非酒精性脂肪性肝炎的临床病理研究

目的：探讨非酒精性脂肪性肝炎（Nonalcoholic steatohepatitis,NASH)的临床和病理学特征。方法：对40例NASH患者的临床资料和穿刺肝组织进行临床和病理学分析,并与酒精性脂肪性肝炎（Alcoholic steatohepatitis,ASH)和丙型肝炎（HCV）患者各20例作对照。结果：90％ NASH患者肥胖（P＜0．01）,血浆总蛋白平均水平高于ASH（P＜0．05）,血清ALT、AST、GGT、TBA、TG平均水平分别是正常范围上限值的2．6、1．5、1．2、1．3倍,但白蛋白水平是正常范围下限值的0．96倍。NASH的组织学改变类似ASH,但有些组织学改变如脂肪变性、汇管区的炎症程度,Mallory小体和空泡状核的出现频率等两者间存在着差异性（P＜0．05或P＜0．01）。NASH有其相对的病理特征：大小泡混合型脂肪变性,以大泡为主;肝组织气球样变性,小叶中央区较常见,气球样变性的细胞胞浆内常常有嗜碱性的细颗粒;肝小叶内炎症,不典型的Mallory小体,汇管区周围易见空泡状核细胞。多数NASH患者的肝小叶中央区（腺泡Ⅲk带）有不同程度的窦周纤维化。结论：结果显示NASH有一些相对的临床和病理学特征,临床、病理及实验室检查相结合能对NASH作出肯定的诊断,其中病理活检仍然是诊断NASH的“金标准”。     

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.     

SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR

Farnesoid X receptor(FXR) is widely accepted as a promising target for various liver diseases; however, panels of ligands in drug development show limited clinical benefits, without a clear mechanism. Here, we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury, which represents the major culprit that limits the clinical benefits of FXR agonists against liver diseases. Up...     

非酒精性脂肪性肝炎发病中抵抗素对肝细胞的致炎作用

目的 探讨抵抗素在非酒精性脂肪性肝炎(NASH)发病中对肝细胞的致炎作用及其分子机制. 方法制作NASH大鼠模型,分别应用荧光实时定量PCR和免疫组织化学染色的方法检测NASH大鼠肝组织抵抗素的表达.体外培养AML～12小鼠肝细胞株,用重组抵抗素或细菌脂多糖处理后48 h,检测细胞培养上清液中肿瘤坏死因子α,白细胞介素6含量的变化,用免疫荧光染色观察肝细胞核因子κB的核转位.采用Student-Newman-Keuls法进行组间比较.结果 NASH大鼠肝组织表现出明显脂肪变性、小叶内炎症和窦周纤维化,随造模时间的延长,抵抗素mRNA和蛋白表达逐渐增强,在造模12周及16周,抵抗索mRNA的表达分别为对照组的2.5倍和4.0倍,抵抗素蛋白的表达主要集中在肝组织中央静脉周围.用重组抵抗素处理AML-12细胞48 h后,细胞培养上清液中肿瘤坏死因子α,白细胞介素6的浓度分别为(1.856±0.049)pg/ml和(9.463±1.216)pg/ml,与脂多糖处理组[(1.791±0.046)pg/ml和(8.738±1.101)pg/ml]比较,差异无统计学意义,但二者均显著高于正常对照组[(1.310±0.038)pg/ml和(3.260±0.213)pg/ml],P＜0.01;用重组抵抗素或脂多糖处理AML-12细胞3 h观察到细胞核因子κB p65的核转位.结论 抵抗素是NASH发病中重要的致炎因子之一,其可以通过核因子κB途径诱导肝细胞产生肿瘤坏死因子α、白细胞介素6等炎性细胞因子,导致肝组织的炎症反应.     

水飞蓟素对非酒精性脂肪性肝炎大鼠小肠组织抗氧化作用的实验研究

目的探讨水飞蓟素对NASH大鼠小肠组织氧化应激损伤的影响。方法 50只Wistar大鼠被随机分为对照组、模型组和水飞蓟素干预组;对照组（10只）用普通饲料喂养,模型组（20只）通过高脂饮食建立NASH模型,水飞蓟素组（20只）给予高脂饮食加水飞蓟素灌胃,12周后评估。结果模型组较正常对照组大鼠血清TG、TC、ALT、AST水平明显升高（P〈0.01）,水飞蓟素组TG、TC、ALT、AST水平较模型组降低,差别有统计学意义（F=36.626～64.327,P〈0.01）;模型组大鼠较正常对照组小肠组织匀浆SOD活性明显降低（83.29±10.32U/mgprot对52.34±7.09U/mgprot）,MDA含量明显升高（0.56±0.07 Nmol/mgprot对0.97±0.09 Nmol/mgprot）,水飞蓟素组SOD活性较模型组有所升高,MDA水平下降,差异有统计学意义（F=23.488和10.609,P〈0.05）;内毒素水平为模型组（0.316±0.020EU/ml）〉水飞蓟素组（0.279±0.022EU/ml）〉正常对照组（0.234±0.021EU/ml）s;IgA水平为模型组〈水飞蓟素组〈正常对照组。结论抗氧化剂水飞蓟素不仅能提高肝脏本身的抗氧化能力,亦可以通过提高肠道抗氧化能力进而加强肠道的屏障作用。