人体测量指标预测肥胖儿童非酒精性脂肪肝的研究

目的 研究人体测量指标对儿童肥胖伴非酒精性脂肪肝的预测作用,探讨不同指标筛查非酒精性脂肪肝的切点值。方法 选取自2018年6月—2019年12月在西安交通大学第二附属医院小儿内分泌门诊就诊的94例肥胖儿童为研究对象,进一步分为肥胖伴非酒精性脂肪肝组与肥胖不伴非酒精性脂肪肝组,52例正常儿童为对照组。测量身高(H)、体重(W)、腰围(WC)、臀围(HC)和血甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C);行肝脏B超的检查。计算体质指数(BMI)、腰臀比(WHR)、腰高比(WHtR)、腹部体积指数(AVI)、脂质蓄积指数(LAP)和内脏脂肪指数(VAI)等指标。通过绘制人体测量指标的受试者工作特征曲线(ROC曲线)评估人体测量指标与肥胖儿童非酒精性脂肪肝的相关性,并比较各项人体测量指标的曲线下面积(AUC)确定切点值。结果 肥胖组BMI、WC、WHR、WHtR、AVI、LAP、VAI及TG均高于对照组(t=23.090、21.068、12.547、22.855、17.578、8.159、5.394、6.183,P＜0.001)。肥胖伴非酒精性脂肪肝组BMI、WC、AVI、LAP、VAI均高于肥胖不伴非酒精性脂肪肝组(t=2.180、2.389、2.362、3.643、2.839,P＜0.05)。人体测量指标的ROC曲线下面积按从大到小的顺序依次为 LAP、VAI、 WC、 AVI、 BMI。对肥胖伴非酒精性脂肪肝的联合诊断指标进行筛查效能分析结果显示,LAP+AVI 曲线下面积为0.706(95%CI:0.595~0.817,P＜0.001);AVI+VAI 曲线下面积为0.685(95%CI:0.570~0.800,P＜0.01);BMI+WC 曲线下面积为0.652(95%CI:0.537~0.768,P＜0.05)。联合指标的ROC曲线下面积从大到小为LAP+AVI、AVI+VAI、BMI+WC。结论 LAP联合AVI对儿童肥胖伴非酒精性脂肪肝具有较好的筛查作用。     

Matcha Green Tea Alleviates Non-Alcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice by Regulating Lipid Metabolism and Inflammatory Responses

Lately, matcha green tea has gained popularity as a beverage and food additive. It has proved to be effective in preventing obesity and related metabolic syndromes. However, the underlying mechanisms of its control effects against non-alcoholic fatty liver disease (NAFLD) are complicated and remain elusive. In the present study, we performed an in vivo experiment using male C57BL/6 mice fed with a high-fat diet and simultaneously treated with matcha for six weeks. Serum biochemical parameters, histological changes, lipid accumulation, inflammatory cytokines, and relevant indicators were examined. Dietary supplementation of matcha effectively prevented excessive accumulation of visceral and hepatic lipid, elevated blood glucose, dyslipidemia, abnormal liver function, and steatosis hepatitis. RNA sequencing analyses of differentially expressed genes in liver samples indicated that matcha treatment decreased the activity of lipid droplet-associated proteins and increased the activity of cytochrome P450 enzymes, suggesting improved metabolic capacity and liver function. The current study provided evidence for new dietary strategies based on matcha supplementation to ameliorate lipotoxicity-induced obesity and NALFD.     

唐山市7～14岁肥胖儿童非酒精性脂肪肝流行现状及危险因素初步分析

目的 初步了解唐山市肥胖儿童非酒精性脂肪肝(NAFLD)流行特点及危险因素,为早期干预提供理论依据。方法 以2018—2019年唐山市学龄儿童体检筛查出的肥胖儿童为研究对象,依年龄分组描述NAFLD患病率,比较NAFLD组与非NAFLD组代谢综合征(MetS)、体重指数(BMI)、腰围(WC)、腰围身高比(WHtR)、转氨酶、尿酸(UA)、糖脂代谢等指标,分析NAFLD发生的危险因素。结果 1)唐山市肥胖儿童NAFLD患病率为34.62%,不同性别间差异无统计学意义(χ²=0.009,P=1.000),NAFLD患病率随年龄增加而增高(r=0.425,P<0.001);2)7～9岁NAFLD组脂代谢紊乱患病率、10～14岁NAFLD脂代谢紊乱、高血压、MetS患病率高于非NAFLD组,差异均有统计学意义(χ²=6.159、10.994、5.543、4.524,P<0.05);3)多因素Logistic回归分析显示NAFLD的危险因素为年龄增长(OR=3.91)、高尿酸血症(OR=2.09)、BMI增加(OR=1.07)、ALT升高(OR=1.04)(P<0.05)。结论 唐山市肥胖儿童总体NAFLD患病率处于较高水平,其患病率随年龄增长而增高;肥胖儿童NAFLD与年龄、高尿酸血症、BMI、ALT水平密切相关。     

Nonalcoholic fatty liver disease and risk of prostatic diseases: Roles of insulin resistance

Nonalcoholic fatty liver disease (NAFLD), the liver component of metabolic syndrome, is considered to be associated with high risk of prostatic diseases but a systematic review has not been conducted. Under a comprehensive review of the eligible clinical studies, a potential positive association between NAFLD and benign prostatic hyperplasia/prostate cancer (BPH/PCa) has been postulated. Insulin resistance and metabolic aberrations are considered to be the potential mechanism for such association. However, the relationship between NAFLD and other prostatic diseases, that is, prostatic inflammation and lower urinary tract symptoms, seems vague due to limited relevant studies in the literatures. The present review highlights that clinicians should be conscious of the detrimental effect of NAFLD on the development of BPH and PCa.     

微小RNA-29a通过沉默信息调节因子2相关酶类1基因调控肝细胞脂肪变性的机制

目的探讨人肝细胞株L02脂肪变性时微小RNA-29a(miR-29a)的表达变化及其靶向沉默信息调节因子2相关酶类1(silent mating type information regulation 2 homolog-1,Sirt1)调节脂肪肝细胞脂肪沉积的机制。方法采用油酸和棕榈酸混合物诱导建立非酒精性脂肪肝细胞模型,验证模型成功后,PCR检测miR-29a和Sirt1的表达变化;生物学预测miR-29a的靶基因;分别转染miR-29a模拟物和抑制剂,过表达miR-29a和抑制miR-29a后再建立人脂肪肝细胞模型。油红O染色观察细胞中脂质蓄积情况并测定甘油三酯含量,荧光定量PCR和免疫印迹法检测Sirt1基因和蛋白表达变化。结果脂肪肝细胞模型组miR-29a相对表达量和甘油三酯含量显著高于对照组(P<0.01),Sirt1相对表达量显著低于对照组(P<0.01);生物学预测Sirt1是miR-29a的靶基因,过表达miR-29a后,细胞内脂滴明显增多,脂肪沉积加重,甘油三酯含量显著增加(P<0.05),细胞中miR-29a的表达显著上调(P<0.01),而Sirt1 mRNA表达显著下调(P<0.05),Sirt1蛋白表达呈下降趋势;与之相反,抑制miR-29a后,细胞中脂滴相对减少,脂肪沉积减轻,甘油三酯含量显著下降(P<0.05),细胞中miR-29a的表达被有效抑制(P<0.01),而Sirt1 mRNA的表达显著上调(P<0.05),Sirt1蛋白表达较对照组呈上升趋势。结论 miR-29a在非酒精性脂肪肝细胞中表达显著上调,miR-29a通过表达上调负调控Sirt1表达从而促进脂肪肝细胞中脂肪沉积。     

Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha‐2‐HS‐glycoprotein

Melatonin plays an important role in regulating circadian rhythms. It also acts as a potent antioxidant and regulates glucose and lipid metabolism, although the exact action mechanism is not clear. The α2‐HS‐glycoprotein gene (AHSG) and its protein, fetuin‐A (FETUA), are one of the hepatokines and are known to be associated with insulin resistance and type 2 diabetes. The aim of this study was to determine whether melatonin improves hepatic insulin resistance and hepatic steatosis in a FETUA‐dependent manner. In HepG2 cells treated with 300 μmol/L of palmitic acid, phosphorylated AKT expression decreased, and FETUA expression increased, but this effect was inhibited by treatment with 10 μmol/L of melatonin. However, melatonin did not improve insulin resistance in FETUA‐overexpressing cells, indicating that improvement in insulin resistance by melatonin was dependent on downregulation of FETUA. Moreover, melatonin decreased palmitic acid‐induced ER stress markers, CHOP, Bip, ATF‐6, XBP‐1, ATF‐4, and PERK. In addition, in the high‐fat diet (HFD) mice, oral treatment with 100 mg/kg/day melatonin for 10 weeks reduced body weight gain to one‐third of that of the HFD group and hepatic steatosis. Insulin sensitivity and glucose intolerance improved with the upregulation of muscle p‐AKT protein expression. FETUA expression and ER stress markers in the liver and serum of HFD mice were decreased by melatonin treatment. In conclusion, melatonin can improve hepatic insulin resistance and hepatic steatosis through reduction in ER stress and the resultant AHSG expression.     

Melatonin safeguards against fatty liver by antagonizing TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal‐regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high‐fat diet (HFD)‐induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho‐ASK1, phospho‐MKK3/6, phospho‐p38, phospho‐MKK4/7, and phospho‐JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor‐associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein β‐arrestin‐1 and enabled it to bind to ASK1, which antagonized the TRAFs‐mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of β‐arrestin‐1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner.