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1.
Z Gastroenterol ; 58(1): 57-62, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31931541

RESUMO

The rising prevalence of the metabolic syndrome has led to an increase of non-alcoholic fatty liver disease (NAFLD), and its progressive-inflammatory form called non-alcoholic steatohepatitis (NASH). In recent years, NAFLD and NASH have become major risk factors for developing liver cirrhosis and hepatocellular carcinoma (HCC). In this case, we report a 46-year-old patient with type 2 diabetes mellitus and metabolic comorbidities including obesity and arterial hypertension, who was referred because of rising liver enzymes. After clinical and diagnostic evaluation, the patient was diagnosed with NASH-associated liver cirrhosis, Child-Pugh stage B. A normal blood sugar level was difficult to achieve, and the patient presented with consistently elevated HbA1c-levels irresponsive to insulin therapy. Due to the underlying liver cirrhosis, the patient was enrolled in the HCC-surveillance program. Sonography during follow up showed a focal lesion. On magnetic resonance imaging (MRI), the diagnosis of HCC (BCLC stage A) was confirmed based on typical contrast enhancement and portal-venous wash-out. The patient was evaluated for liver transplantation with a labMELD of 17, and an intermittent therapy with TACE was initiated. Only 2 months after liver transplantation, the patient developed severe and lethal complications. Overall, this case highlights the different medical issues of patients with metabolic syndrome developing a chronic liver disease. In this patient, a rapid progression from NASH-associated liver cirrhosis to HCC was seen, and therefore highlights the importance of close surveillance to identify and treat potential risk factors early in the course of the disease.


Assuntos
Carcinoma Hepatocelular/complicações , Diabetes Mellitus Tipo 2/complicações , Neoplasias Hepáticas/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Comorbidade , Evolução Fatal , Humanos , Hipertensão/complicações , Resistência à Insulina , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Imagem por Ressonância Magnética , Síndrome Metabólica/diagnóstico , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/complicações
2.
Expert Opin Investig Drugs ; 29(2): 151-161, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31847612

RESUMO

Introduction: Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease in children and adults, a major contributor to health-care expenditures, and now a leading reason for liver transplantation. Adopting lifestyle modifications with regular exercise and a focus on healthy eating habits is the primary recommendation. However, patients are often unable to achieve and sustain such changes for a variety of social, physical, psychological and genetic reasons. Thus, treatments that can prevent and reverse NASH and its associated fibrosis are a major focus of current drug development.Areas covered: This review covers the current understanding of lipotoxic liver injury in the pathogenesis of NASH and how lifestyle modification and the spectrum of drugs currently in clinical trials address the many pathways leading to the phenotype of NASH.Expert opinion: Contrary to the frequently expressed nihilistic view of our understanding of NASH and disappointment with clinical trial results, much is known about the pathogenesis of NASH and there is much reason to be optimistic that effective therapies will be identified in the next 5-10 years. Achieving this will require continued refinement of clinical trial endpoints, continued engagement of trial sponsors and regulatory authorities, and continued participation of dedicated patients in clinical trials.


Assuntos
Desenvolvimento de Medicamentos , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/terapia , Adulto , Animais , Criança , Humanos , Estilo de Vida , Transplante de Fígado , Hepatopatia Gordurosa não Alcoólica/fisiopatologia
4.
Presse Med ; 48(12): 1459-1467, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31757728

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, the most common cause of chronic liver function augmentation and it will be the most common indication for liver transplantation in 2020. The prevalence of NAFLD has increased over time in line with the increase of obesity and type 2 diabetes. There is a discrepancy between the studies concerning the prevalence of NAFLD because of the different diagnostic methods used (ultrasound or magnetic resonance, fibroscan, controlled attenuation parameter (CAP), histology). Because of its high prevalence the impact of NAFLD in public health is real. Therapeutic advances must be made to better understand the natural history of NAFLD and improve the management of this emerging liver disease.


Assuntos
Hepatopatia Gordurosa não Alcoólica/epidemiologia , Saúde Pública , Diagnóstico Diferencial , Técnicas de Diagnóstico Endócrino/normas , Técnicas de Imagem por Elasticidade , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Transplante de Fígado/estatística & dados numéricos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Prevalência , Saúde Pública/estatística & dados numéricos , Saúde Pública/tendências , Fatores de Risco
5.
Zhonghua Gan Zang Bing Za Zhi ; 27(10): 748-753, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31734987

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in China. To provide evidence-based and updated practical recommendations for clinician, this expert recommendations have updated the diagnosis and treatment of NAFLD in five aspects as follows: (1) the framework of NAFLD treatment centre or clinic; (2) screening and evaluation: who should be screened, initial evaluation items, non-invasive assessment of steatohepatitis and advanced fibrosis, when to obtain a liver biopsy in patients with NAFLD, and other metabolic disorders and cardiovascular risk assessment; (3) managements of patient with NAFLD: lifestyle intervention (dietary, exercise and weight loss), drug treating metabolic co-morbidities such as hyperlipidemia, type 2 diabetes mellitus and hypertension, and steatohepatitis and fibrosis; (4) management of special populations with NAFLD: children, pregnant or lactating women, patients co-existence with alcoholic liver disease, chronic HBV and/or HCV infection, and autoimmune disorders; (5) monitoring and follow-up. This consensus aims to modify the optimizing management process and guide physicians make correct and reasonable decisions in the diagnosis and treatment for patients with NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Biópsia , Criança , China , Comorbidade , Diabetes Mellitus Tipo 2 , Feminino , Humanos , Hiperlipidemias , Hipertensão , Lactação , Estilo de Vida , Guias de Prática Clínica como Assunto
6.
Vnitr Lek ; 65(9): 571-575, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31635468

RESUMO

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of a metabolic syndrome, is a leading cause of chronic liver disease worldwide with prevalence 17-46 % in adult population. NAFLD is associated with type 2 diabetes, obesity and genetic factors and includes a spectrum of potentially progressive liver disease that comprises of simple steatosis, non-alcoholic steatohepatitis (NASH), variable degree of fibrosis and, ultimately, cirrhosis. Simple steatosis has been considered a benign condition, while the progression to fibrosis and advanced liver disease is related to NASH development. While steatosis is diagnosed by routine imaging methods, NASH could be diagnosed only by liver biopsy. Life style modification and weight reduction is the method of choice in the treatment of NAFLD. Despite intensive effort, no pharmacological treatment of NAFLD has been approved; based on the results of clinical trials the use of vitamin E or pioglitazone could be considered in the treatment of bioptically proved NASH. New antifibrotic and anti-inflammatory agents for the treatment of NASH are under evaluation. Recently, screening for NAFLD and/or advanced fibrosis in patients with type 2 diabetes has been advocated.


Assuntos
Diabetes Mellitus Tipo 2 , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica , Adulto , Biópsia , Diabetes Mellitus Tipo 2/complicações , Progressão da Doença , Humanos , Fígado , Cirrose Hepática/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia
7.
Nihon Yakurigaku Zasshi ; 154(4): 203-209, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597900

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a rising cause of chronic liver disease worldwide. Although majority of patients with NAFLD are benign and non-progressive, having only steatosis, some fraction of patients develop non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis, hepatocellular carcinoma, and eventually increased liver-related mortality. Among histological features of NAFLD, it has been reported that liver fibrosis is the most important predictor of long-term outcomes. Liver fibrosis is a dynamic process characterized by the over-accumulation of extracellular matrix due to chronic liver injury resulting from any etiology including not only NASH, but also viral infection and alcoholic liver disease. Activation of hepatic stellate cells (HSCs) has been well established as a central driver of fibrosis in experimental animal models and human liver injury. It is a transdifferentiation of quiescent, vitamin-A­storing cells into proliferative and fibrogenic myofibroblasts. However, the discovery of novel pathways and mediators reveals the complexity of HSC activation. These emerging pathways include hedgehog, autophagy, free cholesterol, YAP1, hepcidin, and nuclear/G-protein coupled receptor-mediated signals. In addition, pathways of HSC clearance have been uncovered such as apoptosis, senescence, and reversion to an inactivated state. Thus, clarifying the underlying mechanisms of HSC activation could lead to the identification of novel therapeutic targets for NASH, and several drug candidates are currently being developed in clinical trials.


Assuntos
Células Estreladas do Fígado/citologia , Cirrose Hepática/terapia , Hepatopatia Gordurosa não Alcoólica/terapia , Animais , Transdiferenciação Celular , Humanos
8.
EBioMedicine ; 46: 452-462, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31401193

RESUMO

BACKGROUND: Gastric bypass surgery is a very effective treatment of obesity and type 2 diabetes. However, very few eligible patients are offered surgery. Some patients also prefer less invasive approaches. We aimed to study the effects of the Sleeveballoon - a new device combining an intragastric balloon with a connecting sleeve, which covers the duodenal and proximal jejunal mucosa - on insulin sensitivity, glycemic control, body weight and body fat distribution. METHODS: We compared the effects of Sleeveballoon, Roux-en-Y Gastric-Bypass (RYGB) and sham-operation in 30 high-fat diet (HFD) fed Wistar rats. Whole body and hepatic insulin sensitivity and insulin signaling were studied. Transthoracic echocardiography was performed using a Vevo 2100 system (FUJIFILM VisualSonics Inc., Canada). Gastric emptying was measured using gastrografin. FINDINGS: Hepatic (P = .023) and whole-body (P = .011) insulin sensitivity improved in the Sleeveballoon and RYGB groups compared with sham-operated rats. Body weight reduced in both Sleeveballoon and RYGB groups in comparison to the sham-operated group (503.1 ±â€¯8.9 vs. 614.4 ±â€¯20.6 g, P = .006 and 490.0 ±â€¯17.7 vs. 614.4 ±â€¯20.6 g, P = .006, respectively). Ectopic fat deposition was drastically reduced while glycogen content was increased in both liver and skeletal muscle. Gastric emptying (T1/2) was longer (157.7 ±â€¯29.2 min, P = .007) in the Sleeveballoon than in sham-operated rats (97.1 ±â€¯26.3 min), but shorter in RYGB (3.5 ±â€¯1.1 min, P < .0001). Cardiac function was better in Sleeveballoon and RYGB versus sham-operated rats. INTERPRETATION: The Sleeveballoon reduces peripheral and hepatic insulin resistance, glycaemia, body weight and ectopic fat deposition to a similar level as RYGB, although the contribution of gastric emptying to blood glucose reduction is different.


Assuntos
Glicemia , Derivação Gástrica/efeitos adversos , Derivação Gástrica/métodos , Glucose/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adiposidade , Animais , Biomarcadores , Peso Corporal , Modelos Animais de Doenças , Ecocardiografia , Derivação Gástrica/instrumentação , Esvaziamento Gástrico , Teste de Tolerância a Glucose , Insulina/metabolismo , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Cuidados Pós-Operatórios , Ratos , Transdução de Sinais
9.
Artigo em Inglês | MEDLINE | ID: mdl-31455011

RESUMO

New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD-in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome-and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Prevalência , Medição de Risco , Fatores de Risco
10.
Int J Mol Sci ; 20(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426291

RESUMO

Mitochondria play a central role in non-alcoholic fatty liver disease (NAFLD) progression and in the control of cell death signalling during the progression to hepatocellular carcinoma (HCC). Associated with the metabolic syndrome, NAFLD is mostly driven by insulin-resistant white adipose tissue lipolysis that results in an increased hepatic fatty acid influx and the ectopic accumulation of fat in the liver. Upregulation of beta-oxidation as one compensatory mechanism leads to an increase in mitochondrial tricarboxylic acid cycle flux and ATP generation. The progression of NAFLD is associated with alterations in the mitochondrial molecular composition and respiratory capacity, which increases their vulnerability to different stressors, including calcium and pro-inflammatory molecules, which result in an increased generation of reactive oxygen species (ROS) that, altogether, may ultimately lead to mitochondrial dysfunction. This may activate further pro-inflammatory pathways involved in the progression from steatosis to steatohepatitis (NASH). Mushroom-enriched diets, or the administration of their isolated bioactive compounds, have been shown to display beneficial effects on insulin resistance, hepatic steatosis, oxidative stress, and inflammation by regulating nutrient uptake and lipid metabolism as well as modulating the antioxidant activity of the cell. In addition, the gut microbiota has also been described to be modulated by mushroom bioactive molecules, with implications in reducing liver inflammation during NAFLD progression. Dietary mushroom extracts have been reported to have anti-tumorigenic properties and to induce cell-death via the mitochondrial apoptosis pathway. This calls for particular attention to the potential therapeutic properties of these natural compounds which may push the development of novel pharmacological options to treat NASH and HCC. We here review the diverse effects of mushroom-enriched diets in liver disease, emphasizing those effects that are dependent on mitochondria.


Assuntos
Agaricales , Antioxidantes/uso terapêutico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Hepatopatia Gordurosa não Alcoólica/terapia , Agaricales/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Alimento Funcional/análise , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
11.
World J Gastroenterol ; 25(27): 3590-3606, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31367159

RESUMO

BACKGROUND: Obesity is a major risk factor for a variety of diseases such as diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases. Restricting energy intake, or caloric restriction (CR), can reduce body weight and improve metabolic parameters in overweight or obese patients. We previously found that Lingguizhugan decoction (LZD) in combination with CR can effectively lower plasma lipid levels in patients with metabolic syndrome. However, the mechanism underlying CR and LZD treatment is still unclear. AIM: To investigate whether CR and LZD improve metabolic parameters by modulating gut microbiota. METHODS: We extracted the water-soluble components out of raw materials and dried as LZD extracts. Eight-week old male C57BL/6 mice were treated with a 3-d treatment regime that included 24 h-fasting followed by gavage of LZD extracts for 2 consecutive days, followed by a normal diet (ND) ad libitum for 16 wk. To test the effects of gut microbiota on diet-induced obesity, 8-wk old male C57BL/6 mice received fecal microbiota transplantation (FMT) from CR and LZD-treated mice every 3 d and were fed with high-fat diet (HFD) ad libitum for 16 wk. Control mice received either saline gavage or FMT from ND-fed mice receiving saline gavage as mentioned above. Body weight was monitored bi-weekly. Food consumption of each cage hosting five mice was recorded weekly. To monitor blood glucose, total cholesterol, and total triglycerides, blood samples were collected via submandibular bleeding after 6 h fasting. Oxygen consumption rate was monitored with metabolic cages. Feces were collected, and fecal DNA was extracted. Profiles of gut microbiota were mapped by metagenomic sequencing. RESULTS: We found that CR and LZD treatment significantly reduced the body weight of mice fed with ND (28.71 ± 0.29 vs 28.05 ± 0.15, P < 0.05), but did not affect plasma total cholesterol or total triglyceride levels. We then transplanted the fecal microbiota collected from CR and LZD-treated mice under ND feeding to HFD-fed mice. Intriguingly, transplanting the mice with fecal microbiota from CR and LZD-treated mice potently reduced body weight (44.95 ± 1.02 vs 40.53 ± 0.97, P < 0.001). FMT also reduced HFD-induced hepatosteatosis, in addition to improved glycemic control. Mechanistic studies found that FMT increased OCR of the mice and suppressed the expression and protein abundance of lipogenic genes in the liver. Metagenomic analysis revealed that HFD drastically altered the profile of gut microbiota, and FMT modified the profile of the gut microbiota. CONCLUSION: Our study suggests that CR and LZD improve metabolic parameters by modulating gut microbiota.


Assuntos
Restrição Calórica , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/terapia , Extratos Vegetais/administração & dosagem , Animais , Terapia Combinada/métodos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Microbioma Gastrointestinal/fisiologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Obesidade/etiologia , Obesidade/microbiologia , Resultado do Tratamento
13.
J Steroid Biochem Mol Biol ; 194: 105445, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31381969

RESUMO

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women. Patients with non-alcoholic fatty liver disease (NAFLD) often suffer from metabolic syndrome, atherosclerosis, ischemic heart disease, and extrahepatic tumors, conferring a lower survival than the general population; therefore it is crucial to study the association between NAFLD and PCOS since it remains poorly understood. Insulin resistance (IR) plays a central role in the pathogenesis of NAFLD and PCOS; also, hyperandrogenism enhances IR in these patients. IR, present in the NAFLD-PCOS association could decrease the hepatic production of sex hormone-binding globulin through a possible regulation mediated by hepatocyte nuclear factor 4 alpha. On the other hand, apoptotic processes initiated by androgens actively contribute to the progression of NAFLD. Considering the association between the two conditions, the screening of women with PCOS for the presence of NAFLD appears reasonable. The pathophysiological mechanisms of PCOS-NAFLD association and the initial approach will be reviewed here.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Síndrome do Ovário Policístico , Progressão da Doença , Feminino , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/metabolismo , Fatores de Risco
14.
BMC Gastroenterol ; 19(1): 133, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345163

RESUMO

BACKGROUND: The aim of the present study was to evaluate the effects of curcumin supplementation on inflammatory indices, and hepatic features in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Fifty patients with NAFLD were randomized to receive lifestyle modification advice plus either 1500 mg curcumin or the same amount of placebo for 12 weeks. RESULTS: Curcumin supplementation was associated with significant decrease in hepatic fibrosis (p < 0.001), and nuclear factor-kappa B activity (p < 0.05) as compared with the baseline. Hepatic steatosis and serum level of liver enzymes, and tumor necrosis-α (TNF-α) significantly reduced in both groups (p < 0.05). None of the changes were significantly different between two groups. CONCLUSION: Our results indicated that curcumin supplementation plus lifestyle modification is not superior to lifestyle modification alone in amelioration of inflammation. TRIAL REGISTRATION: IRCT20100524004010N24, this trial was retrospectively registered on May 14, 2018.


Assuntos
Curcumina/administração & dosagem , Inflamação , Fígado , Hepatopatia Gordurosa não Alcoólica , Comportamento de Redução do Risco , Anti-Inflamatórios não Esteroides/administração & dosagem , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Testes de Função Hepática/métodos , Masculino , Pessoa de Meia-Idade , NF-kappa B/análise , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/psicologia , Hepatopatia Gordurosa não Alcoólica/terapia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
15.
Gut ; 68(11): 2065-2079, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31300518

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is associated with a thorough reprogramming of hepatic metabolism. Epigenetic mechanisms, in particular those associated with deregulation of the expressions and activities of microRNAs (miRNAs), play a major role in metabolic disorders associated with NAFLD and their progression towards more severe stages of the disease. In this review, we discuss the recent progress addressing the role of the many facets of complex miRNA regulatory networks in the development and progression of NAFLD. The basic concepts and mechanisms of miRNA-mediated gene regulation as well as the various setbacks encountered in basic and translational research in this field are debated. miRNAs identified so far, whose expressions/activities are deregulated in NAFLD, and which contribute to the outcomes of this pathology are further reviewed. Finally, the potential therapeutic usages in a short to medium term of miRNA-based strategies in NAFLD, in particular to identify non-invasive biomarkers, or to design pharmacological analogues/inhibitors having a broad range of actions on hepatic metabolism, are highlighted.


Assuntos
MicroRNAs/fisiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Humanos , Hepatopatia Gordurosa não Alcoólica/fisiopatologia
16.
Nat Commun ; 10(1): 2993, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278269

RESUMO

Activated hepatic stellate cell (aHSC)-mediated liver fibrosis is essential to the development of liver metastasis. Here, we discover intra-hepatic scale-up of relaxin (RLN, an anti-fibrotic peptide) in response to fibrosis along with the upregulation of its primary receptor (RXFP1) on aHSCs. The elevated expression of RLN serves as a natural regulator to deactivate aHSCs and resolve liver fibrosis. Therefore, we hypothesize this endogenous liver fibrosis repair mechanism can be leveraged for liver metastasis treatment via enforced RLN expression. To validate the therapeutic potential, we utilize aminoethyl anisamide-conjugated lipid-calcium-phosphate nanoparticles to deliver plasmid DNA encoding RLN. The nanoparticles preferentially target metastatic tumor cells and aHSCs within the metastatic lesion and convert them as an in situ RLN depot. Expressed RLN reverses the stromal microenvironment, which makes it unfavorable for established liver metastasis to grow. In colorectal, pancreatic, and breast cancer liver metastasis models, we confirm the RLN gene therapy results in significant inhibition of metastatic progression and prolongs survival. In addition, enforced RLN expression reactivates intra-metastasis immune milieu. The combination of the RLN gene therapy with PD-L1 blockade immunotherapy further produces a synergistic anti-metastatic efficacy. Collectively, the targeted RLN gene therapy represents a highly efficient, safe, and versatile anti-metastatic modality, and is promising for clinical translation.


Assuntos
Terapia Genética/métodos , Cirrose Hepática Experimental/terapia , Neoplasias Hepáticas/terapia , Hepatopatia Gordurosa não Alcoólica/terapia , Relaxina/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Linhagem Celular Tumoral/transplante , Progressão da Doença , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos/genética , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Plasmídeos/genética , Receptores Acoplados a Proteínas-G/metabolismo , Relaxina/metabolismo , Resultado do Tratamento , Microambiente Tumoral/genética , Regulação para Cima
17.
J Gastroenterol Hepatol ; 34 Suppl 1: 5-15, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31282011

RESUMO

Clinical Cases in Hepatitis 2018 was an interactive educational program for Australian physicians (gastroenterologists, hepatologists, and infectious disease specialists) actively involved in the treatment of liver diseases including hepatitis C virus, hepatitis B virus, and non-alcoholic steatohepatitis. This educational program sponsored by Gilead Sciences took place on October 12-13, 2018, and provided timely, informative case-based, and practical education to Australian physicians. This report summarizes keynote lectures from international leaders in the field of hepatitis C virus, hepatitis B virus, and non-alcoholic steatohepatitis and practical clinical case studies designed to inform and educate Australian physicians on managing challenging patients.


Assuntos
Gerenciamento Clínico , Educação Médica Continuada , Hepatopatias/terapia , Austrália , Educação , Feminino , Hepatite B/terapia , Hepatite C/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/terapia
18.
Expert Rev Gastroenterol Hepatol ; 13(9): 849-866, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31353974

RESUMO

Introduction: The relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) is complex and bidirectional. NAFLD increases the risk of incident diabetes and is very prevalent in T2DM patients and T2DM is an aggravating factor for NAFLD. Timely T2DM diagnosis and treatment in subjects with NAFLD and diagnosis, staging and treatment of NAFLD in those with T2DM are critical issues. Areas covered: PubMed/MEDLINE was searched for articles related to concomitant occurrence of NAFLD and T2DM between January 2013 and May 2019. Areas covered included epidemiological, diagnostic and therapeutic aspects. Expert opinion: there is a need for increased awareness on NAFLD adding liver disease as an end-organ complication of T2DM. Emphasis on use of simple non-invasive tools to triage patients with potentially severe liver disease should be made. Management of patients with NAFLD and T2DM relies on lifestyle optimization to achieve significant weight loss. Currently, there is no drug approved for treatment of NAFLD in patients with T2DM although Vitamin E and pioglitazone might be used in selected patients. Approved diabetic medications hold promise for NAFLD treatment and several liver-specific drugs are in evaluation clinical trials. A combination approach will likely represent the future of NAFLD therapeutics.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Diabetes Mellitus Tipo 2/complicações , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações
19.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 415-419, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357755

RESUMO

Main indication of nonalcoholic steatohepatitis (NASH) progression is hepatic fibrosis. The extent of fibrosis correlates negatively with long-term comorbidity and survival of NASH patients. Clinical screening for hepatic fibrosis extent higher than F2 is a main criterion for high risk NASH patients. Currently on-going phase III clinical trials for potential pharmacotherapeutics recruit NASH patients with F2-3, and whether tested pharmacotherapeutics block hepatic fibrosis is one of main end-points for assessment of clinical efficacy. Therefore, understanding molecular mechanisms and identifying potential targets are critical for intervention of NASH progression.


Assuntos
Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica , Ensaios Clínicos Fase III como Assunto , Progressão da Doença , Fibrose , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Cirrose Hepática/terapia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia
20.
Saudi Med J ; 40(6): 531-540, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31219486

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a major national and international health burden. It is one of the most common liver diseases worldwide and the most common cause of abnormal liver enzymes in many developed countries. Non-alcoholic fatty liver disease is also known as an important cause of cryptogenic cirrhosis and second leading cause for liver transplantation. It is commonly associated with metabolic syndrome. Non-alcoholic steatohepatitis (NASH) is the progressive phenotype of NAFLD. In spite of promising performance of non-invasive tools, liver biopsy remains the gold standard test for NASH diagnosis. Over decades, many drugs have been investigated in phase 2 and 3; however, no approved therapy to date. Despite the alarming global rates of NAFLD, there are no local community-based studies on the prevalence of NAFLD or local practice guidelines on its management; this expert review aims to fill this gap.


Assuntos
Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Cirurgia Bariátrica , Biomarcadores/sangue , Biópsia , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Diagnóstico por Imagem , Estilo de Vida Saudável , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Insulina/metabolismo , Fígado/patologia , Transplante de Fígado , Programas de Rastreamento , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Pioglitazona/uso terapêutico , Prevalência , Propionatos/uso terapêutico , Tiazolidinedionas/uso terapêutico , Vitamina E/uso terapêutico
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