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1.
Medicine (Baltimore) ; 98(39): e17305, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574858

RESUMO

Until now, the recognition of sodium taurocholate cotransporting polypeptide (NTCP) deficiency has been mainly based on sporadic case reports. It was previously believed to be mildly symptomatic and resulting in mild liver dysfunction. However, to our knowledge, there have been no reports about the histopathologic and ultrastructural pathologic characteristics of the disease. The aim of the study was to analyze the clinical, histopathologic and ultrastructural pathologic characteristics of NTCP deficiency in 13 pediatric patients.From August 2012 to October 2018, this retrospective study conducted in the Department of Pediatrics of Tongji Hospital, China analyzed the data of 13 NTCP deficient patients with an SLC10A1 gene mutation. Except for NTCP deficiency, no other liver diseases were present in the patients, which was determined by both a genetic testing panel for jaundice and by reviewing medical records. The laboratory results, imaging, histopathologic, and ultrastructural pathologic information were recorded for analysis.The serum level of total bile acid was high in all 13 patients. All patients had adequate growth and development. Eight of the patients (8/13) presented with visible jaundice and 12 (12/13) were found to have hyperbilirubinemia. A needle liver biopsy was performed in 11 cases, which revealed slightly chronic inflammation in all 11 patients. One of the patients (1/13) was found to be suffering from gallstones.The data showed that although NTCP deficiency was often asymptomatic, some of the patients showed obvious clinical expressions, such as jaundice. Among the 13 pediatric patients with NTCP deficiency, both the biochemical and histopathologic features were similar to those of mild hepatocellular jaundice. In addition, it was determined that the clinical features in the patient with gallstones may have been caused by NTCP deficiency.


Assuntos
Ácidos e Sais Biliares/sangue , Icterícia , Hepatopatias , Fígado , Transportadores de Ânions Orgânicos Dependentes de Sódio , Simportadores , Desenvolvimento Infantil , Pré-Escolar , China/epidemiologia , Testes Genéticos/métodos , Humanos , Biópsia Guiada por Imagem/métodos , Lactente , Icterícia/diagnóstico , Icterícia/etiologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/diagnóstico , Hepatopatias/genética , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Testes de Função Hepática/métodos , Glicoproteínas de Membrana/metabolismo , Mutação , Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Pediatria/métodos , Estudos Retrospectivos , Simportadores/deficiência , Simportadores/genética
2.
Med Clin North Am ; 103(6): 991-1003, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582009

RESUMO

Genetic causes of liver disease lead to a wide range of presentations. This article describes hereditary hemochromatosis, Gilbert syndrome, alpha-1 antitrypsin deficiency, Wilson disease, PFIC, BRIC, and LAL-D. The most common cause of hereditary hemochromatosis is a C282Y mutation in the HFE gene. Gilbert syndrome is a benign cause of indirect hyperbilirubinemia. Alpha-1 antitrypsin deficiency causes both lung and liver disease. Wilson disease can cause neurologic disease and liver disease. Progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis are rare causes of cholestasis. LAL-D is a rare disease that can appear similar to NAFLD in adults.


Assuntos
Testes Genéticos , Hepatopatias , Administração dos Cuidados ao Paciente/métodos , Humanos , Hepatopatias/genética , Hepatopatias/terapia
3.
J Agric Food Chem ; 67(41): 11474-11480, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31537057

RESUMO

Patulin (PAT) is the most common food-borne mycotoxin found in fruits and fruit-derived products, while chlorpyrifos (CPF) is a widely used pesticide on fruit and other crops. On the basis of the residue data, certain types of fruits can be contaminated simultaneously by patulin and chlorpyrifos. However, there are no available data about the combined toxicity. Since liver is a possible toxic target of both patulin and chlorpyrifos, we tested whether the combination exposure can cause enhanced hepatotoxicity using both cell culture and animal models. Results showed that the combination resulted in synergistic cytotoxicity in vitro and significantly enhanced liver toxicity in vivo. Mechanistically, PAT inhibited catalase activity via PIG3 induction, while CPF decreased catalase expression. These two mechanisms were converged in response to the combination, leading to enhanced inactivating catalase and boosted reactive oxygen species generation. The finding implicated that it is necessary to consider the combined toxicity in safety assessment of these food-borne contaminants.


Assuntos
Inibidores de Caspase/toxicidade , Clorpirifos/toxicidade , Hepatopatias/etiologia , Patulina/toxicidade , Praguicidas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Caspases/metabolismo , Catalase/antagonistas & inibidores , Catalase/metabolismo , Sinergismo Farmacológico , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
5.
Nat Rev Gastroenterol Hepatol ; 16(8): 497-511, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31165788

RESUMO

Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases ß-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1ß and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.


Assuntos
Doenças dos Ductos Biliares/genética , Síndrome de Alagille/fisiopatologia , Doenças dos Ductos Biliares/tratamento farmacológico , Doenças dos Ductos Biliares/etiologia , Doenças dos Ductos Biliares/fisiopatologia , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Cistos/genética , Cistos/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Humanos , Hepatopatias/genética , Hepatopatias/fisiopatologia , Terapia de Alvo Molecular/métodos , Receptores Notch/fisiologia , Transdução de Sinais/fisiologia
7.
J Med Food ; 22(6): 602-613, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31045470

RESUMO

The fruits, leaves, and roots of Cudrania tricuspidata have been reported to contain large amounts of vitamin B, vitamin C, and flavonoids. They exhibit various physiological activities such as antitumor and anti-inflammatory effects. However, the hepatoprotective effects of C. tricuspidata extracts against oxidative stress-mediated liver injury have not yet been investigated. We thus examined whether C. tricuspidata leaf extracts (CTEs) protect against oxidative stress-mediated liver injury in vitro and in vivo and elucidated the underlying mechanism. The cytoprotective effects of CTE through the NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) activation were presented and measured by biochemical analysis in HepG2 cells. To assess the protective effects of CTE in vivo, mice were administered with CTE (250 and 500 mg/kg; 5 days; p.o.) before a single dose of acetaminophen (APAP) (300 mg/kg; 24 h; i.p.). CTE increased ARE luciferase activity when compared with extracts of other parts of C. tricuspidata. CTE upregulated nuclear translocation of Nrf2 and its target gene expression. In addition, CTE inhibited the generation of reactive oxygen species (ROS) and cell death induced by arachidonic acid (AA) and iron (Fe) treatment in primary hepatocytes or HepG2 cells. The cytoprotective effects of CTE against oxidative stress might be due to kaempferol, the major flavonoid present in CTE. Kaempferol pretreatment blocked AA+Fe-induced ROS production and reversed glutathione depletion, which in turn led to decreased cell death. Furthermore, the protective effects of CTE against liver injury induced by excess APAP in mice or primary hepatocytes were observed. CTE could be a promising therapeutic candidate against oxidative stress-induced liver injury.


Assuntos
Hepatopatias/tratamento farmacológico , Fígado/lesões , Moraceae/química , Extratos Vegetais/administração & dosagem , Animais , Glutationa/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Quempferóis/administração & dosagem , Quempferóis/análise , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo
8.
N Engl J Med ; 380(19): 1834-1842, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31067372

RESUMO

Mesenchymal hamartoma of the liver (MHL) is a benign tumor affecting children that is characterized by a primitive myxoid stroma with cystically dilated bile ducts. Alterations involving chromosome 19q13 are a recurrent underlying cause of MHL; these alterations activate the chromosome 19 microRNA cluster (C19MC). Other cases remain unexplained. We describe two children with MHLs that harbored germline DICER1 pathogenic variants. Analysis of tumor tissue from one of the children revealed two DICER1 "hits." Mutations in DICER1 dysregulate microRNAs, mimicking the effect of the activation of C19MC. Our data suggest that MHL is a new phenotype of DICER1 syndrome. (Funded by the Canadian Institutes of Health Research and others.).


Assuntos
Cromossomos Humanos Par 19 , RNA Helicases DEAD-box/genética , Mutação em Linhagem Germinativa , Hamartoma/genética , Hepatopatias/genética , MicroRNAs/metabolismo , Síndromes Neoplásicas Hereditárias/genética , Ribonuclease III/genética , Pré-Escolar , Feminino , Predisposição Genética para Doença , Hamartoma/diagnóstico por imagem , Hamartoma/patologia , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Hepatopatias/diagnóstico por imagem , Hepatopatias/patologia , Masculino , Mesoderma , Linhagem , Fenótipo
9.
Transplant Proc ; 51(3): 790-793, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979466

RESUMO

Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene, deranging the activity of chloride channels on the epithelial cell surface. Herein we describe end-stage liver disease in 3 infants with rare CFTR gene mutations; 2 of them were heterozygous. Case 1 was a premature male infant with negative CF screening at birth who developed a small bowel obstruction in the neonatal period requiring an ileostomy, with subsequent cholestatic liver disease and portal hypertension. In addition, he was noted to have frequent respiratory infections prompting a sweat test, which was positive. Genetic testing revealed that he was heterozygous for P.1177F. He then underwent a successful liver transplant. Case 2 was a female infant who developed progressive cholestasis with poor weight gain and was found to have neonatal hepatitis on liver biopsy. A sweat test was negative and genetic testing revealed she was heterozygous for CFTR and PEX26 gene mutations. She subsequently developed pneumatosis involving the cecum that was treated conservatively, followed by a successful liver transplant. Case 3 was a male infant who developed progressive liver disease, with liver biopsy showing neonatal hepatitis. He was extensively investigated but had a negative sweat test on repeated studies. Genetic testing revealed that the patient was heterozygous P.K186N-variant in the AKRID1 gene and homozygous P.R75Q-variant in the CFTR gene. Unfortunately, he succumbed to an acute upper gastrointestinal hemorrhage. Rare and unusual CFTR mutations, even in the heterozygous form, may be a feature in otherwise undiagnosed end-stage liver disease of infancy.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Fibrose Cística/patologia , Hepatopatias/genética , Hepatopatias/patologia , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Mutação
10.
Life Sci ; 223: 69-73, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30831126

RESUMO

Pyroptosis is a novel programmed cell death form which is distinct from other types of cell death. As an inherently inflammatory process, it plays a vital role in cellular lysis and release of pro-inflammatory cytokines when hosts defend against infections. Recent studies have reported that pyroptosis was involved in liver diseases and had important functions in the progress and development of liver diseases. Here, we addressed the potential role of pyroptosis in liver diseases on the basis of brief introduction of the morphological characteristics, molecular and pathophysiological mechanisms of pyroptosis.


Assuntos
Inflamassomos/metabolismo , Hepatopatias/etiologia , Piroptose/fisiologia , Animais , Dano ao DNA , Humanos , Inflamassomos/genética , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/patologia , Piroptose/genética
11.
Biol Pharm Bull ; 42(3): 312-318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828061

RESUMO

Orthotopic liver transplantation, rather than drug therapy, is the major curative approach for various inherited metabolic disorders of the liver. However, the scarcity of donated livers is a serious problem. To resolve this, there is an urgent need for novel drugs to treat inherited metabolic disorders of the liver. This requirement, in turn, necessitates the establishment of suitable disease models for many inherited metabolic disorders of the liver that currently lack such models for drug development. Recent studies have shown that human induced pluripotent stem (iPS) cells generated from patients with inherited metabolic disorders of the liver are an ideal cell source for models that faithfully recapitulate the pathophysiology of inherited metabolic disorders of the liver. By using patient iPS cell-derived hepatocyte-like cells, drug efficacy evaluation and drug screening can be performed. In addition, genome editing technology has enabled us to generate functionally recovered patient iPS cell-derived hepatocyte-like cells in vitro. It is also possible to identify the genetic mutations responsible for undiagnosed liver diseases using iPS cell and genome editing technologies. Finally, a combination of exhaustive analysis, iPS cells, and genome editing technologies would be a powerful approach to accelerate the identification of novel genetic mutations responsible for undiagnosed liver diseases. In this review, we will discuss the usefulness of iPS cell and genome editing technologies in the field of inherited metabolic disorders of the liver, such as alpha-1 antitrypsin deficiency and familial hypercholesterolemia.


Assuntos
Descoberta de Drogas/métodos , Edição de Genes , Predisposição Genética para Doença , Células-Tronco Pluripotentes Induzidas/fisiologia , Hepatopatias/genética , Pesquisa Farmacêutica/métodos , Humanos , Hepatopatias/metabolismo
12.
Eur J Paediatr Neurol ; 23(3): 537-540, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30799093

RESUMO

Mitochondrial DNA depletion syndromes (MDS) are a group of clinically and genetically heterogeneous autosomal recessive disorders characterized by a reduction of mtDNA. We report two siblings of Armenian origin with early onset neurodegenerative disease characterized by encephalopathy, severe hypotonia, facial dyskinetic movements, abnormal eye movements, severe failure to thrive, and abnormal renal and hepatic function. Sanger sequencing confirmed two variants in the C10orf2 gene (TWNK) and indicated a diagnosis of MDS. Our recent observation confirms that nephrocalcinosis and proximal tubulopathy can be a part of a clinical picture of MDS associated with TWNK mutations and document peculiar ocular and orobuccolingual dyskinesias. Wrist myoclonia and tongue tremor were new clinical features in our patients. We suggest that the above-mentioned clinical constellation could potentially provide the basis for the diagnosis of MDS.


Assuntos
DNA Helicases/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Proteínas Mitocondriais/genética , Doenças Musculares/genética , Doenças Musculares/patologia , Humanos , Nefropatias/genética , Hepatopatias/genética , Masculino , Mutação , Doenças Neurodegenerativas/genética , Fenótipo , Irmãos , Síndrome
13.
Cell Mol Neurobiol ; 39(2): 169-180, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30656469

RESUMO

A multistep signaling cascade originates in brain centers that regulate hypothalamic growth hormone-releasing hormone (Ghrh) and somatostatin expression levels and release to control the pattern of GH secretion. This process is sexually fine-tuned, and relays important information to the liver where GH receptors can be found. The temporal pattern of pituitary GH secretion, which is sex-specific in many species (episodic in males and more stable in females), represents a major component in establishing and maintaining the sexual dimorphism of hepatic gene transcription. The liver is sexually dimorphic exhibiting major differences in the profile of more than 1000 liver genes related to steroid, lipid, and foreign compound metabolism. Approximately, 90% of these sex-specific liver genes were shown to be primarily dependent on sexually dimorphic GH secretory patterns. This proposes an interesting scenario in which the central nervous system, indirectly setting GH profiles through GHRH and somatostatin control, regulates sexual dimorphism of liver activity in accordance with the need for sex-specific steroid metabolism and performance. We describe the influence of the loss of sexual dimorphism in liver gene expression due to altered brain function. Among other many factors, abnormal brain sexual differentiation, xenoestrogen exposure and D2R ablation from neurons dysregulate the GHRH-GH axis, and ultimately modify the liver capacity for adaptive mechanisms. We, therefore, propose that an inefficient brain control of the endocrine growth axis may underlie alterations in several metabolic processes through an indirect influence of sexual dimorphism of liver genes.


Assuntos
Encéfalo/fisiopatologia , Sistema Endócrino/fisiopatologia , Hepatopatias/fisiopatologia , Fígado/fisiopatologia , Caracteres Sexuais , Animais , Epigênese Genética , Feminino , Humanos , Hepatopatias/genética , Masculino
14.
Hepatol Int ; 13(2): 138-147, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30600479

RESUMO

Routine transcriptomic and proteomic analysis are usually performed at a whole organ or tissue level. These approaches provide an average readout of all cell types present within the tissue but do not allow differentiating the profile of specific cell populations. Laser capture microdissection (LCM) constitutes an excellent tool to isolate cell populations or areas of interest within a tissue. By direct visualization, the selected area is excised by a laser and can be further processed for a variety of downstream analyses. This technology has been widely used in the study of liver diseases, from DNA and RNA sequencing to mass spectrometry. However, LCM also has important limitations. To ensure the best integrity of the molecule of interest, optimal tissue preservation, careful tissue sectioning, and optimization of the staining procedure are required. The present review provides a description of the LCM technology, including tips and technical recommendations to perform the procedure, as well as an overview of studies using LCM technology in the field of liver disease.


Assuntos
Microdissecção e Captura a Laser , Hepatopatias/genética , Hepatopatias/patologia , Humanos , Análise de Sequência de DNA , Análise de Sequência de RNA , Coloração e Rotulagem , Preservação de Tecido
15.
Int J Infect Dis ; 80: 147-152, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30685591

RESUMO

OBJECTIVES: To determine potential associations of the rs2296651 variant (c.800C>T, S267F) of NTCP with HBV and HBV plus concomitant HDV infection as well as with the progression of related liver diseases. METHODS: The S267F variant was genotyped by DNA sequencing in 620 HBV-infected patients and 214 healthy controls (HCs). Among the patients, 450 individuals were tested for HDV by a nested PCR assay. Logistic regression was applied to examine the association. RESULTS: The S267F variant was found more frequently among HCs (16%) compared to HBV-infected (6%) and HBV-HDV co-infected patients (3%) (HBV patients vs HC: OR=0.32, P=0.00002 and HDV patients vs. HC: OR=0.17, P=0.018). The frequency of S267F variant was inversely correlated with CHB, LC or HCC patients compared with HCs (OR=0.31, P=0.001; OR=0.32, P=0.013; OR=0.34, P=0.002, respectively). S267F variant was also associated with decreased risk of the development of advanced liver cirrhosis (LC) and hepatocellular carcinoma (HCC) (Child B and C vs. Child A, OR=0.26, adjusted P=0.016; BCLC B,C,D vs. BCLC A, OR=0.038, P=0.045, respectively). In addition, patients with the genotype CT had lower levels of AST, ALT, total and direct bilirubin as well as higher platelet counts, indicating an association with a more favorable clinical outcome. CONCLUSION: The NTCP S267F variant of the SLC10A1 gene exhibits protective effects against HBV and HDV infection and is associated with a reduced risk of developing to advanced stages of LC and HCC.


Assuntos
Variação Genética , Hepatite B/epidemiologia , Hepatite D/epidemiologia , Hepatopatias/diagnóstico , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/metabolismo , Alelos , Aspartato Aminotransferases/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Estudos de Casos e Controles , Coinfecção , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Hepatite B/genética , Hepatite D/genética , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Hepatopatias/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , RNA Viral/isolamento & purificação , Fatores de Risco , Análise de Sequência de DNA , Vietnã/epidemiologia , Adulto Jovem
16.
Int J Immunogenet ; 46(2): 49-58, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659741

RESUMO

Allele-specific analyses to understand frequency differences across populations, particularly populations not well studied, are important to help identify variants that may have a functional effect on disease mechanisms and phenotypic predisposition, facilitating new Genome-Wide Association Studies (GWAS). We aimed to compare the allele frequency of 11 asthma-associated and 16 liver disease-associated single nucleotide polymorphisms (SNPs) between the Estonian, HapMap and 1000 genome project populations. When comparing EGCUT with HapMap populations, the largest difference in allele frequencies was observed with the Maasai population in Kinyawa, Kenya, with 12 SNP variants reporting statistical significance. Similarly, when comparing EGCUT with 1000 genomes project populations, the largest difference in allele frequencies was observed with pooled African populations with 22 SNP variants reporting statistical significance. For 11 asthma-associated and 16 liver disease-associated SNPs, Estonians are genetically similar to other European populations but significantly different from African populations. Understanding differences in genetic architecture between ethnic populations is important to facilitate new GWAS targeted at underserved ethnic groups to enable novel genetic findings to aid the development of new therapies to reduce morbidity and mortality.


Assuntos
Asma/genética , Frequência do Gene/genética , Genética Populacional , Genoma Humano , Projeto HapMap , Hepatopatias/genética , Polimorfismo de Nucleotídeo Único/genética , Estônia , Humanos
17.
EBioMedicine ; 40: 488-503, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30638865

RESUMO

BACKGROUND: The injured liver loses normal function, with concomitant decrease of key identity genes. Super-enhancers contribute to mammalian cell identity. Here, we identified core transcription factors (TFs) that are active in hepatocytes, using genome-wide analysis and hierarchical ordering of super-enhancer distribution. METHODS: Expression of core TFs was assessed in a cohort of patients with hepatitis or cirrhosis and animal models. Quantitative PCR, chromatin immunoprecipitation assays, and hydrodynamic gene delivery methods were used to assess gene regulation and hepatocyte viability. RNA-sequencing data were generated to investigate the role of LRH1 in hepatocyte protection from injury. RESULTS: Network analysis of super-enhancer-associated gene interactions and expression arrays for cohorts of patients with hepatitis and cirrhosis enabled us to identify a super-enhancer-associated network, and LRH1, HNF4α, PPARα, and RXRα as core TFs. In mouse models, expression of core TFs was robustly inhibited by single and multiple challenge(s) with liver toxicant. RNA-seq analysis revealed changes in expression in the super-enhancer-associated genes sensitively biased toward repression by intoxication. LRH1 gene delivery prevented the loss of hepatic super-enhancer-associated signaling circuitry in toxicant-challenged mice, and protected the liver from injury, indicating the role of LRH1 in hepatocyte identity and viability. In hepatocytes, overexpression of each core TF promoted induction of other TFs. CONCLUSION: Overall, this study identified LRH1-driven pathway as a circuitry responsible for hepatocyte identity by using cistromic analysis, improving our understanding of liver pathophysiology and identifying novel therapeutic targets.


Assuntos
Hepatócitos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/genética , Sobrevivência Celular/genética , Biologia Computacional/métodos , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Ontologia Genética , Histonas/metabolismo , Humanos , Fígado/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos , Ligação Proteica , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Receptores Citoplasmáticos e Nucleares/química
18.
Gene ; 688: 107-118, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30529247

RESUMO

BACKGROUND: Several investigators have reported that complement receptor 1 (CR1) likely play a role in the pathogenesis of tumors, autoimmune and inflammatory diseases. However, the association of genetic polymorphisms of CR1 with risk of hepatitis B virus (HBV)-related liver disease remains unexplored. METHODS: In a case-control study of 399 HBV-related liver disease patients and 227 healthy controls, we genotyped two SNPs in CR1 (rs3811381 and rs2274567) and assessed their associations with risk of HBV-related liver disease. RESULTS: No significant differences were observed in the frequency distribution of genotypes or alleles between CR1 rs3811381 and rs2274567 polymorphisms in patients and controls. However, stratification analysis indicated that these two CR1 polymorphisms may contribute to the risk of HBV- hepatocellular carcinoma (HCC) and chronic hepatitis B (CHB) in subgroups of males, alcohol drinkers and nonsmokers. Further, our results showed that the rs3811381 polymorphism may contribute to HBV-HCC risk in subgroups of older and younger subjects, while the G allele, AG and the combined AG + GG genotypes of rs2274567 may be risk factors for HBV-HCC in younger subjects. In addition, our results indicated that subjects who carried the rs3811381 G allele and the rs2274567 AG genotype were at decreased risk of HBV- liver cirrhosis (LC) in subgroups of females. CONCLUSIONS: Our results support the hypothesis that the CR1 gene rs3811381 and rs2274567 polymorphisms may contribute to HBV-HCC and HBV-CHB risk, particularly in subgroups of males, alcohol drinkers, nonsmokers, while these two CR1 polymorphisms were found to associate with decreased risk of HBV-LC, particularly in females. Further validation of these results is warranted.


Assuntos
Predisposição Genética para Doença/genética , Hepatite B Crônica/genética , Hepatopatias/genética , Hepatopatias/virologia , Fígado/virologia , Polimorfismo de Nucleotídeo Único/genética , Receptores de Complemento 3b/genética , Adulto , Alelos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genótipo , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade
19.
Biochim Biophys Acta Mol Basis Dis ; 1865(3): 577-586, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30582966

RESUMO

Pediatric liver disease (PLD) is a major cause of severe morbidity and prolonged hospitalizations in children. Stratifying patients in terms of prognosis remains challenging. The limited knowledge about molecular mechanisms causing and accompanying PLD remains the main obstacle in a search for reliable prognostic biomarkers. A systematic search of MEDLINE via PubMed and Embase via OVID was conducted on studies published between August 2007 and August 2017. Molecular markers with a prognostic potential in terms of survival, need for liver transplantation or disease progression/regression were selected. In general, identified studies were single center smaller case-control studies or case series with a low level of evidence and a high risk of bias. Only 23 studies comprising 898 patients could be included, mostly focusing on biliary atresia, non-alcoholic fatty liver disease, viral hepatitis, and LT; and markers related to morphogenesis and fibrosis. Furthermore, molecular markers in metabolic pathways and inflammation shown to be relevant, however requiring further validation. Hence, further biological and clinical studies are needed to gain greater molecular insight into PLD.


Assuntos
Biomarcadores/análise , Hepatopatias/diagnóstico , Idade de Início , Estudos de Casos e Controles , Criança , Progressão da Doença , Humanos , Hepatopatias/epidemiologia , Hepatopatias/genética , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , Prognóstico
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