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Aims: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects adipose function. This study aimed to explore the function of adipocytes-derived exosomal (ADEs) miR-122 in NAFLD. Methods: A high-fat and high-fructose diet-induced rat model and a palmitic acid (PA)-induced in vitro model were established. The RNA level of miR-122 and Sirt1 was measured using qRT-PCR. The protein levels of exosome biomarkers, and lipogenesis, inflammation and fibrosis biomarkers were determined by western blotting. Cell viability and apoptosis were assessed using cell counting kit-8 and flow cytometry, respectively. Serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride levels were measured. Liver tissue damage was assessed using haematoxylin and eosin staining. The interaction between miR-122 and Sirt1 3′UTR was assessed using a luciferase reporter gene assay. Results: ADEs exhibited abundant level of miR-122 and promoted lipogenesis, impaired hepatocyte survival, enhanced liver damage and increased serum lipid levels in vivo and in vitro. Inhibition of miR-122 in ADEs alleviated NAFLD progression, lipid and glucose metabolism, liver inflammation and fibrosis both in vivo and in vitro. miR-122 binds directly to the 3′UTR of Sirt1 to suppress its expression. Moreover, Sirt1 overexpression reversed the increase in cell apoptosis, glucose and lipid metabolism, liver inflammation and fibrosis induced by ADEs in vivo and in vitro. Conclusions: The ADEs miR-122 promotes the progression of NAFLD via modulating Sirt1 signalling in vivo and in vitro. The ADEs miR-122 may be a promising diagnostic biomarker and therapeutic target for NAFLD.(AU)

Objetivos: La enfermedad del hígado graso no alcohólico (EHGNA) es una enfermedad hepática crónica que afecta a la función adiposa. Este estudio tiene como objetivo explorar la función de los exosomas derivados de los adipocitos (ADEs) miR-122 en la EHGNA. Métodos: Se estableció un modelo de rata inducido por una dieta alta en grasas y fructosa y un modelo in vitro inducido por ácido palmítico (AP). Se midió el nivel de ARN de miR-122 y Sirt1 mediante qRT-PCR. Los niveles de proteína de los biomarcadores de exosomas y los biomarcadores de lipogénesis, inflamación y fibrosis se determinaron mediante western blotting. La viabilidad celular y la apoptosis se evaluaron mediante el kit de recuento de células-8 y la citometría de flujo, respectivamente. Se midieron los niveles séricos de alanina aminotransferasa, aspartato aminotransferasa, colesterol total y triglicéridos. El daño tisular del hígado se evaluó mediante tinción con hematoxilina y eosina. La interacción entre miR-122 y Sirt1 3’UTR se evaluó mediante un ensayo de gen reportero de luciferasa. Resultados: Los ADEs mostraron un nivel abundante de miR-122 y promovieron la lipogénesis, perjudicaron la supervivencia de los hepatocitos, potenciaron el daño hepático y aumentaron los niveles de lípidos séricos in vivo e in vitro. La inhibición de miR-122 en los ADEs alivió la progresión de la EHGNA, el metabolismo de los lípidos y la glucosa, la inflamación del hígado y la fibrosis tanto in vivo como in vitro. miR-122 se une directamente a la 3’UTR de Sirt1 para suprimir su expresión. Además, la sobreexpresión de Sirt1 revirtió el aumento de la apoptosis celular, el metabolismo de la glucosa y los lípidos, la inflamación del hígado y la fibrosis inducida por los ADEs in vivo e in vitro. Conclusiones: El ADEs miR-122 promueve la progresión de la EHGNA a través de la modulación de la señalización de Sirt1 in vivo e in vitro...(AU)

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AIMS: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects adipose function. This study aimed to explore the function of adipocytes-derived exosomal (ADEs) miR-122 in NAFLD. METHODS: A high-fat and high-fructose diet-induced rat model and a palmitic acid (PA)-induced in vitro model were established. The RNA level of miR-122 and Sirt1 was measured using qRT-PCR. The protein levels of exosome biomarkers, and lipogenesis, inflammation and fibrosis biomarkers were determined by western blotting. Cell viability and apoptosis were assessed using cell counting kit-8 and flow cytometry, respectively. Serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride levels were measured. Liver tissue damage was assessed using haematoxylin and eosin staining. The interaction between miR-122 and Sirt1 3'UTR was assessed using a luciferase reporter gene assay. RESULTS: ADEs exhibited abundant level of miR-122 and promoted lipogenesis, impaired hepatocyte survival, enhanced liver damage and increased serum lipid levels in vivo and in vitro. Inhibition of miR-122 in ADEs alleviated NAFLD progression, lipid and glucose metabolism, liver inflammation and fibrosis both in vivo and in vitro. miR-122 binds directly to the 3'UTR of Sirt1 to suppress its expression. Moreover, Sirt1 overexpression reversed the increase in cell apoptosis, glucose and lipid metabolism, liver inflammation and fibrosis induced by ADEs in vivo and in vitro. CONCLUSIONS: The ADEs miR-122 promotes the progression of NAFLD via modulating Sirt1 signalling in vivo and in vitro. The ADEs miR-122 may be a promising diagnostic biomarker and therapeutic target for NAFLD.

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Our previous study reported a method of using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to analyze the association between abnormal fucosylation of serum glycoproteins and the progression of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). In the present study, the aforementioned method was improved by focusing on fucosylated glycoproteins <10 kD, classification models were established and blind tests were performed on an enlarged sample size (n=299). According to the present results, the classification models had a sensitivity and specificity of 74.31 and 76.32%, respectively, to identify HCC among all serum samples, 81.65 and 83.08%, respectively, to distinguish HCC from HBV-associated cirrhosis and chronic hepatitis Band 88.99 and 84.62%, respectively, to distinguish HCC from HBV-associated cirrhosis. When combined with α-fetoprotein (AFP) measurements (AFP >20 ng/ml), the sensitivity and specificity of the models were significantly elevated to 80.73 and 87.37%, 87.16 and 90.00%, and 92.66 and 93.84%, respectively. In addition, the HBV-HCC vs. HBV-cirrhosis classification model was used to analyze serum samples collected from 9 patients with cirrhosis 1 year before they were diagnosed with HCC, and from 6 patients who had cirrhosis but developed no signs of HCC for the following 3 years. The model identified 7 patients (77.78%) with no significant clinical symptoms of HCC, and gave no false positive results, demonstrating that the classification models established in the present study may be useful for the early diagnosis of HCC. After isolation and purification, two proteins with differential expression were identified as isoform 1 of inter-α-trypsin inhibitor heavy chain 4 precursor, and thymosin ß-4-like protein 3. These may be used as candidate markers for HCC diagnosis. Additionally, the present study indicates that defucosylation of serum glycoproteins may occur during the development and progression of HCC.

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Exercise training can reduce hepatic fat accumulation and cardiovascular risk among patients with non-alcoholic fatty liver disease (NAFLD), but how long these benefits extend beyond the period of active intervention is unclear. Intrahepatic triglyceride (IHTG) content, measured by proton magnetic resonance spectroscopy, and metabolic risk factors among 220 obese people with NAFLD, who were randomly assigned to vigorous/moderate exercise, moderate exercise or no exercise (control), were assessed at 1 year after the 12-month exercise intervention. IHTG content was significantly reduced in the 2 exercise groups compared with the control group over the 12-month active intervention. It was significantly lower (by -2.39%) in the vigorous/moderate exercise group compared with the control group at the 1-year follow-up (95% confidence interval -4.72 to -0.05%; P = .045). Waist circumference and blood pressure remained significantly lower in the vigorous/moderate exercise group and the moderate exercise group compared with the control group at the 1-year follow-up. Visceral adipose fat remained significantly reduced, but with no differences among 3 groups. These findings suggest 12-month exercise intervention induced reductions in hepatic fat accumulation, abdominal obesity and blood pressure for up to 1 year after the active intervention, with some attenuation of the benefits.

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Individuals with metabolically healthy obesity (MHO) are at relatively low risk for the development of metabolic abnormalities and subclinical atherosclerosis. This study aims to examine whether hepatic fat accumulation determines metabolic phenotype of obesity and associated with subclinical atherosclerosis. A total of 485 obese adults (aged 40-65 years) who received magnetic resonance spectroscopy were divided into metabolically abnormally obesity (MAO) and MHO groups according to metabolic status. MHO individuals had lower levels of intrahepatic triglyceride (IHTG) content and carotid intima-media thickness (CIMT) than MAO individuals. In multivariable linear regression analyses, IHTG content was independently associated with metabolic syndrome components and CIMT. Based on receiver operating characteristic curve analysis, the IHTG content displayed a higher area under the curve (AUC) for detecting the MAO phenotype (AUC = 0.70, 95%CI = 0.65-0.75) and increased CIMT (AUC = 0.60, 95%CI = 0.54-0.66) than BMI, waist circumference, and body fat percent. MHO individuals were 1.9 times (p < 0.001) more likely to have metabolic syndrome per 1 SD change in IHTG content in multivariable-adjusted models. Likewise, the risk for high CIMT increased 29% per 1 SD change in IHTG content [OR (95% CI):1.29(1.01-1.64)]. These findings suggest that hepatic fat is a potential predictor of metabolically unhealthy obesity phenotype and subclinical atherosclerosis.

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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are associated with some common critical cardio-metabolic risk factors. The aim of this study was to explore the association between intrahepatic triglyceride (IHTG) content and CKD in obese subjects. METHODS: A total of 1068 obese participants received anthropometric, biochemical measurements and hepatic ultrasonography. Of those, 485 participants received magnetic resonance spectroscopy ((1)H-MRS) for the determination of IHTG content. CKD was defined as a urinary albumin:creatinine ratio (UACR)≥30 mg/g and/or estimated glomerular filtration rate (eGFR)<60 mL/min per 1.73 m(2). RESULTS: The prevalence of CKD was significantly higher in NAFLD subjects compared to subjects without NAFLD, while the prevalence of CKD was gradually increased as the IHTG content increased by quartiles (P for trend<0.001). After adjustment for multivariate metabolic factors, the risk of abnormal albuminuria and CKD was increased by 68% [OR (95% CI): 1.68 (1.21-2.33), P<0.01] and 54% [OR (95% CI): 1.54 (1.14-2.07), P<0.01] respectively per one standard deviation (SD) increase in IHTG content. The association between IHTG content and CKD was not changed by conventional risk factors, including age, BMI and hypertension (all P<0.05). CONCLUSION: IHTG content is independently associated with CKD in obese adults.

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BACKGROUND AND AIM: Liver enzymes including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) are well recognized as surrogate makers reflecting non-alcoholic fatty liver disease (NAFLD). However, the associations of serum ALT, AST and GGT with hepatic lipid contents are not well established. The aim of this study was to investigate the relationship between liver enzymes and intrahepatic triglyceride (IHTG) contents, and explore the feasibility in using liver enzymes to reflect accumulation of IHTG in obese subjects. METHODS: A cross-sectional analysis was conducted in 475 obese adults aged 40-65 years. Anthropometric parameters and blood biochemical indexes including liver enzymes, glucose and lipid profiles were measured. The liver triglyceride contents of subjects were determined by (1)H-MRS. RESULTS: Serum ALT, AST and GGT were positively correlated with IHTG contents (p < 0.01). Serum ALT, AST and GGT levels at the highest quartile of IHTG contents were significantly elevated as compared with those in the lowest quartile (p < 0.01). Multivariate linear regression analysis demonstrated that serum ALT, but not AST or GGT was independently associated with IHTG contents. By logistic regression analysis, the odds ratio for higher IHTG contents was increased by 1.464 times/1 SD increase in serum ALT level after adjusting for multiple confounding factors [OR (95% CI) 2.464 (1.584-3.834)]. However, these relationships could not be observed between serum AST or GGT with IHTG contents. CONCLUSIONS: Serum ALT level is independently correlated with the hepatic triglyceride contents in obese subjects and more appropriate to be used as a predictor for the degree of NAFLD rather than AST and GGT.

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