RESUMEN

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) has a growing epidemiologic and economic burden. It is associated with Western diet (WD) patterns, and its pathogenesis involves metabolic disorders (obesity, dyslipidemia, hyperglycemia, and diabetes) and gut dysbiosis, features that are usually neglected or not reproduced by most animal models. Thus, we established a 6-mo WD-induced NAFLD mouse model associated with metabolic disorder, investigating its main features at the gut microbiome-liver-adipose tissue axis, also evaluating the correlations of gut dysbiosis to the other disease outcomes. METHODS: Male C57 BL6 mice received a high-fat (30% lard and 0.2% cholesterol, ∼57% calories) and sucrose-rich (20%) chow, and a high-sugar solution (23.1 and 18.9 g/L of D-fructose and D-glucose) for 6 mo. RESULTS: The model featured high serum cholesterol levels, glucose intolerance, and hyperinsulinemia. WD intervention resulted in extensive macro/microvesicular liver steatosis and pericellular fibrosis-resembling human disease-accompanied by hepatic stellate cell activation and CD68+ macrophage infiltration, increased protein levels of proinflammatory p65-nuclear factor-κB, interleukin-6 and tumor necrosis factor-α, with decreased antioxidant regulator Nrf2. Mice showed clear obesity with adipocyte hypertrophy, and CD68+macrophage/mast cell infiltration in adipose tissue while a reduction in number of goblet cells was also observed in the small intestine. Moreover, the pyrosequencing of the 16 S ribosomal RNA of gut cecal content showed decreased bacterial diversity, enriched Firmicutes and Proteobacteria, decreased Bacteroidetes and Fusobacteria, and increased ratio of Firmicutes to Bacteroidetes. Bacteroidetes and Bacteroides had the highest number of significant correlations with liver-adipose tissue axis outcomes. In silico analysis of gut microbiome in NAFLD obese patients revealed a depletion in Bacteroides, which also correlated to disease outcomes. CONCLUSION: This mice model gathered suitable phenotypical alterations in gut-liver-adipose tissue axis that resembled NAFLD associated with metabolic disorders in humans and may be considered for preclinical investigation.

Asunto(s)

Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Dieta Occidental/efectos adversos , Microbioma Gastrointestinal/fisiología , Disbiosis/metabolismo , Hígado/metabolismo , Obesidad/etiología , Modelos Animales de Enfermedad , Tejido Adiposo/metabolismo , Bacteroides , Colesterol , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL

RESUMEN

PURPOSE: The constitutive elements of the metabolic syndrome (MetS) are linked with both non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease. Controlled attenuation parameter (CAP), and vibration controlled transient elastography (VCTE), are able to detect and quantify NAFLD, while conventional and two-dimensional speckle tracking echocardiography (2D-STE) is capable to identify subclinical changes in cardiac function. We wanted to evaluate whether there is any correspondence between left ventricular (LV) diastolic dysfunction and different degrees of liver steatosis and fibrosis in MetS subjects with NAFLD. PATIENTS AND METHODS: A total of 150 adult subjects having MetS and a normal left ventricular (LV) systolic function were recorded in the study, while 150 age- and sex- matched adults without MetS were enrolled as controls. NAFLD was established by VCTE and CAP. The left heart systolic and diastolic function was evaluated by conventional and 2D-ST echocardiography. Left atrial (LA) stiffness was calculated as the ratio between the E/A ratio and the LA reservoir-strain. RESULTS: In univariate regression analysis, the variables associated with LV diastolic dysfunction in MetS patients were: liver steatosis grade ≥2, liver fibrosis grade ≥2, the longitudinal LA peak strain during the reservoir phase, the LA strain rate during ventricular contraction and the LA stiffness. In multivariate logistic regression, two variables were selected as independent predictors of LV diastolic dysfunction, namely the liver stiffness (P=0.0003) and the LA stiffness (P<0.0001). LA stiffness predicted subclinical LV diastolic dysfunction in MetS patients with a sensitivity of 45% and a specificity of 96% when using a cut-off value >0.38, and was significantly correlated with liver steatosis stage ≥2 and liver fibrosis stage ≥2. CONCLUSION: The present study confirms the association between liver stiffness, LA stiffness and LV diastolic dysfunction in MetS patients. Our study suggests that liver elastography and 2D-STE should become habitual assessments in MetS patients.

RESUMEN

PURPOSE: The components of metabolic syndrome (MS) are risk factors for developing both cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). Strain (SI) and strain­rate imaging (SRI) are able to recognize early changes in cardiac function. Vibration-controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) detect and quantify liver fibrosis and steatosis. We aimed to assess whether there is any correlation between liver fibrosis and steatosis and left ventricular (LV) dysfunction in MS patients. PATIENTS AND METHODS: A total of 150 adults with MS were registered in the study. They were compared with a control group of 150 age- and sex-matched adults without MS. After the classic echocardiographic assessment of LV function, two-dimensional speckle echocardiography (2D-STE) was used to evaluate LV peak systolic strain (S) and peak systolic strain rate (SR), while liver steatosis and fibrosis were evaluated by VCTE and CAP. RESULTS: LV diastolic dysfunction was significantly more frequent among the patients with MS. We found significant differences between the two groups regarding the presence of subtle LV systolic dysfunction, detected by reduced values of S and SR. The risk for LV diastolic dysfunction was 3.6 times higher in MS with severe steatosis and 8 times higher in patients with severe fibrosis, P<0.0001. The risk for LV systolic dysfunction was double in MS with severe steatosis and 1.7 times higher in MS with severe fibrosis, P<0.0001. CONCLUSION: In MS patients with normal LV ejection fraction, conventional echocardiography parameters identified diastolic LV dysfunction, while SI and SRI identified subtle impairment of systolic LV dysfunction. The presence of hepatic steatosis and fibrosis increases significantly the risk for cardiac dysfunction in MS patients (P<0.0001).