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1.
Medicine (Baltimore) ; 100(4): e24432, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530243

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become a global pandemic, and its incidence is increasing year by year. At present, there are no definite curative drugs for the treatment of NAFLD in modern medicine. Surprisingly, complementary and alternative therapies play an important role and have special advantages. In this study, we will adopt Bayesian network meta-analysis (NMA) to evaluate the efficiency and safety of complementary therapy and alternative therapies for NAFLD. METHODS: We will collect randomized controlled trials (RCTs) related to the treatment of NAFLD in PubMed, Cochrane Library, CNKI, and other databases. Two reviewers will screen the literature and extract data in line with the inclusion and exclusion criteria, and then assess the risk of bias according to Cochrane risk of bias assessment tool. The Bayesian NMA will be performed by Stata16.0 and WinBUGS1.4.3. RESULTS: Our study will compare and rank the efficacy and safety of diverse complementary and alternative therapies for NAFLD. CONCLUSION: This study can provide credible evidence for the efficacy and safety of complementary therapies and alternative therapies in the treatment of NAFLD. We expect to assist clinicians and patients to choose the optimal therapeutic regimen. PROTOCOL REGISTRATION NUMBER: INPLASY2020120136.


Assuntos
Terapias Complementares/métodos , Hepatopatia Gordurosa não Alcoólica/terapia , Teorema de Bayes , Humanos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Resultado do Tratamento
2.
Medicine (Baltimore) ; 100(3): e24277, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33546051

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease is a common reason for chronic liver disease in children and adults. The increasing incidence of the disease has become one of the most critical public health problems in the 21st century, closely related to genetic and environmental factors. So far, apart from changing lifestyle and diet, modern medicine still lacks effective treatment measures. Chinese patent medicine has the advantages of apparent curative effect, overall regulation and fewer side effects. However, there is a lack of research on the simultaneous comparison of various Chinese patent medicines. Therefore, we used a reticular meta-analysis to indirectly compare the efficacy and safety of different oral Chinese patent medicines through standard reference. METHOD: We will conduct a comprehensive and systematic search of Chinese and English databases from the beginning to December 2020. All randomized controlled trials (RCTs) of oral Chinese patent medicine for NAFLD in children will be searched. The 2 researchers then independently filter the retrieved literature, extract the data according to the data extraction table and assess the risk of bias. We will perform a pair of meta-analyses and a Bayesian network meta-analysis. STATA and Win BUGS software will be used for data analysis. RESULTS: This study will thoroughly compare and analyze the differences in the efficacy of all kinds of TCPM in NAFLD treatment in childhood or adolescence. CONCLUSION: This study will provide reference and evidence support for clinical drug selection optimization. ETHICS AND DISSEMINATION: This study does not require ethical approval. INPLASY REGISTRATION NUMBER: 2020120068.


Assuntos
Protocolos Clínicos , Medicamentos de Ervas Chinesas/normas , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adolescente , Teorema de Bayes , Criança , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Metanálise em Rede
3.
Medicine (Baltimore) ; 100(6): e24743, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578624

RESUMO

ABSTRACT: Limited data are available regarding the association of non-alcoholic fatty liver disease (NAFLD) with the risk of type 2 diabetes mellitus (T2DM) in China. Therefore, the purpose of this study is to evaluate the gender-specific association between NAFLD and T2DM risk in a middle-aged and elderly Chinese population.This cross-sectional study was carried out in a group of 1492 Chinese adults (60.30% males) aged between 45 and 69 years old, in Hangzhou city, Zhejiang province who were attending their annual health check-up from June 2015 to December 2016 in the Medical Center for Physical Examination, Zhejiang Hospital. Face-to-face interviews were conducted using a written questionnaire. NAFLD was divided into none, mild, moderate/severe based on ultrasound examination. Logistic regression analyses were employed to determine the relationship between NAFLD and the risk of T2DM, with adjustment of potential confounding variables.Of the 1492 participants, 163 (10.92%) were diagnosed with T2DM. Educational level, smoking, body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose (FG), triglycerides (TG), alanine aminotransferase (ALT), asparagine aminotransferase (AST)and the prevalence of T2DM were significantly higher in males than in females (P < .05). Besides, females had significantly higher levels of high density lipoprotein-cholesterol (HDL-C) (1.51 ±â€Š0.37 vs 1.29 ±â€Š0.42, P < .001) than males. Pearson bivariate correlation analysis indicated that FG was positively associated with weight, BMI, WC, WHR, SBP, DBP, TG, TC, ALT and AST in both males and females (P < .05). Besides, FG was inversely associated with HDL-C in females (P < .001). After adjusting for confounding variables, NAFLD was positively associated with the risk of T2DM, and the effect of NAFLD on T2DM was stronger in males (OR = 2.442, 95%CI: 1.003-3.757) than in females (OR = 1.814, 95%CI: 1.011-3.257).Our data showed that NAFLD was significantly associated with the risk of T2DM in middle-aged and elderly males than in females. Further prospective cohort studies are needed to determine the causal effect of NAFLD on T2DM.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Idoso , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Fatores de Risco , Fatores Sexuais , Ultrassonografia
4.
Isr Med Assoc J ; 23(2): 94-98, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33595214

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is emerging as an important public health condition. The effect of Ramadan fasting on several metabolic conditions has been previously assessed. OBJECTIVES: To assess the impact of Ramadan fasting on non-alcoholic steatohepatitis (NASH) severity scores. METHODS: A retrospective, case control study was conducted in Nazareth Hospital between 2017 and 2019. We included NAFLD patients who had been diagnosed by abdominal ultrasonography. The study population was divided in two matched groups: NASH subjects who fasted all of Ramadan and NAFLD/NASH subjects who did not fast (control). Metabolic/NASH severity scores, homeostatic model assessment of ß-cell function and insulin resistance (HOMA-IR), NAFLD Fibrosis Score (NFS), BARD scores, and fibrosis-4 (FIB4) scores were assessed in both groups before and after the Ramadan month. RESULTS: The study included 155 NASH subjects, 74 who fasted and 81 who did not. Among the fasting group, body mass index decreased from 36.7 ± 7.1 to 34.5 ± 6.8 after fasting (P < 0.003), NFS declined from 0.45 ± 0.25 to 0.23 ± 0.21 (P < 0.005), BARD scores declined from 2.3 ± 0.98 to 1.6 ± 1.01 (P < 0.005), and FIB4 scores declined from 1.93 ± 0.76 to 1.34 ± 0.871 (P < 0.005). C-reactive protein decreased from 14.2 ± 7.1 to 7.18 ± 6.45 (P < 0.005). Moreover, HOMA-IR improved from 2.92 ± 1.22 to 2.15 ± 1.13 (P < 0.005). CONCLUSIONS: Ramadan fasting improved on inflammatory markers, insulin sensitivity, and noninvasive measures for NASH severity assessment.


Assuntos
Jejum/fisiologia , Resistência à Insulina/fisiologia , Islamismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Adulto , Idoso , Biomarcadores/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença
5.
Nat Commun ; 12(1): 66, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397952

RESUMO

IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.


Assuntos
Hepatócitos/metabolismo , Interleucina-11/metabolismo , Lipídeos/toxicidade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais , Adulto , Animais , Comunicação Autócrina/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Comportamento Alimentar , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Interleucina-6/metabolismo , Camundongos Knockout , Modelos Biológicos , Comunicação Parácrina/efeitos dos fármacos , Fenótipo , Transdução de Sinais/efeitos dos fármacos
6.
Arq Bras Cir Dig ; 33(3): e1549, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33470379

RESUMO

BACKGROUND: Strongly associated with obesity, non-alcoholic fatty liver disease is considered the hepatic manifestation of the metabolic syndrome. It presents as simple steatosis and steatohepatitis, which can progress to cirrhosis and its complications. Among the therapeutic alternatives is bariatric surgery. AIM: To compare the effect of the two most frequent bariatric procedures (sleeve and bypass) on liver disease regarding to epidemiological, demographic, clinical and laboratory parameters. METHODS: The results of intraoperative and 12 months after surgery liver biopsies were used. The NAFLD activity score (NAS) was used to assess and compare the stages of liver disease. RESULTS: Sixteen (66.7%) patients underwent Bypass procedure and eight (33.3%) Sleeve. It was observed that the variation in the NAFLD activity score was significantly greater in the Bypass group than in Sleeve (p=0.028) and there was a trend regarding the variation in fibrosis (p=0.054). CONCLUSION: Both surgical techniques were effective in improving the hepatic histology of most operated patients. When comparing sleeve and bypass groups, bypass showed better results, according to the NAS score.


Assuntos
Cirurgia Bariátrica/métodos , Derivação Gástrica/métodos , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade Mórbida/cirurgia , Perda de Peso , Adulto , Biópsia , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/cirurgia , Obesidade Mórbida/complicações , Fatores de Risco , Resultado do Tratamento
7.
Environ Pollut ; 271: 116304, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33401208

RESUMO

Epidemiological studies have demonstrated that the general population's exposure to bisphenol A (BPA) substitutes is ubiquitous. Bisphenol F (BPF), one of the main BPA substitutes, is increasingly replacing BPA in plastics for food and beverage applications. Accumulating evidence suggests that BPA exposure is associated with nonalcoholic fatty liver disease (NAFLD)-like changes. However, the potential effects of BPF on lipid homeostasis remain poorly understood. In the present study, an epidemiological analysis with LC-MS-MS revealed that the BPF concentrations in the serum of NAFLD patients were significantly higher than those in a control group. Supporting this result, using Oil Red O, BODIPY 493/503, LipidTox Deep Red staining and gas chromatography-time-of-flight mass spectrometry (TOF-MS) assays, we found that BPF exposure induced NAFLD-like changes, with obvious lipid droplet deposition, triglyceride (TG) and fatty acids increase in mouse livers. Meanwhile, lipid droplet deposition and TG increase induced by BPF were also observed in HepG2 cells, accompanied by autophagic flux blockade, including autophagosome accumulation and the decreased degradation of SQSTM1/p62. Using adenoviruses dual-reporter plasmid RFP-GFP-LC3, RFP-GFP-PLIN2 transfection, AO staining, and EGFR degradation assays, we demonstrated that BPF treatment impaired lysosomal degradative capacity, since BPF treatment obviously impaired lysosomal acidification, manifested as decreased lysosomal hydrolase cathepsin L (CTSL) and mature cathepsin D (CTSD) in HepG2 and mouse liver issues. Additionally, v-ATPase D, a multi-subunit enzyme that mediates acidification of eukaryotic intracellular organelles, significantly decreased after BPF exposure in both the vitro and in vivo studies. This study ascertained a novel mechanism involving dysfunctional of lysosomal degradative capacity induced by BPF, which contributes to lipophagic disorders and causes lipid droplet deposition. This work provides evidence that lysosomes may be a target organelle where BPF exerts its potential toxicity; therefore, novel intervention strategies targeting lysosome are promising for BPF-induced NAFLD-like changes.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Compostos Benzidrílicos/toxicidade , Humanos , Gotículas Lipídicas , Lisossomos , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Fenóis
8.
Gene ; 775: 145431, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33444683

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic that often progresses to liver cirrhosis and hepatocellular carcinoma. In contrast to most world populations where NAFLD is mostly prevalent among obese, NAFLD among Indians and generally among South and South-East Asians is unique and highly prevalent among individuals who are lean. Genetics of NAFLD in Indian populations is understudied. In this study, we have used an exome-wide approach to identify genetic determinants of hepatic fat content (HFC) in India. METHODS: HFC was measured in 244 participants using Proton magnetic resonance spectroscopy (H1-MRS). Quantitative trait loci (QTL) mapping was done exome-wide, to identify SNPs associated with HFC. The effects of the interaction between adiposity and QTLs on HFC were studied using a regression model. Association of the significant loci with disease severity was studied in 146 NAFLD patients among 244 participants, who underwent liver biopsy. RESULTS: Our study identified 4 significantly associated SNPs (rs738409 and rs2281135 (PNPLA3), rs3761472 (SAMM50), rs17513722 (FAM161A) and rs4788084), with HFC after adjusting for the effects of covariates (p-value < 0.0005). rs738409, rs2281135 (PNPLA3), and rs3761472 (SAMM50) were associated with hepatocyte ballooning, lobular and portal inflammation and non-alcoholic steatohepatitis (NASH) (p-value < 0.05). rs4788048 is an eQTL for IL27 and SULT1A2 genes, both of which are highly expressed in healthy livers and are likely to be involved in NAFLD pathogenesis. CONCLUSIONS: Our study identified the novel association of rs4788084 with HFC, which regulates the expression of IL-27, an immune regulatory gene. We further showed that adiposity affected the HFC, irrespective of the genetic predisposition.


Assuntos
Interleucinas/genética , Gordura Intra-Abdominal/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma/métodos , Adulto , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/genética , Regiões Promotoras Genéticas , Espectroscopia de Prótons por Ressonância Magnética , Índice de Gravidade de Doença , Ultrassonografia
10.
Nat Commun ; 12(1): 187, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420074

RESUMO

The gut microbiota is reported to modulate the immune response in hepatocellular carcinoma (HCC). Here, we employ metagenomic and metabolomic studies to characterise gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) related cirrhosis, with or without HCC, and evaluate its effect on the peripheral immune response in an ex vivo model. We find that dysbiosis characterises the microbiota of patients with NAFLD-cirrhosis, with compositional and functional shifts occurring with HCC development. Gene function of the microbiota in NAFLD-HCC supports short chain fatty acid production, and this is confirmed by metabolomic studies. Ex vivo studies show that bacterial extracts from the NAFLD-HCC microbiota, but not from the control groups, elicit a T cell immunosuppressive phenotype, characterised by expansion of regulatory T cells and attenuation of CD8 + T cells. Our study suggest that the gut microbiota in NAFLD-HCC is characterised by a distinctive microbiome/metabolomic profile, and can modulate the peripheral immune response.


Assuntos
Carcinoma Hepatocelular/imunologia , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Imunidade , Neoplasias Hepáticas/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Idoso , Bactérias/genética , Linfócitos T CD8-Positivos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Citocinas , Fibras na Dieta , Disbiose/imunologia , Ácidos Graxos Voláteis/sangue , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Feminino , Humanos , Fígado/patologia , Cirrose Hepática , Neoplasias Hepáticas/patologia , Masculino , Metabolômica , Metagenômica , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Fenótipo
11.
Nat Commun ; 12(1): 650, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510172

RESUMO

Hepatic inflammation is the driving force for the development and progression of NASH. Treatment targeting inflammation is believed to be beneficial. In this study, adoptive transfer of CD4+ T cells converted double negative T cells (cDNT) protects mice from diet-induced liver fat accumulation, lobular inflammation and focal necrosis. cDNT selectively suppress liver-infiltrating Th17 cells and proinflammatory M1 macrophages. IL-10 secreted by M2 macrophages decreases the survival and function of cDNT to protect M2 macrophages from cDNT-mediated lysis. NKG2A, a cell inhibitory molecule, contributes to IL-10 induced apoptosis and dampened suppressive function of cDNT. In conclusion, ex vivo-generated cDNT exert potent protection in diet induced obesity, type 2 diabetes and NASH. The improvement of outcome is due to the inhibition on liver inflammatory cells. This study supports the concept and the feasibility of potentially utilizing this autologous immune cell-based therapy for the treatment of NASH.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transferência Adotiva/métodos , Animais , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Inflamação/genética , Interleucina-10/metabolismo , Fígado/patologia , Macrófagos/classificação , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/terapia
13.
Phytomedicine ; 80: 153388, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113501

RESUMO

BACKGROUND: Insulin resistance (IR) and lipotoxicity were evidenced as the major nonalcoholic steatohepatitis (NASH) initiators. However, absence of the effective treatment against NASH progression raised our aim to discover a new promising insulin modulator and NSH preventer. PURPOSE: Our study aimed to extract and prepare a nitriles rich fraction (NRF) from Diceratella elliptica (DC.) Jonsell, investigate its insulin-sensitizing & anti-NASH potentialities and address its molecular targets in IR-NASH pathogenesis. STUDY DESIGN: NRF was prepared using natural autolysis method and compounds were identified. Then, seventy male Wistar rats were feed high fat diet (HFD) or normal pellets for 35 days. In day 14th, HFD rats were injected by Streptozotocin (STZ) once and treatment was started in day 21st with either NRF (30, 60 and 120 mg/kg; orally) or pioglitazone (PioG) (10 mg/kg; i.p) beside HFD. While, NRF-alone rats were treated with NRF (120 mg/kg; orally) beside the normal pellets. Body weight, glucose homeostasis, hepatopathological examinations were performed. METHODS: Gas liquid chromatography-mass spectrophotometry (GLC/MS) was used for compounds' identification while spectrophotometer was used for total glucosinolates (GLS) quantification. Also, the biochemical and molecular investigations concerned with liver lipotoxicity, oxidative stress, inflammation and insulin signaling pathway were investigated and confirmed with the computational prediction of the major compounds' targets. RESULTS: Butenyl and benzyl GLS were the major along with other volatile compounds. NRF had significantly increased the insulin sensitivity and improved NASH-hisptopathology showing hepatoprotective effect. While, the fraction's anti-NASH potentiality was evidenced in the normalized hepatic steatosis markers, inflammation and oxidative stress key transcriptional factors resulting in induction of insulin receptor substrates (IRSs) phosphorylation and its downstream effectors. CONCLUSION: NRF has reversed IR, stimulated leptin secretion and prevented NASH initiation showing promising anti-NASH and anti-fibrotic effects.


Assuntos
Brassicaceae/química , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Glucosinolatos/análise , Leptina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Nitrilos/química , Nitrilos/farmacologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona/farmacologia , Extratos Vegetais/química , Ratos Wistar , Transdução de Sinais
14.
Metabolism ; 114: 154342, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810487

RESUMO

Nonalcoholic fatty liver disease (NAFLD), a form of chronic liver disease that occurs in individuals with no significant alcohol abuse, has become an increasing concern for global health. NAFLD is defined as the presence of lipid deposits in hepatocytes and it ranges from hepatic steatosis (fatty liver) to steatohepatitis. Emerging data from both preclinical studies and clinical trials suggest that the peroxisome proliferator-activated receptor (PPAR)ß/δ plays an important role in the control of carbohydrate and lipid metabolism in liver, and its activation might hinder the progression of NAFLD. Here, we review the latest information on the effects of PPARß/δ on NAFLD, including its capacity to reduce lipogenesis, to alleviate inflammation and endoplasmic reticulum stress, to ameliorate insulin resistance, and to attenuate liver injury. Because of these effects, activation of hepatic PPARß/δ through synthetic or natural ligands provides a promising therapeutic option for the management of NAFLD.


Assuntos
Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR delta/metabolismo , PPAR beta/metabolismo , Animais , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/fisiologia
15.
Metabolism ; 114: 154349, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32888949

RESUMO

BACKGROUND: The functions of Acly in regulating nonalcoholic fatty liver disease (NAFLD) have been identified; however, the dynamic control of Acly expression under the pathological state of metabolic disorders has not been fully elucidated. Previous studies reported an ubiquitin-proteasome-mediated degradation of Acly, but the mechanism is still largely unknown. METHODS: Co-IP-based mass spectrum (MS/MS) assays were performed in HepG2 and Hepa1-6 hepatocytes and mouse liver tissue. The protein-protein interaction and ubiquitin modification of Hrd1 on Acly were confirmed by co-IP based immuno-blotting. Acetyl-CoA levels and lipogenesis rates were determined. The roles of Hrd1 on NAFLD and insulin resistance were tested by adenovirus-mediated overexpression in db/db mice or in separated primary hepatocytes. RESULTS: Hrd1, a subunit of the endoplasmic reticulum-associated degradation (ERAD) complex, interacted with and ubiquitinated Acly, thereby reducing its protein level. Hrd1 suppressed the acetyl-CoA level and inhibited lipogenesis through an Acly-dependent pathway. The expression of hepatic Hrd1 was negatively associated with NAFLD, whereas overexpression of Hrd1 ameliorated hepatic steatosis and enhanced insulin sensitivity, both in db/db mice and in separated mouse primary hepatocytes. CONCLUSIONS: Our results suggest that Acly, a master enzyme that regulates lipogenesis, is degraded by Hrd1 through ubiquitin modification. The activation of Hrd1 in hepatocytes might therefore represent a strategic approach for NAFLD therapy.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia , Animais , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Resistência à Insulina/fisiologia , Lipogênese/fisiologia , Camundongos , Espectrometria de Massas em Tandem
16.
Metabolism ; 114: 154409, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33096076

RESUMO

BACKGROUND AND OBJECTIVES: The gut-liver axis plays an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH), and increased intestinal permeability causes transfer of endotoxin to the liver, which activates the immune response, ultimately leading to hepatic inflammation. Nuclear receptor Rev-erbα is a critical regulator of circadian rhythm, cellular metabolism, and inflammatory responses. However, the role and mechanism of Rev-erbα in gut barrier function and NASH remain unclear. In the present study, we investigated the involvement of Rev-erbα in the regulation of intestinal permeability and the treatment of NASH. METHODS AND RESULTS: The expression of tight junction-related genes and Rev-erbs decreased in the jejunum, ileum and colon of mice with high cholesterol, high fat diet (CL)-induced NASH. Chromatin immunoprecipitation analysis indicated that REV-ERBα directly bound to the promoters of tight junction genes to regulate intestinal permeability. Pharmacological activation of REV-ERBα by SR9009 protected against lipopolysaccharide-induced increased intestinal permeability both in vitro and in vivo, and these effects were associated with the activation of autophagy and decreased apoptotic signaling of epithelial cells. In addition, the chronopharmacological effects of SR9009 were more potent at Zeitgeber time 0 (ZT0) than at ZT12, which was contrary to the rhythm of Rev-erbs in the gastrointestinal tract. The administration of SR9009 attenuated hepatic lipid accumulation, insulin resistance, inflammation, and fibrosis in mice with CL diet-induced NASH, which might be partly attributed to the enhancement of intestinal barrier function. CONCLUSION: Chronopharmacological activation of REV-ERBα might be a potential strategy to treat intestinal barrier dysfunction-related disorders and NASH.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pirrolidinas/uso terapêutico , Receptores Citoplasmáticos e Nucleares/agonistas , Proteínas Repressoras/agonistas , Tiofenos/uso terapêutico , Junções Íntimas/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Glicemia , Células CACO-2 , Colesterol/sangue , Humanos , Insulina/sangue , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Permeabilidade/efeitos dos fármacos , Pirrolidinas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiofenos/farmacologia , Junções Íntimas/metabolismo , Triglicerídeos/sangue
20.
Adv Exp Med Biol ; 1307: 417-440, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32424494

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading liver disease globally. NAFLD patients can have a progressive phenotype, non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis, liver failure and cancer. There is a close bi-directional relationship between NAFLD and type 2 diabetes mellitus (T2DM); NAFLD increases the risk for T2DM and its complications whereas T2DM increases the severity of NAFLD and its complications. The large global impact of NAFLD and T2DM on healthcare systems requires a paradigm shift from specialty care to early identification and risk stratification of NAFLD in primary care and diabetes clinics. Approach to diagnosis, risk stratification and management of NAFLD is discussed. In addition to optimizing the control of coexisting cardiometabolic comorbidities, early referral of NAFLD patients at high risk of having NASH or significant fibrosis to hepatology specialist care may improve management and allow access for clinical trials. Lifestyle modifications, vitamin E, pioglitazone and metformin are currently available options that may benefit patients with T2DM and NAFLD. The burst of clinical trials investigating newer therapeutic agents for NAFLD and NASH offer hope for new, effective and safe therapies in the near future.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Cirrose Hepática , Metformina/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/terapia
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