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1.
Signal Transduct Target Ther ; 5(1): 256, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139693

RESUMO

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal-oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia-ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Infecções por Coronavirus/epidemiologia , Gastroenteropatias/epidemiologia , Hepatopatias/epidemiologia , Pneumonia Viral/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Fezes/virologia , Gastroenteropatias/complicações , Gastroenteropatias/genética , Gastroenteropatias/virologia , Trato Gastrointestinal/lesões , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Humanos , Fígado/fisiopatologia , Fígado/virologia , Hepatopatias/genética , Hepatopatias/patologia , Hepatopatias/virologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia
3.
Nat Rev Gastroenterol Hepatol ; 17(8): 457-472, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32483353

RESUMO

Liver disease is a major global health-care problem, affecting an estimated 844 million people worldwide. Despite this substantial burden, therapeutic options for liver disease remain limited, in part owing to a paucity of detailed analyses defining the cellular and molecular mechanisms that drive these conditions in humans. Single-cell transcriptomic technologies are transforming our understanding of cellular diversity and function in health and disease. In this Review, we discuss how these technologies have been applied in hepatology, advancing our understanding of cellular heterogeneity and providing novel insights into fundamental liver biology such as the metabolic zonation of hepatocytes, endothelial cells and hepatic stellate cells, and the cellular mechanisms underpinning liver regeneration. Application of these methodologies is also uncovering critical pathophysiological changes driving disease states such as hepatic fibrosis, where distinct populations of macrophages, endothelial cells and mesenchymal cells reside within a spatially distinct fibrotic niche and interact to promote scar formation. In addition, single-cell approaches are starting to dissect key cellular and molecular functions in liver cancer. In the near future, new techniques such as spatial transcriptomics and multiomic approaches will further deepen our understanding of disease pathogenesis, enabling the identification of novel therapeutic targets for patients across the spectrum of liver diseases.


Assuntos
Perfilação da Expressão Gênica , Hepatopatias/genética , Fígado/metabolismo , Análise de Célula Única , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Gastroenterologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/fisiologia , Hepatócitos/metabolismo , Hepatócitos/fisiologia , Humanos , Inflamação/imunologia , Macrófagos do Fígado/imunologia , Fígado/citologia , Fígado/imunologia , Fígado/fisiologia , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Hepatopatias/imunologia , Hepatopatias/metabolismo , Macrófagos/imunologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Regeneração , Análise de Sequência de RNA
4.
Ann Hematol ; 99(9): 2065-2072, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32572524

RESUMO

Sickle hepatopathy is a severe and not rare complication of sickle cell disease (SCD), showing mainly a cholestatic pattern. So far, no effective approaches to prevent or treat this condition have been recognized. We conducted a single-center observational study in 68 adult sickle cell patients, encompassing 17 with sickle cell anemia (SCA), 38 with sickle cell thalassemia (HbS/ß-Thal), and 13 with HbSC disease. The aim of our study was to assess liver damage in the three main forms of SCD, through the evaluation of clinical, laboratory, and imaging findings. In our population, the role of hepatotropic viruses, high BMI, and alcohol consumption in liver damage was ruled out. SCA and HbS/ß-Thal patients with lower Hb (p < 0.001), higher HbS (p < 0.001), and frequent vaso-occlusive crises showed functional (GGT values: SCA and HbS/ß-Thal vs HbSC p = 0.047 and p = 0.009, respectively) and structural liver abnormalities, defined by abdominal ultrasound and vibration-controlled transient elastography (liver stiffness values: SCA and HbS/ß-Thal vs HbSC p 0.022 and p 0.19, respectively), more severe than HbSC patients. Through univariate and multivariate analyses, male sex, SCA genotype, lower HbF, frequent transfusions, increased GGT values, and abnormal liver ultrasound and stiffness were identified as potentially early markers of sickle hepatopathy.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico por imagem , Genótipo , Hepatopatias/sangue , Hepatopatias/diagnóstico por imagem , Adulto , Anemia Falciforme/genética , Feminino , Humanos , Hepatopatias/genética , Masculino , Pessoa de Meia-Idade , Fatores de Risco
6.
Exp Mol Pathol ; 115: 104472, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32454104

RESUMO

BACKGROUND AND AIMS: Liver diseases and related complications represent an increasing source of morbidity and mortality and have become a significant economic burden worldwide. Dysregulated energy metabolism, alteration of redox homeostasis, immune responses, inflammation, fibrosis, and malfunctioning of the gut-liver axis are key driving forces of liver diseases. Emerging evidence suggested that long coding RNAs (lncRNAs) played crucial roles in the pathogenesis and development of various diseases. Among them, lncRNA H19 is a maternally expressed lncRNA and has attracted great attention in the research of liver diseases due to its extensive involvement in the epigenetic regulation, inflammation, tissue regeneration, and cancer initiation and development. RESULTS: In the current review, we will first introduce the definition of lncRNA H19, the regulation of lncRNA H19 expression and molecular targets of lncRNA H19. We then summarize the recent advances of studies focusing on the role of H19 in the pathogenesis of liver diseases, including fatty liver diseases, cholestasis, fibrosis and cancer, and in the modulation of gut-liver axis. CONCLUSION: Based on the complex roles of lncRNA H19 played in liver injury and gastrointestinal disorders, targeting H19 has great potency to become a new strategy to diagnose and treat gut- and liver-related disorders.


Assuntos
Biomarcadores/metabolismo , Trato Gastrointestinal/metabolismo , Hepatopatias/diagnóstico , Hepatopatias/genética , Fígado/metabolismo , Terapia de Alvo Molecular , RNA Longo não Codificante/metabolismo , Humanos , Hepatopatias/terapia , RNA Longo não Codificante/genética
7.
Hum Pathol ; 100: 1-9, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32330484

RESUMO

Three types of intracytoplasmic inclusions immunoreactive to fibrinogen are collectively diagnosed as hepatic fibrinogen storage disease. This study aimed to better characterize ground glass (type II) and globular (type III) fibrinogen inclusions by the pathological examination of 3 cases and a literature review. Three adults (age: 32-64 years; male/female = 2:1) were unexpectedly found to have fibrinogen-positive ground glass changes (type II inclusions) by liver needle biopsy, against a background of acute hepatitis E, resolving acute cholangitis, or severe lobular hepatitis of unknown etiology. One patient also had fibrinogen-positive intracytoplasmic globules (type III inclusions) in the first biopsy, but they were not present in a second biopsy. None had coagulation abnormalities or hypofibrinogenemia. On immunostaining, both inclusions were strongly positive for not only fibrinogen but also C-reactive protein and C4d. Ultrastructurally, ground glass changes corresponded to membrane-bound cytoplasmic inclusions containing amorphous, granular material. The pathological features of type II fibrinogen inclusions were identical to those of pale bodies in hepatocellular carcinoma. The literature review suggested that type I fibrinogen inclusions characterized by a polygonal appearance are strongly associated with mutations in fibrinogen genes, coagulopathy, and family history, whereas type II/III inclusions are immunoreactive to multiple proteins and typically develop in cases of other unrelated liver diseases. In conclusion, type II and III fibrinogen inclusions do not represent a true hereditary storage disease but instead the collective retention of multiple proteins. Given the lack of clinical significance, a less specific name (e.g., pale body) may be more appropriate for those inclusions.


Assuntos
Fibrinogênio/análise , Corpos de Inclusão/química , Hepatopatias/metabolismo , Fígado/química , Erros Inatos do Metabolismo/metabolismo , Adulto , Biomarcadores/análise , Biópsia , Proteína C-Reativa/análise , Complemento C4b/análise , Feminino , Fibrinogênio/genética , Humanos , Imuno-Histoquímica , Corpos de Inclusão/genética , Corpos de Inclusão/ultraestrutura , Fígado/ultraestrutura , Hepatopatias/classificação , Hepatopatias/genética , Hepatopatias/patologia , Masculino , Erros Inatos do Metabolismo/classificação , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/patologia , Pessoa de Meia-Idade , Fragmentos de Peptídeos/análise , Terminologia como Assunto
8.
Biochim Biophys Acta Gene Regul Mech ; 1863(7): 194545, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32194213

RESUMO

Histone lysine methyltransferase 2 (KMT2) proteins form multimeric enzymatic complexes that methylate lysine 4 on histone H3 (H3K4) at transcription regulatory elements in the genome. A strong association of H3K4 methylation with active transcription has led to intense efforts to reveal the functional involvement of KMT2 complexes in transcriptional regulation. A number of biochemical and cellular studies have shown that KMT2 complexes regulate transcription of target genes via H3K4 methylation. However, in many cases, loss of KMT2 complex enzymatic activity fails to fully account for observed transcriptional defects. Accumulating evidence indicates that, in certain contexts, KMT2 complex-mediated transcriptional regulation can occur in an H3K4 methylation-independent manner. Here, we comprehensively review functions of KMT2 complexes in gene expression, focusing on what we currently know about the molecular mechanisms by which the KMT2 complexes regulate transcription. We also discuss how aberrant transcriptional regulation by KMT2 complexes contributes to different human diseases, such as cancer.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Ativação Transcricional , Animais , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Humanos , Hepatopatias/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética
9.
J Ethnopharmacol ; 252: 112602, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32004632

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperthyroidism is closely associated with liver injury. The preliminary clinical observation suggests that Yinning Tablet, a hospitalized preparation of traditional Chinese formula for hyperthyroidism, improves not only hyperthyroidism, but also hyperthyroidism-associated liver injury. AIM: To evaluate the effect and underlying mechanisms of Yinning Tablet on thyroid hormone-induced liver injury. MATERIALS AND METHODS: Female rats were orally administered L-thyroxine (1 mg/kg) once daily for 60 days, and co-treated with the carefully identified Yinning Tablet extract (0.6-2.4 g/kg) during the last 30 days. Blood and liver variables were determined enzymatically, histologically, by ELISA, radioimmunoassay, Real-Time PCR or Western blot, respectively. RESULTS: Co-treatment with the extract attenuated L-thyroxine-induced increases in serum alanine transaminase and aspartate transaminase activities, the ratio of liver weight to body weight, cytoplasmic vacuolization in hepatocytes, infiltrated inflammatory cells and confused structures in liver tissue, accompanied by attenuation of increased serum triiodo-l-thyronine concentration and hepatic deiodinase type I overexpression in rats. Importantly, Yinning Tablet suppressed L-thyroxine-triggered hepatic Bax, cleaved caspases-3, -8 and -9 protein overexpression, and Bcl-2 protein downregulation. Furthermore, the increases in cytochrome c protein expression, Ca2+-ATPase activity and malondialdehyde content, and decreases in activities of Na+/K+-ATPase, catalase, superoxide dismutase and glutathione peroxidase, and total antioxidant capacity in liver tissue were attenuated. CONCLUSION: The present results suggest that Yinning Tablet ameliorates thyroid hormone-induced liver injury in rats by regulating mitochondria-mediated apoptotic signals. Our findings go insight into the pharmacological basis of the hospitalized preparation for treatment of hyperthyroidism-associated liver injury.


Assuntos
Hipertireoidismo/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Tiroxina , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Medicamentos de Ervas Chinesas , Feminino , Formulários de Hospitais como Assunto , Hipertireoidismo/complicações , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/patologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Tiroxina/sangue , Transcriptoma/efeitos dos fármacos , Tri-Iodotironina/sangue
11.
Int J Mol Sci ; 21(4)2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32102330

RESUMO

Hepatic disorders have been increasing in recent years because of high carbohydrate diets. Hepatocytes depend mainly on the basal autophagy to maintain hepatic glucose/lipid homeostasis in mammals. However, the regulatory mechanisms of autophagy in hepatic energy metabolism are still unknown in fish species. Accordingly, mutant zebrafish lines of autophagy-related genes beclin1 and atg7 were generated by CRISPR/Cas9 gene-editing technology. Interestingly, unlike atg7+/-, male beclin1+/- zebrafish displayed liver defects in the morphology and histology, including abnormal hepatocyte proliferation, hemorrhagic and inflammatory phenotypes. A significant decrease in hepatocyte glycogen and an increase in hepatocyte lipids were detected in the histological assay that coincidence with the hepatic gene expression. Meanwhile, loss of heterozygosity for beclin1 creates a suitable microenvironment for hepatic tumorigenesis via phosphorylation of Akt kinase, which in turn affects liver autophagy. The reduction in autophagy activity in male beclin1+/- liver leads to a disturbance in the glucose/lipid metabolism and negatively regulates apoptosis accompanied by the induction of cellular proliferation and acute inflammatory response. Our findings highlight an important role of beclin1 in zebrafish liver development and energy metabolism, suggesting the crucial role of autophagy in maintaining homeostasis of the nutrient metabolism in fish species.


Assuntos
Proteína Beclina-1/metabolismo , Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Hepatopatias/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Apoptose/genética , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/genética , Metabolismo dos Carboidratos , Proliferação de Células/genética , Heterozigoto , Hepatopatias/genética , Masculino , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
12.
Exp Eye Res ; 193: 107940, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32032630

RESUMO

Optic fissure closure defects result in uveal coloboma, a potentially blinding condition affecting between 0.5 and 2.6 per 10,000 births that may cause up to 10% of childhood blindness. Uveal coloboma is on a phenotypic continuum with microphthalmia (small eye) and anophthalmia (primordial/no ocular tissue), the so-called MAC spectrum. This review gives a brief overview of the developmental biology behind coloboma and its clinical presentation/spectrum. Special attention will be given to two prominent, syndromic forms of coloboma, namely, CHARGE (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies/deafness) and COACH (Cerebellar vermis hypoplasia, Oligophrenia, Ataxia, Coloboma, and Hepatic fibrosis) syndromes. Approaches employed to identify genes involved in optic fissure closure in animal models and recent advances in live imaging of zebrafish eye development are also discussed.


Assuntos
Anormalidades Múltiplas/genética , Ataxia/genética , Encéfalo/anormalidades , Colestase/genética , Coloboma/genética , Predisposição Genética para Doença , Hepatopatias/genética , Úvea/anormalidades , Animais , Humanos
13.
PLoS One ; 15(2): e0229374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084209

RESUMO

BACKGROUND: Although genetic features vary across ethnicities, few genome-wide association studies (GWAS) have reported the genetic determinants of liver enzyme expression. This study was aimed to evaluate the associations of genome-wide single nuclear polymorphisms (SNPs) with the liver enzymes in a Korean population. METHODS: We performed a GWAS to identify genetic loci influencing liver function, as measured by concentrations of alkaline phosphatase (ALP), alanine transaminase (ALT), gamma-glutamyl transferase (GGT) and total bilirubin (BIL) in in Korean study participants. RESULTS: A total of 6,488 subjects (4,457 in the discovery and 2,031 in the validation set) were included. The mean subject age was 50.0±10.6 years (male, 53.7%). Among a total of 546,738 SNPs tested, rs651007 and rs579459 located in the ABO gene showed strong associations with ALP (P = 1.63×10-8 and 5.61×10-8, respectively [discovery set]; P = 4.08×10-15 and 9.92×10-16, respectively [validation set]). Additionally, rs5751901 and rs2006092, which are located in the GGT1 gene, showed strong associations with GGT (P = 6.44×10-15 and 1.26×10-15, respectively [discovery set]; P = 4.13×10-10 and 5.15×10-11, respectively [validation set]). Among the 13 SNPs that showed genome-wide significance with total bilirubin levels, rs10929302 and rs6742078 showed the most significant association (P = 3.08×10-64 and 2.05×10-62, respectively [discovery set]; P = 1.33×10-116 and 2.24×10-118, respectively [validation set]). No genome-wide significant associations was found for ALT. CONCLUSIONS: We demonstrated that ABO, GGT1 and UGT1A family were associated with ALP, GGT and BIL, respectively in Korean population. These findings differ from reported results in GWAS in European populations in terms of associated genes and locations, suggesting different genetic mechanisms of liver enzyme regulation according to ethnicity.


Assuntos
Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Biomarcadores/análise , Hepatopatias/epidemiologia , Fígado/enzimologia , Polimorfismo de Nucleotídeo Único , gama-Glutamiltransferase/sangue , Bilirrubina/sangue , Grupos Étnicos/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Hepatopatias/enzimologia , Hepatopatias/genética , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia
16.
J Immunol ; 204(5): 1322-1333, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31996460

RESUMO

With the development of liver surgery, ischemia-reperfusion (IR) injury has received increasing attention. Roquin-1 has been shown to play an important role in innate immune and immune balance. We demonstrate that Roquin-1 expression increased at 1 h after IR and then decreased in C57B/L mice. The immunofluorescence double-label showed that Roquin-1 was mainly expressed in macrophages (mø). Furthermore, we used clodronate liposomes to remove mø, and injected the bone marrow-derived mø (BMDM) through the tail vein in 1 h before IR. We found that liver IR injury was aggravated by Roquin-1 interference. The results of PCR and ELISA suggested that after interference with Roquin-1, mø increased toward M1 and decreased toward M2. Then, interference with Roquin-1 promoted the polarization of mø to M1 and inhibited the polarization of M2. By Western blot technology and AMPKα and mTOR inhibitors, we found that Roquin-1 promotes the phosphorylation of mTOR and STAT3 by inhibiting the phosphorylation of AMPKα. We used AICAR to activate AMPKα in mø and found that the level of ubiquitination of AMPKα was decreased after activation of AMPKα. Furthermore, by bioinformatics methods, we identified potential ubiquitination sites on AMPKα. By the point mutation experiments in vitro, we confirmed that the ubiquitination of these sites is regulated by Roquin-1. Meanwhile, Roquin-1 interference inhibited the activation and function of AMPKα. This topic describes the protection of liver IR injury by Roquin-1 and discusses its main mechanism for regulating AMPKα activity through ubiquitination and affecting the polarization of mø.


Assuntos
Hepatopatias/imunologia , Fígado/imunologia , Macrófagos/imunologia , Traumatismo por Reperfusão/imunologia , Ubiquitina-Proteína Ligases/imunologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/imunologia , Animais , Ativação Enzimática/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Fígado/patologia , Hepatopatias/genética , Hepatopatias/patologia , Macrófagos/patologia , Masculino , Camundongos , Mutação Puntual , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética , Ubiquitinação/imunologia
17.
J Agric Food Chem ; 68(8): 2393-2405, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31995979

RESUMO

Hyperglycemia-induced oxidative stress can cause liver damage in diabetes, and protein hydrolysates with antidiabetic and antioxidant properties are emerging as a potential therapy. In this study, protective effects of casein hydrolysates against live oxidative damage in streptozotocin/high-fat-induced diabetic rats were studied and potentially bioactive peptides were explored by an integrated approach of differential peptide and in silico analysis. Results showed that different casein hydrolysates significantly alleviated liver oxidative damage (p < 0.05) via different mechanisms. Particularly, casein hydrolyzed by a papain-flavourzyme combination (P-FCH) treatment significantly improved liver antioxidant enzyme activities by enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) transcription (p < 0.05). Furthermore, 18 peptides were screened as potential bioactive peptides by analyzing differential peptides among different hydrolysates combined with in silico prediction. Among them, the dipeptide WM might directly inhibit the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 interaction as potential Nrf2 activators. These results suggested that P-FCH might be an alternative way to treat liver damage in diabetes.


Assuntos
Caseínas/química , Diabetes Mellitus Experimental/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Peptídeos/administração & dosagem , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Peptídeos/química , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
18.
Proc Natl Acad Sci U S A ; 117(3): 1678-1688, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31915293

RESUMO

Primary human hepatocytes (PHHs) are an essential tool for modeling drug metabolism and liver disease. However, variable plating efficiencies, short lifespan in culture, and resistance to genetic manipulation have limited their use. Here, we show that the pyrrolizidine alkaloid retrorsine improves PHH repopulation of chimeric mice on average 10-fold and rescues the ability of even poorly plateable donor hepatocytes to provide cells for subsequent ex vivo cultures. These mouse-passaged (mp) PHH cultures overcome the marked donor-to-donor variability of cryopreserved PHH and remain functional for months as demonstrated by metabolic assays and infection with hepatitis B virus and Plasmodium falciparum mpPHH can be efficiently genetically modified in culture, mobilized, and then recultured as spheroids or retransplanted to create highly humanized mice that carry a genetically altered hepatocyte graft. Together, these advances provide flexible tools for the study of human liver disease and evaluation of hepatocyte-targeted gene therapy approaches.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatopatias/genética , Alcaloides de Pirrolizidina/farmacologia , Animais , Transplante de Células , Quimera , Modelos Animais de Doenças , Feminino , Terapia Genética , Hepatite B , Vírus da Hepatite B , Hepatócitos/transplante , Proteínas de Homeodomínio/genética , Humanos , Hidrolases/genética , Subunidade gama Comum de Receptores de Interleucina/genética , Fígado/patologia , Hepatopatias/patologia , Malária , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Plasmodium falciparum
19.
Nat Commun ; 11(1): 45, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896749

RESUMO

Unlike protein-coding genes, the majority of human long non-coding RNAs (lncRNAs) are considered non-conserved. Although lncRNAs have been shown to function in diverse pathophysiological processes in mice, it remains largely unknown whether human lncRNAs have such in vivo functions. Here, we describe an integrated pipeline to define the in vivo function of non-conserved human lncRNAs. We first identify lncRNAs with high function potential using multiple indicators derived from human genetic data related to cardiometabolic traits, then define lncRNA's function and specific target genes by integrating its correlated biological pathways in humans and co-regulated genes in a humanized mouse model. Finally, we demonstrate that the in vivo function of human-specific lncRNAs can be successfully examined in the humanized mouse model, and experimentally validate the predicted function of an obesity-associated lncRNA, LINC01018, in regulating the expression of genes in fatty acid oxidation in humanized livers through its interaction with RNA-binding protein HuR.


Assuntos
Fígado/fisiologia , RNA Longo não Codificante/fisiologia , Animais , Sequência de Bases , Sequência Conservada , Proteína Semelhante a ELAV 1/genética , Proteína Semelhante a ELAV 1/metabolismo , Epigênese Genética , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Estudo de Associação Genômica Ampla , Hepatócitos/fisiologia , Humanos , Fígado/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Metiltransferases/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Locos de Características Quantitativas
20.
Annu Rev Pathol ; 15: 1-22, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31299162

RESUMO

The involvement of the biliary tract in the pathophysiology of liver diseases and the increased attention paid to bile ducts in the bioconstruction of liver tissue for regenerative therapy have fueled intense research into the fundamental mechanisms of biliary development. Here, I review the molecular, cellular and tissular mechanisms driving differentiation and morphogenesis of the intrahepatic and extrahepatic bile ducts. This review focuses on the dynamics of the transcriptional and signaling modules that promote biliary development in human and mouse liver and discusses studies in which the use of zebrafish uncovered unexplored processes in mammalian biliary development. The review concludes by providing a framework for interpreting the mechanisms that may help us understand the origin of congenital biliary diseases.


Assuntos
Ductos Biliares Extra-Hepáticos/embriologia , Ductos Biliares Intra-Hepáticos/embriologia , Sistema Biliar/embriologia , Hepatopatias/congênito , Hepatopatias/etiologia , Animais , Sistema Biliar/patologia , Diferenciação Celular/genética , Embrião de Mamíferos , Embrião não Mamífero , Hepatócitos/fisiologia , Humanos , Hepatopatias/genética , Camundongos , Morfogênese/genética , Morfogênese/fisiologia , Transdução de Sinais/genética , Peixe-Zebra/embriologia , Peixe-Zebra/fisiologia
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