Methodist Hospital Research Institute, Center for Diabetes Research, Weill Cornell Medical College, Houston, TX 77030, USA.
Hepatology. 2010 Dec;52(6):2001-11. doi: 10.1002/hep.23941. Epub 2010 Oct 11.
Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity that can progress to nonalcoholic steatohepatitis (NASH), a serious liver pathology that can advance to cirrhosis. The mechanisms responsible for NAFLD progression to NASH remain unclear. Lack of a suitable animal model that faithfully recapitulates the pathophysiology of human NASH is a major obstacle in delineating mechanisms responsible for progression of NAFLD to NASH and, thus, development of better treatment strategies. We identified and characterized a novel mouse model, middle-aged male low-density lipoprotein receptor (LDLR)(-/-) mice fed a high-fat diet (HFD), which developed NASH associated with four of five metabolic syndrome (MS) components. In these mice, as observed in humans, liver steatosis and oxidative stress promoted NASH development. Aging exacerbated the HFD-induced NASH such that liver steatosis, inflammation, fibrosis, oxidative stress, and liver injury markers were greatly enhanced in middle-aged versus young LDLR(-/-) mice. Although expression of genes mediating fatty acid oxidation and antioxidant responses were up-regulated in young LDLR(-/-) mice fed HFD, they were drastically reduced in MS mice. However, similar to recent human trials, NASH was partially attenuated by an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPARγ) ligand, rosiglitazone. In addition to expected improvements in MS, newly identified mechanisms of PPARγ ligand effects included stimulation of antioxidant gene expression and mitochondrial β-oxidation, and suppression of inflammation and fibrosis. LDLR-deficiency promoted NASH, because middle-aged C57BL/6 mice fed HFD did not develop severe inflammation and fibrosis, despite increased steatosis.
MS mice represent an ideal model to investigate NASH in the context of MS, as commonly occurs in human disease, and NASH development can be substantially attenuated by PPARγ activation, which enhances β-oxidation.
非酒精性脂肪性肝病（NAFLD）是肥胖的常见并发症，可进展为非酒精性脂肪性肝炎（NASH），这是一种严重的肝脏病理，可进展为肝硬化。导致 NAFLD 进展为 NASH 的机制尚不清楚。缺乏能够忠实地再现人类 NASH 病理生理学的合适动物模型是阐明导致 NAFLD 进展为 NASH 的机制以及因此开发更好的治疗策略的主要障碍。我们鉴定并表征了一种新型小鼠模型，即中年雄性低密度脂蛋白受体（LDLR）（-/-）小鼠，用高脂肪饮食（HFD）喂养，该模型发展为与五种代谢综合征（MS）成分中的四种相关的 NASH。在这些小鼠中，与人类一样，肝脏脂肪变性和氧化应激促进了 NASH 的发展。衰老加剧了 HFD 诱导的 NASH，使得中年 LDLR（-/-）小鼠的肝脂肪变性、炎症、纤维化、氧化应激和肝损伤标志物大大增强。尽管年轻的 LDLR（-/-）小鼠喂食 HFD 时介导脂肪酸氧化和抗氧化反应的基因表达上调，但在 MS 小鼠中却急剧减少。然而，与最近的人类试验类似，胰岛素增敏过氧化物酶体增殖物激活受体-γ（PPARγ）配体罗格列酮部分减轻了 NASH。除了 MS 的预期改善外，PPARγ 配体作用的新机制还包括刺激抗氧化基因表达和线粒体β-氧化，以及抑制炎症和纤维化。LDLR 缺陷促进了 NASH 的发生，因为用 HFD 喂养的中年 C57BL/6 小鼠尽管脂肪变性增加，但并未发生严重的炎症和纤维化。
MS 小鼠是研究 MS 背景下 NASH 的理想模型，因为这在人类疾病中很常见，并且 PPARγ 激活可显著减轻 NASH 的发展，增强β-氧化。
