RESUMO
BACKGROUND AND AIMS: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis - NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). METHODS: We included 252 liver specimens of NAFLD patients - in whom histological disease ranged from mild to severe - which were linked to clinical and biochemical information. Tissue molecular explorations included MT-CYB sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4-hydroxynonenal - a product of lipid peroxidation and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative damage - were measured. RESULTS: Compared to simple steatosis, NASH is associated with a higher level of MT-CYB variance, 12.1 vs. 15.6 substitutions per 103 bp (P = 5.5e-10). The burden of variants was associated with increased levels of 2-hydroxyglutarate, branched-chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals. CONCLUSION: NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.
Assuntos
Citocromos b/genética , Dano ao DNA , DNA Mitocondrial , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/sangue , Adulto , Idoso , Aldeídos/sangue , Aminoácidos de Cadeia Ramificada/sangue , Progressão da Doença , Ácido Glutâmico/sangue , Glutaratos/sangue , Humanos , Peroxidação de Lipídeos , Pessoa de Meia-Idade , Mutação , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Índice de Gravidade de Doença , TranscriptomaRESUMO
BACKGROUND: Current evidence suggests that lean and obese patients with nonalcoholic fatty liver disease (NAFLD) share an altered metabolic and cardiovascular profile. However, there is an incomplete understanding of the natural history of "lean-NAFLD." Indeed, an unanswered question is whether lean (BMI ≤ 25 Kg/m2 ) NAFLD-patients are protected from severe histological outcomes. AIM: To perform a meta-analysis with the goal of providing a quantitative estimation of the magnitude of fibrosis, as well as histological features associated with the disease severity, in lean versus overweight/obese-NAFLD patients. METHODS: Through a systematic search up to July 2017, we identified eight studies that compared histological outcomes in lean (n = 493) versus overweight/obese (n = 2209) patients. RESULTS: Relative to lean-NAFLD, overweight/obese-NAFLD patients showed significantly (P = .032) higher fibrosis scores; the observed difference in means between the two groups, which is the absolute difference between the mean value of fibrosis score [0-4] ± standard error, was 0.28 ± 0.13. The risk of having nonalcoholic steatohepatitis-NASH (OR 0.58 95% CI 0.34-0.97) was significantly lower in lean-NAFLD (n = 322) than in overweight/obese-NAFLD (n = 1357), P = .04. Relative to lean-NAFLD, overweight/obese-NAFLD patients also have significantly greater NAFLD activity (difference in means ± SE: 0.58 ± 0.16, P = .0004) and steatosis (difference in means ± SE: 0.23 ± 0.07, P = .002) scores. CONCLUSIONS: Lean-NAFLD patients tend to show less severe histological features as compared to overweight/obese-NAFLD patients. Subsequent longitudinal assessment is needed to understand the clinical impact of these findings; however, the significant ~ 25% increment of mean fibrosis score in overweight/obese patients suggests that obesity could predict a worse long-term prognosis.
Assuntos
Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Sobrepeso/complicações , Índice de Massa Corporal , Humanos , Fígado/patologiaRESUMO
BACKGROUND: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is closely associated with the co-occurrence of multiple pathological conditions characterising the metabolic syndrome (MetS), obesity in particular. However, NAFLD also develops in lean subjects, whose risk factors remain poorly defined. METHODS: We performed a meta-analysis of 15 studies, along with the data pertaining to our own population (n=336 patients). Data from lean (n=1966) and obese (n=5938) patients with NAFLD were analysed; lean (n=9946) and obese (n=6027) subjects without NAFLD served as controls. RESULTS: Relative to the lean non-NAFLD controls, lean patients with NAFLD were older (3.79±0.72 years, P=1.36×10-6 ) and exhibited the entire spectrum of the MetS risk factors. Specifically, they had a significant (P=10-10 ) increase in plasma glucose levels (6.44±1.12 mg/dL) and HOMA-IR (0.52±0.094-unit increment), blood lipids (triglycerides: 48.37±3.6, P=10-10 and total cholesterol: 7.04±3.8, mg/dL, P=4.2×10-7 ), systolic (5.64±0.7) and diastolic (3.37±0.9) blood pressure (mm Hg), P=10-10 , and waist circumference (5.88±0.4 cm, P=10-10 ); values denote difference in means±SE. Nevertheless, the overall alterations in the obese group were much more severe when compared to lean subjects, regardless of the presence of NAFLD. Meta-regression suggested that NAFLD is a modifier of the level of blood lipids. CONCLUSION: Lean and obese patients with NAFLD share a common altered metabolic and cardiovascular profile. The former, while having normal body weight, showed excess of abdominal adipose tissue as well as other MetS features.
Assuntos
Síndrome Metabólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/epidemiologia , Fatores Etários , Glicemia , Pressão Sanguínea , Índice de Massa Corporal , Colesterol/sangue , Humanos , Lipídeos/sangue , Fatores de Risco , Circunferência da CinturaRESUMO
Shortened leukocyte telomere length (LTL) is a novel biomarker for age and age-related diseases. Several epidemiological studies have examined the association between telomere length in surrogate tissues (for example, blood cells) and hypertension, and meanwhile the majority of studies reported an association some individual studies do not. We carried out a systematic review and meta-analysis to address the hypothesis that, in humans, telomere length is related with hypertension. Searches were conducted in Pubmed by September 2015 and reference lists of retrieved citations were hand searched. Eligible studies measured telomeres for both hypertensive and normotensive subjects. No restrictions were placed on sample size, publication type, age or gender. We calculated summary estimates using fixed and random effects meta-analysis. Publication bias and heterogeneity among studies were further tested. Meta-analyses from 3097 participants (1415 patients with hypertension and 1682 control subjects) showed a significant standardized mean difference between LTL in hypertensive patients and controls, either in the fixed (P<5 × 10-6) or the random model (P<0.005). Heterogeneity among studies was substantial (Q-statistic P-value <0.001, I2 97.73%). Sensitivity analysis indicated that no single study changed the standardized mean difference qualitatively (0.022> random model P-value >0.002). Egger's test for asymmetry of effect sizes (intercept±s.e.=-7.278±3.574; P=0.072) did not show evidence for strong study publication bias. Leukocyte telomeres may be shorter in hypertensive than in normotensive individuals. Larger studies controlling for confounder effects are needed to confirm these findings and further explore sources of heterogeneity.
Assuntos
Hipertensão/fisiopatologia , Homeostase do Telômero , Humanos , LeucócitosRESUMO
BACKGROUND: Previous epidemiological studies suggest that patients diagnosed with nonalcoholic fatty liver disease (NAFLD) who drink light to moderate amounts of alcohol (up to ~30 g per day) have less severe histological lesions compared with nondrinkers. However, while the cross-sectional nature of current evidence precludes assessment of causality, cumulative lifetime-exposure of moderate alcohol consumption on histological outcomes has never been evaluated. AIM: To overcome these limitations, a Mendelian randomisation study was performed using a validated genetic variant (rs1229984 A;G) in the alcohol dehydrogenase (ADH1B) gene as a proxy of long-term alcohol exposure. METHODS: We first assessed whether the instrumental variant (rs1229984) was associated with the amount of alcohol consumption in our cohort. We further explored the association between the variant and histological outcomes; a sample of 466 individuals, including 266 patients with NAFLD confirmed by liver biopsy, was studied. RESULTS: We found that carriers of the A-allele consumed significantly lower amounts of alcohol compared with noncarriers (2.3 ± 5.3 vs. 8.18 ± 21 g per day, mean ± s.d., P = 0.03). The analysis of association with the disease severity showed that carriers of the A-allele had lower degree of histological steatosis (1.76 ± 0.83 vs. 2.19 ± 0.78, P = 0.03) and lower scores of lobular inflammation (0.54 ± 0.65 vs. 0.95 ± 0.92, P = 0.02) and NAFLD-Activity Score (2.9 ± 1.4 vs. 3.7 ± 1.4, P = 0.015) compared with noncarriers. CONCLUSION: Mendelian randomisation analysis suggests no beneficial effect of moderate alcohol consumption on NAFLD disease severity.
Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Adulto , Idoso , Alelos , Biópsia , Feminino , Variação Genética , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The xenobiotic nuclear pregnane X receptor is implicated in many physiological pathways and diseases, including bile acid detoxification and cholestasis. Aim To estimate the contribution of common gene variants of the xenobiotic receptor (pregnane X receptor, PXR) to genetic susceptibility to intrahepatic cholestasis of pregnancy. METHODS: A total of 101 intrahepatic cholestasis of pregnancy patients and 171 healthy pregnant women in the third trimester of their pregnancies were included. Four tag single nucleotide polymorphisms (SNPs) (rs12488820 C/T, rs2472671 C/T, rs2461823 A/G, and rs1054191 A/G) encompassing 36 kb in chromosome 3, with a minor allele frequency > or =0.10 and representing 33 polymorphic sites were genotyped. Besides these, three additional SNPs (rs3814057, rs6785049, and rs7643645) were included because they showed previous evidence of functionality. RESULTS: Genotypic test for single SNPs showed that rs2461823 genotypes were significantly associated with intrahepatic cholestasis of pregnancy (P < 0.0069), OR per G allele: 1.44, 95% CI: 1.01-2.05, P < 0.042. The Cochran-Armitage test for trend and the allelic test showed a significant association with disease status (P < 0.04 and 0.03 respectively), G being the risk allele. A positive association between rs2461823 and ALT, AST, and bilirubin concentrations was observed. Neonate birth weight adjusted by the Capurro index was significantly associated with rs2461823 (P < 0.05); the proportion of the total variation attributed to rs2461823 genotypes was 7.8%. CONCLUSION: Common PXR polymorphisms may contribute to the genetic susceptibility to intrahepatic cholestasis of pregnancy.
Assuntos
Colestase Intra-Hepática/genética , Variação Genética , Complicações na Gravidez/genética , Receptores de Esteroides/genética , Adulto , Análise de Variância , Ácidos e Sais Biliares/metabolismo , Peso ao Nascer , Colestase Intra-Hepática/epidemiologia , Colestase Intra-Hepática/metabolismo , Cromossomos Humanos Par 3/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/epidemiologia , Idade Gestacional , Homeostase , Humanos , Incidência , Recém-Nascido , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/metabolismo , Terceiro Trimestre da Gravidez , Receptor de Pregnano X , Estações do Ano , América do Sul/epidemiologia , XenobióticosRESUMO
AIM: We performed a systematic review of the literature by means of a meta-analysis to evaluate the influence of the aldosterone synthase gene (CYP11B2) C-344T polymorphism on left ventricular mass (LVM) and related phenotypes. DESIGN: From 485 reports, we included 14 studies about the association between the C-344T variant and left ventricular mass and left ventricular structure-related phenotypes, from which information about number of subjects in each category, outcomes data and genotyping performed with a validated molecular method could be extracted. Fixed and random effect models were used to pool data from individual studies, and the results in the abstract show the extreme genotype comparison, homozygous TT vs homozygous CC. RESULTS: From a total of 2157 subjects, we found no significant association between LVM and the C-344T variant (D: 0.049, 95% CI: 0.091 to 0.179, p = 0.462). Similarly, no significant association was found for interventricular septal-wall thickness (D: 0.027, 95% CI: -0.090 to 0.143, p = 0.654, n: 2105). However, homozygous TT hypertensive subjects had increased LVM (D: 0.251, 95% CI: 0.020 to 0.481, p = 0.04, n: 332). Lastly, in 10 homogeneous studies posterior wall thickness (PWT) was lower in homozygous CC individuals (D: 0.142, 95% CI: 0.016 to 0.268, p = 0.028, n = 1994). CONCLUSION: Independently of hypertension, homozygous individuals for the -344T allele may have 2.4% higher PWT compared to homozygous subjects for the C-344 allele. Besides, homozygous hypertensive TT subjects show a 6.9% increase in LVM compared to CC homozygous subjects.
Assuntos
Citocromo P-450 CYP11B2/genética , Hipertrofia Ventricular Esquerda/genética , Diástole , Predisposição Genética para Doença , Genótipo , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/patologia , Humanos , Hipertensão/genética , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , SístoleRESUMO
OBJECTIVE: The major function of the circadian system is the internal cycling of physiological and metabolic events. The present study sought to explore the effect of rotating shift work schedule on leucocyte count and its relationship with risk factors of metabolic syndrome (MS). DESIGN AND PARTICIPANTS: From a population-based design, 1351 men of self-reported European ancestry were included in a cross-sectional study: 877 day workers were compared with 474 rotating shift workers. Medical history, health examination including anthropometric and arterial blood pressure measurements, a questionnaire on health-related behaviours and biochemical determinations was given to all participants. RESULTS: In comparison with day workers, rotating shift workers had elevated (mean +/- SE) body mass index (27.1 +/- 0.3 vs. 26.3 +/- 0.2, P < 0.0154), waist-hip ratio (0.95 +/- 0.01 vs. 0.93 +/- 0.01, P < 0.00024), diastolic arterial blood pressure (78 +/- 1 vs. 76 +/- 1, P < 0.033), fasting insulin (65.5 +/- 2.9 vs. 55.9 +/- 1.9 pmol L(-1), P < 0.017), Homeostasis Model Assessment index (2.12 +/- 0.11 vs. 1.77 +/- 0.07, P < 0.0027), triglycerides (1.71 +/- 0.1 vs. 1.5 +/- 0.1 mmol L(-1), P < 0.002), uric acid (292.7 +/- 2.8 vs. 282 +/- 3.4 micromol L(-1), P < 0.01) and leucocyte count (7030 +/- 84 vs. 6730 +/- 58, P < 0.0094). In multiple regression analysis, leucocyte count was correlated with rotating shift work independently of age, smoking, education and components of MS. CONCLUSION: The odds ratio for MS in rotating shift workers compared with day workers was 1.51 (95% CI 1.01-2.25), independently of age and physical activity. Increased leucocyte count, a biological marker of systemic inflammation, was associated with rotating shift work.