (early growth response gene-1) may play an important role in the transcriptional regulation of SOCS1 (suppressor of cytokine signaling 1), SOCS3 (suppressor of cytokine signaling 3), and Fos gene family in the liver, as the low expression of EGR1 in patients with insulin resistance may promote the occurrence and development of NAFLD. Similarly, correlation analysis showed that EGR1 was positively correlated with the expression of SOCS1, SOCS3, and the genes of Fos gene family, and EGR1 was negatively correlated with the degree of steatosis. CONCLUSIONS Newly identified hub genes and their transcriptional regulation may promote understanding of the molecular mechanisms underlying insulin resistance related to the progression of NAFLD and provide a new therapy target and biomarkers.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce/genética , Resistência à Insulina/genética , Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Progressão da Doença , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Insulina/metabolismo , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Análise de Componente Principal , Mapas de Interação de Proteínas , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
11.
Int J Mol Sci ; 20(8)2019 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010049

RESUMO

Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed.


Assuntos
Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Animais , Progressão da Doença , Microbioma Gastrointestinal , Predisposição Genética para Doença , Humanos , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia
12.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018538

RESUMO

Non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in the world. However, there are still no drugs for NAFLD/NASH in the market. Gastrodin (GAS) is a bioactive compound that is extracted from Gastrodia elata, which is used as an active compound on nervous system diseases. Recent reports showed that GAS and Gastrodia elata possess anti-oxidant activity and lipid regulating effects, which makes us curious to reveal the anti-NAFLD effect of GAS. A high cholesterol diet (HCD) was used to induce a NAFLD larval zebrafish model, and the lipid regulation and anti-oxidant effects were tested on the model. Furthermore, qRT-PCR studied the underlying mechanism of GAS. To conclude, this study revealed a lipid regulation and anti-oxidant insights of GAS on NAFLD larval zebrafish model and provided a potential therapeutic compound for NAFLD treatment.


Assuntos
Antioxidantes/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Gastrodia/química , Glucosídeos/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Antioxidantes/isolamento & purificação , Álcoois Benzílicos/isolamento & purificação , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/isolamento & purificação , Larva/efeitos dos fármacos , Larva/genética , Larva/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
13.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945694

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver without any history of chronic alcohol consumption. It encompasses a wide spectrum of diseases that range from simple steatosis to nonalcoholicsteatohepatitis. NAFLD is strongly associated with obesity, insulin resistance / type-2 diabetes mellitus and the metabolic syndrome. NAFLD is a complex disorder; environmental and genetic factors interact with NAFLD manifestation and determine its progression. In this review, an attempt was made to provide current information on the genetic variants of NAFLD in Asian populations. Literature search was performed by using PubMed, Medline and Google Scholar database. Candidate gene, validation and genomewide association studies (GWASs) were included in this review. A total of 41 studies fulfilled inclusion criteria of which 12 candidate gene studies exclusively focussed on the PNPLA3 gene and 17 other studies on other important candidate genes such as NCANCILP2, PPARG,AGTR1, FABP1, APOC3 etc. reported significant association with NAFLD. Eight validation studies identified associations of variants on PNPLA3, LYPLAL1, TM6SF2, ADIPOR2, STAT3, GCKR, SAMM50 etc. with NAFLD. Thus, so far, four GWASs have been conducted in Asian population that reported PNPLA3, SAMM50, PARVB and GATAD2A genes which were significantly associated with NAFLD. Findings indicate that PNPLA3, APOC3, PPARG, NCAN and GCKR genes emerge out to be the important biological markers associated with NAFLD.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Marcadores Genéticos , Predisposição Genética para Doença , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/genética , Ásia/epidemiologia , Humanos , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Prognóstico
14.
PLoS Comput Biol ; 15(4): e1006760, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31002661

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndromes spanning a wide spectrum of diseases, from simple steatosis to the more complex nonalcoholic steatohepatitis. To identify the deregulation that occurs in metabolic processes at the molecular level that give rise to these various NAFLD phenotypes, algorithms such as pathway enrichment analysis (PEA) can be used. These analyses require the use of predefined pathway maps, which are composed of reactions describing metabolic processes/subsystems. Unfortunately, the annotation of the metabolic subsystems can differ depending on the pathway database used, making these approaches subject to biases associated with different pathway annotations, and these methods cannot capture the balancing of cofactors and byproducts through the complex nature and interactions of genome-scale metabolic networks (GEMs). Here, we introduce a framework entitled Minimum Network Enrichment Analysis (MiNEA) that is applied to GEMs to generate all possible alternative minimal networks (MiNs), which are possible and feasible networks composed of all the reactions pertaining to various metabolic subsystems that can synthesize a target metabolite. We applied MiNEA to investigate deregulated MiNs and to identify key regulators in different NAFLD phenotypes, such as a fatty liver and liver inflammation, in both humans and mice by integrating condition-specific transcriptomics data from liver samples. We identified key deregulations in the synthesis of cholesteryl esters, cholesterol, and hexadecanoate in both humans and mice, and we found that key regulators of the hydrogen peroxide synthesis network were regulated differently in humans and mice. We further identified which MiNs demonstrate the general and specific characteristics of the different NAFLD phenotypes. MiNEA is applicable to any GEM and to any desired target metabolite, making MiNEA flexible enough to study condition-specific metabolism for any given disease or organism.


Assuntos
Biologia Computacional/métodos , Redes e Vias Metabólicas , Hepatopatia Gordurosa não Alcoólica , Animais , Ceramidas/metabolismo , Bases de Dados Factuais , Perfilação da Expressão Gênica , Humanos , Peróxido de Hidrogênio/metabolismo , Metabolismo dos Lipídeos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transcriptoma/genética , Transcriptoma/fisiologia
15.
Nat Commun ; 10(1): 1587, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962478

RESUMO

Caloric restriction and intermittent fasting are emerging therapeutic strategies against obesity, insulin resistance and their complications. However, the effectors that drive this response are not completely defined. Here we identify arginase 2 (Arg2) as a fasting-induced hepatocyte factor that protects against hepatic and peripheral fat accumulation, hepatic inflammatory responses, and insulin and glucose intolerance in obese murine models. Arg2 is upregulated in fasting conditions and upon treatment with the hepatocyte glucose transporter inhibitor trehalose. Hepatocyte-specific Arg2 overexpression enhances basal thermogenesis, and protects from weight gain, insulin resistance, glucose intolerance, hepatic steatosis and hepatic inflammation in diabetic mouse models. Arg2 suppresses expression of the regulator of G-protein signalling (RGS) 16, and genetic RGS16 reconstitution reverses the effects of Arg2 overexpression. We conclude that hepatocyte Arg2 is a critical effector of the hepatic glucose fasting response and define a therapeutic target to mitigate the complications of obesity and non-alcoholic fatty liver disease.


Assuntos
Arginase/metabolismo , Jejum/fisiologia , Fígado/metabolismo , Termogênese/fisiologia , Animais , Arginase/genética , Restrição Calórica , Colesterol/genética , Colesterol/metabolismo , Diabetes Mellitus Experimental/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Teste de Tolerância a Glucose , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Resistência à Insulina/fisiologia , Fígado/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas RGS/genética , Proteínas RGS/metabolismo , Termogênese/genética , Trealose/farmacologia
16.
Food Funct ; 10(5): 2450-2460, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-30969285

RESUMO

Cichorium glandulosum(CG) can treat various diseases with multiple targets effectively. It has been widely used in folk medicine to treat nonalcoholic fatty liver disease (NAFLD) as well as type 2 diabetes mellitus (T2DM). However, the active compounds and underlying mechanisms of CG on T2DM accompanied with NAFLD (T2DM-NAFLD) remain unclear. In this study, a systems pharmacology method was used to explain the pharmacology mechanism of CG for treatment of T2DM-NAFLD. Twenty four main compounds were detected by UPLC-Q-TOF-MS, of which 13 showed favorable pharmacokinetic profiles. We demonstrated with target fishing and pathway analysis that CG has protective effects on T2DM-NAFLD, probably through the regulation of 88 targets and 86 pathways. Forty nine targets were related to T2DM, and 39 were related to NAFLD, while 27 targets, primarily involved in insulin resistance and inflammation were common to T2DM and NAFLD related pathways. A NF-κB signaling pathway was chosen to validate the impacts of CG on T2DM-NAFLD because CG can ameliorate T2DM-NAFLD by regulating the NF-κB signaling pathway according to animal experiments. These findings systematically interpreted the active compounds and mechanism of the efficiency of CG for treating T2DM-NAFLD. This study not only laid a basis for understanding the active compounds and action mechanism of CG, but also provides a reference for a study of the mechanism of a herbal medicine for the treatment of multiple diseases.


Assuntos
Asteraceae/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos de Ervas Chinesas/química , Feminino , Humanos , Insulina/metabolismo , Resistência à Insulina , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fitoterapia , Ratos , Ratos Sprague-Dawley
17.
Nat Commun ; 10(1): 1684, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975991

RESUMO

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/metabolismo , Animais , Biópsia , Conjuntos de Dados como Assunto , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Epigênese Genética , Fibrose , Células HEK293 , Hepatócitos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/genética
18.
Biomed Res Int ; 2019: 8690592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931332

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence globally, but little is known about its specific molecular mechanisms. During the past decade, noncoding RNAs (ncRNAs) have been linked to NAFLD initiation and progression. They are a class of RNAs that play an important role in regulating gene expression despite not encoding proteins. This review summarizes recent research on the relationship between ncRNAs and NAFLD. We discussed the potential applicability of ncRNAs as a biomarker for early NAFLD diagnosis and assessment of disease severity. With further study, ncRNAs should prove to be valuable new targets for NAFLD treatment and benefit the development of noninvasive diagnostic methods.


Assuntos
Biomarcadores , Hepatopatia Gordurosa não Alcoólica/diagnóstico , RNA não Traduzido/genética , Regulação da Expressão Gênica/genética , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia
19.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925684

RESUMO

Atherosclerosis and nonalcoholic fatty liver disease (NAFLD) are frequent causes of death in the Western countries. Recently, it has been shown that autophagy dysfunction plays an important role in the pathogenesis of both atherosclerosis and NAFLD; thus, activators of autophagy might be useful for novel therapeutic interventions. Trehalose-a naturally occuring disaccharide present in plants, bacteria, fungi, insects, and certain types of shrimps-is a known inducer of autophagy. However, according to the literature, its anti-atherosclerotic and anti-steatotic potential seem to depend on the experimental setting. The aim of our study was to comprehensively describe the influence of a prolonged treatment with orally administered trehalose on the development of atherosclerotic lesions and hepatic steatosis in apolipoprotein E knockout (apoE-/-) mice in an experimental set up reflecting both moderate and severe proatherogenic conditions: male apoE-/- mice on a chow diet (CD) and female apoE-/- mice fed with a high-fat diet (HFD). We found that exogenous trehalose inhibited atherosclerosis and attenuated hepatic steatosis in apoE-/- mice. Such effects of trehalose were not associated with changes of plasma cholesterol, low-density lipoproteins (LDL), or high-density lipoproteins (HDL). Moreover, the anti-steatotic action of trehalose in the liver was associated with the induction of autophagy. The exact molecular mechanisms of both the anti-atherosclerotic action of trehalose and its inhibitory effect on liver steatosis require further clarification.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Autofagia/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Trealose/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Trealose/administração & dosagem , Trealose/farmacologia
20.
Nat Commun ; 10(1): 947, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30814508

RESUMO

Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker.


Assuntos
Estresse do Retículo Endoplasmático , Fígado/metabolismo , Proteínas de Membrana/metabolismo , Animais , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Ingestão de Alimentos , Técnicas de Silenciamento de Genes , Intolerância à Glucose , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/genética , Obesidade/metabolismo
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