Department of Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.
Gubra, Hørsholm , Denmark.
Am J Physiol Gastrointest Liver Physiol. 2019 Apr 1;316(4):G462-G472. doi: 10.1152/ajpgi.00358.2018. Epub 2019 Jan 17.
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions ranging from simple steatosis (NAFL), over nonalcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis with end-stage disease. The hepatic molecular events underlying the development of NAFLD and transition to NASH are poorly understood. The present study aimed to determine hepatic transcriptome dynamics in patients with NAFL or NASH compared with healthy normal-weight and obese individuals. RNA sequencing and quantitative histomorphometry of liver fat, inflammation and fibrosis were performed on liver biopsies obtained from healthy normal-weight ( n = 14) and obese ( n = 12) individuals, NAFL ( n = 15) and NASH ( n = 16) patients. Normal-weight and obese subjects showed normal liver histology and comparable gene expression profiles. Liver transcriptome signatures were largely overlapping in NAFL and NASH patients, however, clearly separated from healthy normal-weight and obese controls. Most marked pathway perturbations identified in both NAFL and NASH were associated with markers of lipid metabolism, immunomodulation, extracellular matrix remodeling, and cell cycle control. Interestingly, NASH patients with positive Sonic hedgehog hepatocyte staining showed distinct transcriptome and histomorphometric changes compared with NAFL. In conclusion, application of immunohistochemical markers of hepatocyte injury may serve as a more objective tool for distinguishing NASH from NAFL, facilitating improved resolution of hepatic molecular changes associated with progression of NAFLD. NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. NAFLD is associated with the metabolic syndrome and can progress to the more serious form, nonalcoholic steatohepatitis (NASH), and ultimately lead to irreversible liver damage. Using gold standard molecular and histological techniques, this study demonstrates that the currently used diagnostic tools are problematic for differentiating mild NAFLD from NASH and emphasizes the marked need for developing improved histological markers of NAFLD progression.
非酒精性脂肪性肝病 (NAFLD) 代表了一系列从单纯脂肪变性 (NAFL)，到伴有或不伴有纤维化的非酒精性脂肪性肝炎 (NASH)，再到终末期肝硬化的疾病谱。NAFLD 发展和向 NASH 转化的肝脏分子事件尚未完全清楚。本研究旨在比较正常体重和肥胖的健康人群、NAFL 患者和 NASH 患者的肝转录组动态。对取自正常体重 ( n = 14) 和肥胖 ( n = 12) 个体、NAFL ( n = 15) 和 NASH ( n = 16) 患者的肝活检组织进行 RNA 测序和肝脂肪、炎症和纤维化的定量组织形态计量学分析。正常体重和肥胖组的肝组织学正常且基因表达谱相似。NAFL 和 NASH 患者的肝转录组谱有很大的重叠，但与正常体重和肥胖对照组明显分离。在 NAFL 和 NASH 患者中确定的最显著的途径改变与脂质代谢、免疫调节、细胞外基质重塑和细胞周期调控的标志物有关。有趣的是，与 NAFL 相比，具有 Sonic hedgehog 肝细胞染色阳性的 NASH 患者具有明显的转录组和组织形态计量学变化。总之，应用肝细胞损伤的免疫组织化学标志物可能是一种更客观的工具，用于区分 NASH 与 NAFL，有助于更好地确定与 NAFLD 进展相关的肝脏分子变化。
非酒精性脂肪性肝病 (NAFLD) 是西方国家最常见的肝脏疾病。NAFLD 与代谢综合征有关，可进展为更严重的非酒精性脂肪性肝炎 (NASH)，最终导致不可逆转的肝损伤。使用金标准的分子和组织学技术，本研究表明，目前使用的诊断工具在区分轻度 NAFLD 与 NASH 方面存在问题，并强调迫切需要开发用于 NAFLD 进展的改进的组织学标志物。
