Longitudinal characterization of diet-induced genetic murine models of non-alcoholic steatohepatitis with metabolic, histological, and transcriptomic hallmarks of human patients
Longitudinal characterization of diet-induced genetic murine models of non-alcoholic steatohepatitis with metabolic, histological, and transcriptomic hallmarks of human patients
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DOI：
10.1242/bio.041251
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发表时间：
2019-05-01
期刊：
影响因子：
2.4
通讯作者：
Oka, Kozo
中科院分区：
文献类型：
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作者：
Abe, Naomichi;Kato, Sayuka;Oka, Kozo
非酒精性脂肪性肝炎（NASH）是西方世界快速增长的肝脏疾病。目前，只有少数动物模型显示了人类NASH的代谢和组织学特征。我们旨在以时间依赖性方式探索表现出人类NASH的代谢、组织学和转录组学特征的鼠NASH模型。为此，使用鼠品系C57 BL/6 J、ob/ob和KK-A（y），并给予三种类型的营养方案：正常食物饮食（NCD）;高脂肪、高果糖和高胆固醇饮食（快餐饮食; FFD）;或胆碱缺乏、L-氨基酸限定的高脂肪饮食（CDAHFD），持续2、4、8、12、18、24和30周。FFD和CDAHFD方案下的所有菌株均发生脂肪性肝炎。在用FFD处理的品系中，ob/ob小鼠的非酒精性脂肪性肝病（NAFLD）活动评分、纤维化进展和代谢异常（如高胰岛素血症和肥胖）比C57 BL/6 J和KK-A（y）小鼠更明显。在喂食FFD的ob/ob小鼠中，证实了肝冠状结构的发育。此外，参与脂肪性肝炎和纤维化的分子途径显示，早在开始FFD方案的2周内就发生了显著变化。喂食FFD的Ob/ob小鼠表现出与人类NASH相似的代谢、组织学和转录组学功能障碍，这表明它们作为发现NASH新药的实验模型的潜力。
Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disease in the Western world. Currently, only a few animal models show both the metabolic and histological features of human NASH. We aimed to explore murine NASH models in a time dependent manner that exhibit metabolic, histological and transcriptomic hallmarks of human NASH. For this, the murine strains C57BL/6J, ob/ob, and KK-A(y) were used and three types of nutritional regimes were administered: normal chow diet (NCD); high-fat, high-fructose, and high-cholesterol diet (fast food diet; FFD); or choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), for 2, 4, 8, 12,18, 24, and 30 weeks. All strains under the FFD and CDAHFD regimes developed steatohepatitis. Among the strains treated with FFD, the non-alcoholic fatty liver disease (NAFLD) activity score, fibrosis progression and metabolic abnormalities such as hyperinsulinemia and obesity were more pronounced in ob/ob mice than in C57BL/6J and KK-A(y) mice. In ob/ob mice fed FFD, the development of hepatic crown-like structures was confirmed. Furthermore, molecular pathways involved in steatohepatitis and fibrosis showed significant changes from as early as 2 weeks of starting the FFD regime. Ob/ob mice fed FFD showed metabolic, histological, and transcriptomic dysfunctions similar to human NASH, suggesting their potential as an experimental model to discover novel drugs for NASH.