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1.
PLoS Genet ; 16(8): e1008955, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776921

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excess lipid accumulation in the liver without significant consumption of alcohol. The transmembrane 6 superfamily member 2 (TM6SF2) E167K missense variant strongly associates with NAFLD in humans. The E167K mutation destabilizes TM6SF2, resulting in hepatic lipid accumulation and low serum lipid levels. However, the molecular mechanism by which TM6SF2 regulates lipid metabolism remains unclear. By using tandem affinity purification in combination with mass spectrometry, we found that apolipoprotein B (APOB), ER lipid raft protein (ERLIN) 1 and 2 were TM6SF2-interacting proteins. ERLINs and TM6SF2 mutually bound and stabilized each other. TM6SF2 bound and stabilized APOB via two luminal loops. ERLINs did not interact with APOB directly but still increased APOB stability through stabilizing TM6SF2. This APOB stabilization was hampered by the E167K mutation that reduced the protein expression of TM6SF2. In mice, knockout of Tm6sf2 and knockdown of Tm6sf2 or Erlins decreased hepatic APOB protein level, causing lipid accumulation in the liver and lowering lipid levels in the serum. We conclude that defective APOB stabilization, as a result of ERLINs or TM6SF2 deficiency or E167K mutation, is a key factor contributing to NAFLD.


Assuntos
Apolipoproteína B-100/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Hepatopatia Gordurosa não Alcoólica/genética , Animais , Colesterol/genética , Colesterol/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Imunoprecipitação , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Lipídeos/genética , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica/genética , Transfecção
2.
Lancet Gastroenterol Hepatol ; 5(11): 970-985, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32763196

RESUMO

BACKGROUND: Non-invasive tests that can identify patients with non-alcoholic steatohepatitis (NASH) at higher risk of disease progression are lacking. We report the development and validation of a blood-based diagnostic test to non-invasively rule in and rule out at-risk NASH (defined as non-alcoholic fatty liver disease [NAFLD] activity score [NAS] ≥4 and fibrosis stage ≥2). METHODS: In this prospective derivation and global validation study, blood samples, clinical data, and liver biopsy results from three independent cohorts with suspected NAFLD were used to develop and validate a non-invasive blood-based diagnostic test, called NIS4. Derivation was done in the discovery cohort, which comprised 239 prospectively recruited patients with biopsy-confirmed NASH (NAFLD NAS ≥3; fibrosis stage 0-3) from the international GOLDEN-505 phase 2b clinical trial. A complete matrix based on 23 variables selected for univariate association with the presence of at-risk NASH and avoiding high multi-collinearity was used to derive the model in a bootstrap-based process that minimised the Akaike information criterion. The overall diagnostic performance of NIS4 was externally validated in two independent cohorts: RESOLVE-IT diag and Angers. The RESOLVE-IT diag cohort comprised the first 475 patients screened for potential inclusion into the RESOLVE-IT phase 3 clinical trial. Angers was a retrospective cohort of 227 prospectively recruited patients with suspected NAFLD and clinical risk factors for NASH or fibrosis stage 2 or more according to abnormal elastography results or abnormal liver biochemistry. Both external validation cohorts were independently analysed and were combined into a pooled validation cohort (n=702) to assess clinical performance of NIS4 and other non-invasive tests. FINDINGS: The derived NIS4 algorithm comprised four independent NASH-associated biomarkers (miR-34a-5p, alpha-2 macroglobulin, YKL-40, and glycated haemoglobin; area under the receiver operating characteristics curve [AUROC] 0·80, 95% CI 0·73-0·85), and did not require adjustment for age, sex, body-mass index (BMI), or aminotransferase concentrations. Clinical cutoffs were established within the discovery cohort to optimise both rule out and rule in clinical performance while minimising indeterminate results. NIS4 was validated in the RESOLVE-IT diag cohort (AUROC 0·83, 95% CI 0·79-0·86) and the Angers cohort (0·76, 0·69-0·82). In the pooled validation cohort, patients with a NIS4 value less than 0·36 were classified as not having at-risk NASH (ruled out) with 81·5% (95% CI 76·9-85·3) sensitivity, 63·0% (57·8-68·0) specificity, and a negative predictive value of 77·9% (72·5-82·4), whereas those with a NIS4 value of more than 0·63 were classified as having at-risk NASH (ruled in) with 87·1% (83·1-90·3) specificity, 50·7% (45·3-56·1) sensitivity, and a positive predictive value of 79·2% (73·1-84·2). The diagnostic performance of NIS4 within the external validation cohorts was not influenced by age, sex, BMI, or aminotransferase concentrations. INTERPRETATION: NIS4 is a novel blood-based diagnostic that provides an effective way to non-invasively rule in or rule out at-risk NASH in patients with metabolic risk factors and suspected disease. Use of NIS4 in clinical trials or in the clinic has the potential to greatly reduce unnecessary liver biopsies in patients with lower risk of disease progression. FUNDING: Genfit.


Assuntos
Proteína 1 Semelhante à Quitinase-3/análise , Hemoglobina A Glicada/análise , Cirrose Hepática , Fígado , MicroRNAs/análise , Hepatopatia Gordurosa não Alcoólica , alfa-Macroglobulinas/análise , Área Sob a Curva , Biomarcadores/sangue , Biópsia/métodos , Testes de Química Clínica/métodos , Testes de Química Clínica/normas , Regras de Decisão Clínica , Progressão da Doença , Técnicas de Imagem por Elasticidade/métodos , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Gravidade do Paciente , Valor Preditivo dos Testes , Medição de Risco/métodos
3.
Lancet Gastroenterol Hepatol ; 5(11): 996-1007, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32805205

RESUMO

BACKGROUND: The laxative drug lubiprostone improves intestinal permeability in healthy volunteers. We aimed to assess efficacy and safety of lubiprostone in patients with non-alcoholic fatty liver disease (NAFLD) with constipation via attenuation of intestinal permeability. METHODS: This randomised, double-blind, placebo-controlled, phase 2a study in Yokohama City University Hospital, Japan, recruited patients (aged 20-85 years) with NAFLD and constipation, alanine aminotransferase (ALT) at least 40 U/L, liver stiffness (≤6·7 kPa), and hepatic fat fraction at least 5·2% when assessed by MRI-proton density fat fraction. Eligible patients were randomly assigned (11:10:9) by a computer-based system and stratified by age and sex to receive 24 µg lubiprostone, 12 µg lubiprostone, or placebo, orally, once per day for 12 weeks. The primary endpoint was the absolute changes in ALT at 12 weeks. Efficacy analysis was done by intention to treat. Safety was assessed in all treated patients. This trial was registered with University Hospital Medical Information Network Clinical Trials Registry (UMIN000026635). FINDINGS: Between March 24, 2017, and April 3, 2018, we screened 288 patients, of whom 150 (52%) were randomly assigned to treatment: 55 patients were assigned to receive 24 µg lubiprostone, 50 to receive 12 µg lubiprostone, and 45 to receive placebo. A greater decrease in the absolute ALT levels from baseline to 12 weeks was seen in the 24 µg lubiprostone group (mean -13 U/L [SD 19]) than in the placebo group (1 U/L [24]; mean difference -15 U/L [95% CI -23 to -6], p=0·0007) and in the 12 µg lubiprostone group (-12 U/L [21]) than in the placebo group (mean difference -13 U/L [-22 to -5], p=0·0023). 18 (33%) of 55 patients in the 24 µg group had at least one adverse event, as did three (6%) of 47 patients in the 12 µg group and three (7%) of 43 in the placebo group. The most common adverse event was diarrhoea (17 [31%] of patients in the 24 µg group, three [6%] in the 12 µg group, none in the placebo group). No life-threatening events or treatment-related deaths occurred. INTERPRETATION: Lubiprostone was well tolerated and reduced the levels of liver enzymes in patients with NAFLD and constipation. Further studies are necessary to better define the efficacy and tolerability of lubiprostone in patients with NAFLD without constipation. FUNDING: Mylan EPD G.K.


Assuntos
Alanina Transaminase/sangue , Diarreia , Fígado , Lubiprostona , Hepatopatia Gordurosa não Alcoólica , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/etiologia , Diarreia/induzido quimicamente , Diarreia/diagnóstico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Laxantes/administração & dosagem , Laxantes/efeitos adversos , Fígado/diagnóstico por imagem , Fígado/metabolismo , Testes de Função Hepática , Lubiprostona/administração & dosagem , Lubiprostona/efeitos adversos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Resultado do Tratamento
4.
PLoS One ; 15(7): e0236353, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730345

RESUMO

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH), a subtype of non-alcoholic fatty liver disease (NAFLD) that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma, is characterized by hepatic inflammation. Despite evolving therapies aimed to ameliorate inflammation in NASH, the transcriptional changes that lead to inflammation progression in NAFLD remain poorly understood. The aim of this pilot study was to define transcriptional changes in early, non-fibrotic NAFLD using two independent biopsy-proven NAFLD cohorts. METHODS: We extracted RNA from liver tissue of 40 patients with biopsy-proven NAFLD based on NAFLD Activity Score (NAS) (23 patients with NAS ≤3, 17 with NAS ≥5) and 21 healthy controls, and we compared changes in expression of 594 genes involved in innate immune function. Using plasma from an independent cohort of 67 patients with NAFLD and 15 healthy controls, we validated the gene changes observed using a multiplex protein assay. RESULTS: Compared to healthy controls, NAFLD patients with NAS ≥5 had differential expression of 211 genes, while those with NAS ≤3 had differential expression of only 14 genes. Notably, osteopontin (SPP1) (3.74-fold in NAS ≤3, 8.28-fold in NAS ≥5) and CXCL10 (2.27-fold in NAS ≤3, 8.28-fold in NAS ≥5) gene expression were significantly upregulated with histologic progression of NAFLD. Plasma osteopontin (SPP1) and CXCL10 are significantly increased in the presence of NAFLD, regardless of histologic grade. In addition, the plasma levels of these two proteins distinguish clearly between the presence or absence of NAFLD (AUC>0.90). CONCLUSIONS: Osteopontin (SPP1) and CXCL10 are upregulated early in non-fibrotic NAFLD and may serve as valuable non-invasive biomarkers.


Assuntos
Quimiocina CXCL10/sangue , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Osteopontina/sangue , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Transcrição Genética , Transcriptoma/genética
5.
Nutr Metab Cardiovasc Dis ; 30(9): 1564-1572, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32636123

RESUMO

BACKGROUND AND AIMS: We previously demonstrated that children with Down syndrome (DS) exhibited a greater risk of steatosis than the general pediatric population. This trend was independent of obese phenotype, thus suggesting a role of genetic predisposition. Therefore, we investigated the prevalence of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) in function of genetic susceptibility and adipocytokine levels in children with DS. METHODS AND RESULTS: A total of 84 Caucasian children with DS (age range 5-17 years), were included in this study. For all children, we collected data on anthropometric and biochemical parameters, and liver ultrasound (US). We also measured adipocytokines circulating levels and specific polymorphisms closed to NAFLD. We found a prevalence of 64.3% of liver steatosis at US, with a severe steatosis of about 4% in children with DS. The presence of steatosis in children with DS was associated with the presence of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 variant, which also correlated with interleukin (IL)-6 levels. Moreover, we found that the 52.4% had a waist circumference > 90th percentile, 21.4% were hypertensive, 7.14% had hyperglycemia, 9.5% had hypertriglyceridemia, and 17.9% showed high-density lipoprotein cholesterol ≤ 40 mg/dl. Finally, the IL-6 and adiponectin levels correlated with steatosis, and several adipocytokines correlated with single MetS traits in children with DS. CONCLUSION: The present study explores for the first time potential pathomechanisms connecting pediatric NAFLD and MetS in DS. We found that the PNPLA3 variant is associated with steatosis, but not with MetS, in children with DS.


Assuntos
Síndrome de Down/genética , Lipase/genética , Proteínas de Membrana/genética , Síndrome Metabólica/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Adiponectina/sangue , Adolescente , Fatores Etários , Biomarcadores/sangue , Glicemia/metabolismo , Criança , Pré-Escolar , Síndrome de Down/sangue , Síndrome de Down/diagnóstico , Síndrome de Down/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Interleucina-6/sangue , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Fenótipo , Prevalência , Medição de Risco , Fatores de Risco , Roma/epidemiologia
6.
Nutr Metab Cardiovasc Dis ; 30(10): 1820-1825, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32636124

RESUMO

BACKGROUND AND AIMS: Emerging evidence suggests that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are decreased in patients with imaging-defined nonalcoholic fatty liver disease (NAFLD), but no data are currently available on the association between plasma NT-proBNP levels and the histological severity of NAFLD. METHODS AND RESULTS: We enrolled 351 (73.5% men) consecutive adult patients with biopsy-proven NAFLD without a prior history of cardiovascular disease (CVD). Plasma NT-proBNP levels were measured using a commercially available immunochemical system (VITROS® 5600, Johnson, New Jersey). Fifty-three percent of these subjects had nonalcoholic steatohepatitis (NASH). After stratification of patients by plasma NT-proBNP tertiles; compared to those in the 1st tertile (NT-proBNP ≤16 pg/ml), the odds ratio for NASH was 0.52 (95% CI 0.29-0.95) in patients in the 2nd tertile (NT-proBNP of 17-33 pg/ml) and 0.49 (95% CI 0.26-0.93) in those in the 3rd tertile (NT-proBNP ≥34 pg/ml) of plasma NT-proBNP levels, even after adjustment for age, sex, body mass index, homeostasis model assessment (HOMA)-estimated insulin resistance, pre-existing diabetes, hypertension, and dyslipidemia. CONCLUSION: In subjects with biopsy-proven NAFLD without known CVD, this cross-sectional study shows for the first time, that lower plasma NT-proBNP levels are strongly associated with a higher prevalence of NASH.


Assuntos
Fígado/patologia , Peptídeo Natriurético Encefálico/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Fragmentos de Peptídeos/sangue , Adulto , Biomarcadores/sangue , China/epidemiologia , Estudos Transversais , Regulação para Baixo , Feminino , Humanos , Biópsia Guiada por Imagem , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Valor Preditivo dos Testes , Prevalência , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença
7.
Medicine (Baltimore) ; 99(22): e20399, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481431

RESUMO

Cytokeratin 18 (CK18) and fibroblast growth factor 21 (FGF21) are elevated in patients with nonalcoholic fatty liver disease (NAFLD) and are useful markers for identifying or monitoring outcomes. Exercise therapy is one of the established treatments for NAFLD; however, few studies have investigated the effectiveness of exercise therapy on CK18 and FGF21 levels. Therefore, the aim of the present study was to assess the effects of 12 weeks of simple resistance exercise on CK18 and FGF21 levels in patients with NAFLD.Fifty patients with NAFLD were assigned to a resistance exercise group (n = 23) or a control group (n = 27) for a trial period of 12 weeks. During the study, the resistance exercise group performed two exercises (push-ups and squats) three times a week on nonconsecutive days, whereas the control group proceeded with regular physical activities under a restricted diet. We then compared serum levels of CK18 fragments (M65) and FGF21 between groups just before and after the 12-week period.Serum M65 levels (880.0 ±â€Š503.6 vs 648.9 ±â€Š450.2 U/L; P < .01) were significantly decreased in the exercise group. However, no significant differences were observed in body mass index or skeletal muscle. The decreases in serum M65 (-231.1 ±â€Š354.7 vs 56.2 ±â€Š375.0 U/L; P = .02), and FGF21 levels (-41.7 ±â€Š98.2 vs. 33.2 ±â€Š127.6 pg/mL; P = .03) were significantly greater in the exercise than in the control group. Changes in M65 levels in the exercise group were significantly correlated with changes in alanine aminotransferase levels (r = 0.618, P < .01).Simple resistance exercise reduced CK18 and FGF21 levels in patients with NAFLD. These findings suggest that resistance exercise consisting of push-ups and squats helps prevent the progression of NAFLD.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Queratina-18/sangue , Hepatopatia Gordurosa não Alcoólica/terapia , Treinamento de Resistência/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estudos Retrospectivos
8.
Toxicol Lett ; 332: 1-6, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32579995

RESUMO

Non-alcoholic fatty liver disease (NAFLD) can be typically classified into two subgroups: non-alcoholic fatty liver and non-alcoholic steatohepatitis. Mouse models of NAFLD are useful tools for understanding the pathogenesis and progression of NAFLD and for developing drugs for its treatment. Here, we investigated the time-dependent changes in serum lipids and biochemical markers of hepatic function, hepatic inflammation, and fibrosis in mice fed a normal diet (ND) or a NAFLD diet (choline deficient, L-amino acid-defined, high-fat diet; CDAHFD) for 12 weeks. CDAHFD-fed mice showed significantly reduced serum levels of total cholesterol, triglyceride, and high-density lipoprotein cholesterol throughout the treatment period compared with ND-fed mice. The changes in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and total bilirubin showed an inverse U-shaped curve in the CDAHFD-fed mice. The serum alkaline phosphatase levels decreased in both ND- and CDAHFD-fed mice in a time-dependent manner. Furthermore, CDAHFD-fed mice showed a significant increase in the number of inflammatory foci and hepatic fibrosis at 6-12 weeks, although inflammatory foci and hepatic fibrogenesis were observable at relatively early stages as well (1-4 weeks). In conclusion, the long-term profile of serological biomarkers, hepatic inflammation, and fibrosis in CDAHFD-fed mice identified in this study may provide a better understanding of NAFLD pathogenesis.


Assuntos
Hepatite/patologia , Cirrose Hepática/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Biomarcadores/análise , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , HDL-Colesterol/sangue , Dieta , Hepatite/sangue , Hepatite/enzimologia , Metabolismo dos Lipídeos , Fígado/enzimologia , Fígado/metabolismo , Cirrose Hepática/sangue , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/enzimologia , Triglicerídeos/sangue
9.
PLoS Med ; 17(4): e1003100, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32353039

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. Many individuals have risk factors associated with NAFLD, but the majority do not develop advanced liver disease: cirrhosis, hepatic decompensation, or hepatocellular carcinoma. Identifying people at high risk of experiencing these complications is important in order to prevent disease progression. This review synthesises the evidence on metabolic risk factors and their potential to predict liver disease outcomes in the general population at risk of NAFLD or with diagnosed NAFLD. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of population-based cohort studies. Databases (including MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov) were searched up to 9 January 2020. Studies were included that reported severe liver disease outcomes (defined as liver cirrhosis, complications of cirrhosis, or liver-related death) or advanced fibrosis/non-alcoholic steatohepatitis (NASH) in adult individuals with metabolic risk factors, compared with individuals with no metabolic risk factors. Cohorts selected on the basis of a clinically indicated liver biopsy were excluded to better reflect general population risk. Risk of bias was assessed using the QUIPS tool. The results of similar studies were pooled, and overall estimates of hazard ratio (HR) were obtained using random-effects meta-analyses. Of 7,300 unique citations, 22 studies met the inclusion criteria and were of sufficient quality, with 18 studies contributing data suitable for pooling in 2 random-effects meta-analyses. Type 2 diabetes mellitus (T2DM) was associated with an increased risk of incident severe liver disease events (adjusted HR 2.25, 95% CI 1.83-2.76, p < 0.001, I2 99%). T2DM data were from 12 studies, with 22.8 million individuals followed up for a median of 10 years (IQR 6.4 to 16.9) experiencing 72,792 liver events. Fourteen studies were included in the meta-analysis of obesity (BMI > 30 kg/m2) as a prognostic factor, providing data on 19.3 million individuals followed up for a median of 13.8 years (IQR 9.0 to 19.8) experiencing 49,541 liver events. Obesity was associated with a modest increase in risk of incident severe liver disease outcomes (adjusted HR 1.20, 95% CI 1.12-1.28, p < 0.001, I2 87%). There was also evidence to suggest that lipid abnormalities (low high-density lipoprotein and high triglycerides) and hypertension were both independently associated with incident severe liver disease. Significant study heterogeneity observed in the meta-analyses and possible under-publishing of smaller negative studies are acknowledged to be limitations, as well as the potential effect of competing risks on outcome. CONCLUSIONS: In this review, we observed that T2DM is associated with a greater than 2-fold increase in the risk of developing severe liver disease. As the incidence of diabetes and obesity continue to rise, using these findings to improve case finding for people at high risk of liver disease will allow for effective management to help address the increasing morbidity and mortality from liver disease. TRIAL REGISTRATION: PROSPERO CRD42018115459.


Assuntos
Doenças Metabólicas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos Observacionais como Assunto/métodos , Vigilância da População , Humanos , Incidência , Hepatopatias/sangue , Hepatopatias/diagnóstico , Hepatopatias/epidemiologia , Doenças Metabólicas/sangue , Doenças Metabólicas/diagnóstico , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Vigilância da População/métodos , Fatores de Risco
10.
Life Sci ; 254: 117795, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417373

RESUMO

AIMS: The primary focus of this study was to explore the effects of cyclic AMP response element-binding protein H (CREBH) on the development of nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: CREBH knockout (KO) and wildtype (WT) mice were averagely divided into a methionine and choline-deficient (MCD) or high fat (HF) diet group and respective chow diet (CD) groups. Mice were sacrificed after 4-week treatment for MCD model and 24-week treatment for HF model. KEY FINDINGS: Characteristics of nonalcoholic steatohepatitis-related liver fibrosis in KO-MCD/HF group were verified by hepatic histological analyses. Compared with WT-MCD/HF group, levels of plasma ALT and hepatic hydroxyproline increased in KO-MCD/HF group. Significantly higher levels of MCP-1, αSMA, Desmin, COL-1, TIMP-1, TGF-ß1, TGF-ß2 were found while MMP-9 and FGF21 mRNA levels decreased in KO-MCD/HF group. There was also a distinct difference of mRNA levels of TNFα, CTGF and CCND1 in KO-HF group compared with controls. Protein levels of MCP-1, BAX, αSMA, COL-1, TGF-ß1 and SMAD2/3 significantly increased in KO-MCD/HF group and CCND1 was also upregulated in KO-HF group compared to their counterparts. SIGNIFICANCE: CREBH knockout may primarily regulate the TGF-ß1 signaling pathway via TGF-ß2 and FGF21 resulting in more severe inflammation and fibrosis in NAFLD.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Cirrose Hepática/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fator de Crescimento Transformador beta/metabolismo , Alanina Transaminase/sangue , Animais , Deficiência de Colina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/deficiência , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/biossíntese , Hidroxiprolina/metabolismo , Lipídeos/sangue , Cirrose Hepática/sangue , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Metionina/deficiência , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/genética
11.
Am J Gastroenterol ; 115(8): 1289-1292, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32453041

RESUMO

INTRODUCTION: We investigated the longitudinal impact of antinuclear antibody (ANA) on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD). METHODS: ANA were found in 16.9% of 923 biopsy-proven NAFLD patients, but none of them had histologic autoimmune hepatitis (AIH) or developed AIH after a mean follow-up of 106±50 months. RESULTS: Although ANA-positive cases had a higher prevalence of nonalcoholic steatohepatitis at baseline, the occurrence of liver-related events, hepatocellula carcinoma, cardiovascular events, extrahepatic malignancy, and overall survival were similar to ANA-negative. DISCUSSION: Once AIH has been ruled out, the long-term outcomes and survival are unaffected by the presence of ANA in patients with NAFLD.


Assuntos
Anticorpos Antinucleares/sangue , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Biópsia , Inglaterra/epidemiologia , Feminino , Humanos , Itália/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/mortalidade , Hepatopatia Gordurosa não Alcoólica/patologia , Prevalência , Estudos Prospectivos , Análise de Sobrevida
12.
PLoS One ; 15(5): e0233087, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407372

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a pathological condition caused by excess triglyceride deposition in the liver. The SMXA-5 severe fatty liver mouse model has been established from the SM/J and A/J strains. To explore the genetic factors involved in fatty liver development in SMXA-5 mice, we had previously performed quantitative trait locus (QTL) analysis, using (SM/J×SMXA-5)F2 intercross mice, and identified Fl1sa on chromosome 12 (centromere-53.06 Mb) as a significant QTL for fatty liver. Furthermore, isoamyl acetate-hydrolyzing esterase 1 homolog (Iah1) was selected as the most likely candidate gene for Fl1sa. Iah1 gene expression in fatty liver-resistant A/J-12SM mice was significantly higher than in fatty liver-susceptible A/J mice. These data indicated that the Iah1 gene might be associated with fatty liver development. However, the function of murine Iah1 remains unknown. Therefore, in this study, we created Iah1 knockout (KO) mice with two different backgrounds [C57BL/6N (B6) and A/J-12SM (A12)] to investigate the relationship between Iah1 and liver lipid accumulation. Liver triglyceride accumulation in Iah1-KO mice of B6 or A12 background did not differ from their respective Iah1-wild type mice under a high-fat diet. These results indicated that loss of Iah1 did not contribute to fatty liver. On the other hands, adipose tissue dysfunction causes lipid accumulation in ectopic tissues (liver, skeletal muscle, and pancreas). To investigate the effect of Iah1 deficiency on white adipose tissue, we performed DNA microarray analysis of epididymal fat in Iah1-KO mice of A12 background. This result showed that Iah1 deficiency might decrease adipokines Sfrp4 and Metrnl gene expression in epididymal fat. This study demonstrated that Iah1 deficiency did not cause liver lipid accumulation and that Iah1 was not a suitable candidate gene for Fl1sa.


Assuntos
Hidrolases de Éster Carboxílico/genética , Deleção de Genes , Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica/genética , Adiposidade , Animais , Peso Corporal , Hidrolases de Éster Carboxílico/metabolismo , Colesterol/sangue , Dieta Hiperlipídica , Epididimo/metabolismo , Regulação Enzimológica da Expressão Gênica , Metabolismo dos Lipídeos/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/sangue
13.
Zhonghua Gan Zang Bing Za Zhi ; 28(3): 247-253, 2020 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-32306658

RESUMO

Objective: To investigate the application value of reactive oxygen species (ROS) and adiponectin (ADPN) in the judgment of liver inflammation in chronic hepatitis B virus infection combined with nonalcoholic fatty liver disease (NAFLD). Methods: A total of 159 cases with NAFLD (21 cases), chronic hepatitis B virus infection (57 cases), and chronic hepatitis B virus infection combined with NAFLD (81 cases) were collected between June 2016 to December 2018, and the visited patients diagnosis were confirmed by histopathological examination of the liver. ROS and ADPN level retained in serum was determined by enzyme-linked immunosorbent assay. Histopathological examination of liver tissue was used as the gold standard to discuss the diagnostic value of the serum in patients with chronic hepatitis B virus infection combined with NAFLD for the occurrence of nonalcoholic steatohepatitis. One-way analysis of variance was used for the comparison among multiple groups, and LSD-t test was used for pairwise comparison between groups. Measurement data for non-normal distributions were expressed as M (P25, P75). Comparisons between groups were performed using the Mann-Whitney U or Kruskal-Wallis H test. Chi-square test was used to compare the count data between groups. Correlation analysis was performed using Spearman correlation analysis. Histopathological grouping of liver tissue was used as the gold standard, and the area under the receiver operating characteristic curve was used to evaluate the diagnostic efficacy of the regression formula. Results: (1) In patients with chronic hepatitis B virus infection combined with NAFLD, the levels of ROS in the non-hepatic steatosis group and the mild hepatic steatosis group were significantly lower than those in the moderate and severe hepatic steatosis group, while the ADPN level in the non-hepatic steatosis group was significantly higher than liver steatosis group, P < 0.05. (2) The results of correlation analysis showed that ROS was significantly correlated with NAS score, change in the degree of fatty liver and lobular inflammation (all P < 0.05).There was a significant negative correlation between ADPN and the change in the degree of fatty liver (P < 0.05). (3) Logistic regression analysis results showed that the diagnostic formula for chronic hepatitis B virus infection combined with nonalcoholic steatohepatitis was 0.02 × controlled attenuation index + 0.584 × white blood cells/10(9) + 0.587 × ROS-10.982. The area under receiver operating characteristic curve of the subject was = 0.896. The sensitivity, specificity, positive and negative predictive value were 97.1%, 71.2%, 64.2%, and 97.9%. Conclusion: ADPN and ROS have certain reference value in differentiating the change in the degree of fatty liver and inflammation in chronic hepatitis B virus infection combined with NAFLD and the diagnostic formula has higher application value in the diagnosis and exclusion of chronic hepatitis B virus infection combined with nonalcoholic steatohepatitis.


Assuntos
Adiponectina/sangue , Hepatite B Crônica/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/virologia , Espécies Reativas de Oxigênio/sangue , Biópsia , Vírus da Hepatite B , Hepatite B Crônica/complicações , Humanos , Fígado
14.
Br J Nutr ; 124(4): 450-456, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32312333

RESUMO

Non-alcoholic fatty liver disease (NAFLD) includes a range of disorders from simple steatosis to non-alcoholic steatohepatitis. There is no proven drug treatment for NAFLD, and diet modification is considered part of the main line of treatment for this disease. The aim of this study was to investigate the efficacy of garlic supplementation in NAFLD patients. The effect of garlic powder supplementation on hepatic steatosis, liver enzymes and lipid profile was investigated in NAFLD patients. Ninety NAFLD patients were randomly assigned to take either a garlic powder supplement or a placebo for 12 weeks. The treatment group received four tablets of garlic daily (each tablet contained 400 mg garlic powder). The control group received four tablets of placebo (each placebo contained 400 mg starch). At the end of the study, hepatic steatosis was significantly reduced in the treatment group compared with the control group (P = 0·001). In addition, a significant decrease was seen in the serum concentration of alanine transaminase (P < 0·001), aspartate transaminase (P = 0·002), γ-glutamyltransferase (P = 0·003) as well as total cholesterol (P = 0·009), TAG (P < 0·001), HDL-cholesterol (P < 0·001) and LDL-cholesterol (P = 0·01) in the treatment group compared with the control group. No significant difference was seen between the two groups in serum concentration of alkaline phosphatase. Overall, garlic powder supplementation improved hepatic features and lipid profile among NAFLD patients.


Assuntos
Suplementos Nutricionais , Alho , Hepatopatia Gordurosa não Alcoólica/terapia , Adulto , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Método Duplo-Cego , Feminino , Humanos , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Resultado do Tratamento , gama-Glutamiltransferase/sangue
15.
PLoS One ; 15(3): e0230307, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32168345

RESUMO

Multiple factors are involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), but the exact immunological mechanisms that cause inflammation and fibrosis of the liver remain enigmatic. In this current study, cellular samples of a cohort of NAFLD patients (peripheral blood mononuclear cells (PBMC): n = 27, liver samples: n = 15) and healthy individuals (PBMC: n = 26, liver samples: n = 3) were analyzed using 16-color flow cytometry, and the frequency and phenotype of 23 immune cell subtypes was assessed. PBMC of NAFLD patients showed decreased frequencies of total CD3+, CD8+ T cells, CD56dim NK cells and MAIT cells, but elevated frequencies of CD4+ T cells and Th2 cells compared to healthy controls. Intrahepatic lymphocytes (IHL) of NAFLD patients showed decreased frequencies of total T cells, total CD8+ T cells, Vd2+γδ T cells, and CD56bright NK cells, but elevated frequencies of Vδ2-γδ T cells and CD56dim NK cells compared to healthy controls. The activating receptor NKG2D was significantly less frequently expressed among iNKT cells, total NK cells and CD56dim NK cells of PBMC of NAFLD patients compared to healthy controls. More strikingly, hepatic fibrosis as measured by fibroscan elastography negatively correlated with the intrahepatic frequency of total NK cells (r2 = 0,3737, p = 0,02). Hepatic steatosis as measured by controlled attenuation parameter (CAP) value negatively correlated with the frequency of circulating NKG2D+ iNKT cells (r2 = 0,3365, p = 0,0047). Our data provide an overview of the circulating and intrahepatic immune cell composition of NAFLD patients, and point towards a potential role of NK cells and iNKT cells for the regulation of hepatic fibrosis and steatosis in NAFLD.


Assuntos
Inflamação/sangue , Cirrose Hepática/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Adulto , Biópsia , Complexo CD3/sangue , Complexo CD3/imunologia , Antígeno CD56/sangue , Antígeno CD56/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Imagem por Elasticidade , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Inflamação/patologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Fígado/diagnóstico por imagem , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Células Th2/imunologia
16.
PLoS One ; 15(3): e0229896, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155178

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease; however, progression to nonalcoholic steatohepatitis (NASH) is associated with most adverse outcomes. CYP2B metabolizes multiple xeno- and endobiotics, and male Cyp2b-null mice are diet-induced obese (DIO) with increased NAFLD. However, the DIO study was not performed long enough to assess progression to NASH. Therefore, to assess the role of Cyp2b in fatty liver disease progression from NAFLD to NASH, we treated wildtype (WT) and Cyp2b-null mice with a normal diet (ND) or choline-deficient, L-amino acid-defined high fat diet (CDAHFD) for 8 weeks and determined metabolic and molecular changes. CDAHFD-fed WT female mice gained more weight and had greater liver and white adipose tissue mass than their Cyp2b-null counterparts; males experienced diet-induced weight loss regardless of genotype. Serum biomarkers of liver injury increased in both CDAHFD-fed female and male mice; however CDAHFD-fed Cyp2b-null females exhibited significantly lower serum ALT, AST, and ASP concentrations compared to WT mice, indicating Cyp2b-null females were protected from liver injury. In both genders, hierarchical clustering of RNA-seq data demonstrates several gene ontologies responded differently in CDAHFD-fed Cyp2b-null mice compared to WT mice (lipid metabolism > fibrosis > inflammation). Oil Red O staining and direct triglycerides measurements confirmed that CDAHFD-fed Cyp2b-null females were protected from NAFLD. CDAHFD-fed Cyp2b-null mice showed equivocal changes in fibrosis with transcriptomic and serum markers suggesting less inflammation due to glucocorticoid-mediated repression of immune responses. In contrast to females, CDAHFD-fed Cyp2b-null males had higher triglyceride levels. Results indicate that female Cyp2b-null mice are protected from NAFLD while male Cyp2b-null mice are more susceptible to NAFLD, with few significant changes in NASH development. This study confirms that increased NAFLD development does not necessarily lead to progressive NASH. Furthermore, it indicates a role for Cyp2b in fatty liver disease that differs based on gender.


Assuntos
Família 2 do Citocromo P450/genética , Metabolismo dos Lipídeos/genética , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Família 2 do Citocromo P450/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Testes de Função Hepática , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , RNA-Seq , Fatores Sexuais
17.
Complement Ther Med ; 49: 102290, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32147076

RESUMO

OBJECTIVES: The current study evaluated the effects of green coffee extract (GCE) on serum lipid profile and adiponectin levels in patients with nonalcoholic fatty liver disease (NAFLD). DESIGN: This randomized, double-blind, placebo-controlled clinical trial was conducted on NAFLD patients aged 20-60 years and body mass index (BMI) of 25-35 kg/m2. SETTING: Patients were recruited from the Bahman poly-clinic (Neyshabur, Iran) between January and June 2016. INTERVENTIONS: The study subjects were randomly assigned to receive a daily dose of 400 mg GCE (n = 24) or placebo (n = 24) for eight weeks. MAIN OUTCOME MEASURES: Serum liver enzyme levels, lipid profile, adiponectin concentrations, and hepatic steatosis grade were measured for all patients at baseline and the end of the trial. RESULTS: GCE supplementation significantly reduced BMI [mean difference (MD): -0.57 and 95 % confidence interval (CI): -0.84 to -0.29, P < 0.001] and increased serum high-density lipoprotein cholesterol (MD: 7.06, 95 % CI: 0.25-13.87, P < 0.05) compared to the control group. Serum total cholesterol decreased significantly within the GCE group (MD: -13.33, 95 % CI: -26.04 to -0.61, P < 0.05). Triglyceride levels reduced significantly in GCE group compared to the placebo group (MD: -37.91; 95 % CI: -72.03 to -3.80; P = 0.03). However, this reduction was not significant when was further adjusted for mean changes in BMI and daily energy intake (MD: -23.43; 95 % CI: -70.92 to 24.06; P = 0.32). Hepatic steatosis grade, liver enzymes, and adiponectin levels did not show significant differences between the two groups after the intervention. CONCLUSIONS: GCE supplementation improved serum lipid profile and BMI in individuals with NAFLD. GCE may be useful in controlling NAFLD risk factors.


Assuntos
Adiponectina/sangue , Café , Suplementos Nutricionais , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue
18.
Artigo em Inglês | MEDLINE | ID: mdl-32139603

RESUMO

BACKGROUND AND AIM: Imaging-confirmed non-alcoholic fatty liver disease (NAFLD) with normal alanine aminotransferase (nALT) levels is infrequently the subject for further evaluation. Early diagnosis of non-alcoholic steatohepatitis (NASH) is needed to prevent disease progression. Thus, we tested the clinical utility of serum Golgi protein 73 (GP73) levels and developed a new non-invasive score to diagnose NASH in patients with biopsy-confirmed NAFLD and persistent nALT levels. METHODS: Serum GP73 and cytokeratin-18 M30 fragments (CK18-M30) levels were measured in 345 patients with biopsy-proven NAFLD. We developed a new score, named G-NASH model (by incorporating serum GP73), and combined it with serum CK18-M30 measurement in a sequential non-invasive approach to accurately identify NASH among patients with NAFLD and persistent nALT levels. RESULTS: 105 (30.4%) patients had persistent nALT, 53 of whom had histologically confirmed NASH. Both serum GP73 and CK18-M30 levels alone had poor diagnostic accuracy in identifying NASH (55.2% and 51.6%, respectively) in these patients. Conversely, G-NASH model performed better than other established non-invasive scoring systems, and by using our proposed sequential non-invasive approach 82.9% of patients with NASH were correctly identified. CONCLUSIONS: NASH is highly prevalent in patients with NAFLD with persistent nALT levels. The G-NASH model accurately identifies NASH in this patient group.


Assuntos
Alanina Transaminase/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Adulto , Biomarcadores/sangue , Feminino , Humanos , Queratina-18/sangue , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Sensibilidade e Especificidade
19.
Nat Commun ; 11(1): 719, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024826

RESUMO

Lipid overload results in lipid redistribution among metabolic organs such as liver, adipose, and muscle; therefore, the interplay between liver and other organs is important to maintain lipid homeostasis. Here, we show that liver responds to lipid overload first and sends hepatocyte-derived extracellular vesicles (EVs) targeting adipocytes to regulate adipogenesis and lipogenesis. Geranylgeranyl diphosphate synthase (Ggpps) expression in liver is enhanced by lipid overload and regulates EV secretion through Rab27A geranylgeranylation. Consistently, liver-specific Ggpps deficient mice have reduced fat adipose deposition. The levels of several EV-derived miRNAs in the plasma of non-alcoholic fatty liver disease (NAFLD) patients are positively correlated with body mass index (BMI), and these miRNAs enhance adipocyte lipid accumulation. Thus, we highlight an inter-organ mechanism whereby the liver senses different metabolic states and sends corresponding signals to remodel adipose tissue to adapt to metabolic changes in response to lipid overload.


Assuntos
Tecido Adiposo/metabolismo , Vesículas Extracelulares/metabolismo , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Animais , Índice de Massa Corporal , Dieta Hiperlipídica/efeitos adversos , Vesículas Extracelulares/genética , Farnesiltranstransferase/genética , Humanos , Lipogênese , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/sangue , Complexos Multienzimáticos/genética , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas rab27 de Ligação ao GTP/genética , Proteínas rab27 de Ligação ao GTP/metabolismo
20.
Nutr Metab Cardiovasc Dis ; 30(4): 709-716, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32007335

RESUMO

BACKGROUND AND AIMS: Mediterranean diet has been associated with decreased cardiovascular morbidity and mortality. Both fish and olive oil are key components of this diet. Therefore, we compared their effects on nonalcoholic fatty liver disease (NAFLD) and atherogenesis in a mouse model, fed a high fat diet. METHODS AND RESULTS: Forty nine, female LDL receptor knockout (LDLR KO) mice were allocated into 3 groups and fed an atherogenic high fat (HF) diet for 9 weeks. The HF group was fed a high fat diet alone. A HF + OO group was fed a HF diet with added olive oil (60 ml/kg feed), and the third group (HF + FO) was fed a HF diet with added fish oil (60 ml/kg feed). Both additions of fish and olive oil, significantly decreased plasma cholesterol elevation compared to HF diet. Nevertheless, only fish oil addition reduced significantly atherosclerotic lesion area by 51% compared to HF group. Liver levels of eicosapentenoic (EPA) and docosahexaenoic (DHA) acids were several folds higher in HF + FO group than in HF and HF + OO groups. Liver levels of oleic acid were higher in HF + OO compared to the other groups. Moreover, Fish oil addition significantly decreased NAFLD scores related to steatosis and inflammation and lowered the expression of the inflammatory genes interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP1). CONCLUSION: These results suggest that fish oil addition on top of an atherogenic, HF diet, is beneficial, while olive oil is not, in its effect on plaque formation and NAFLD in LDLR KO mice.


Assuntos
Aterosclerose/prevenção & controle , Dieta Hiperlipídica , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Azeite de Oliva/administração & dosagem , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Quimiocina CCL2/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Feminino , Interleucina-6/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ácido Oleico/administração & dosagem , Ácido Oleico/metabolismo , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Tempo
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