PDF(Pubmed)
Abstract：
While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl4), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of α-smooth muscle actin (α-SMA), collagen type I, and TGF-β, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients.
摘要：
虽然肥胖相关的非酒精性脂肪性肝病（NAFLD）与代谢功能障碍有关，如胰岛素抵抗和脂肪组织炎症，瘦NAFLD更经常进展为肝纤维化，即使在没有代谢综合征。这篇综述旨在总结目前有关瘦NAFLD肝纤维化机制的知识。最常用的瘦肉NAFLD模型包括蛋氨酸/胆碱缺乏（MCD）饮食，含有四氯化碳（CCl4）的高脂肪饮食，以及高果糖和高胆固醇的饮食.瘦NAFLD模型中的主要促纤维化机制包括细胞外信号调节激酶（ERK）途径的激活增加，α-平滑肌肌动蛋白（α-SMA）的表达升高，胶原蛋白I型，和TGF-β，和纤维形成标志物如生腱蛋白-X和金属蛋白酶抑制剂的调节。此外,巨噬细胞信号通路的激活促进肝星状细胞（HSC）的激活进一步促进纤维化的发展。动物模型不能覆盖所有的临床特征，是明显的瘦或肥胖的NAFLD患者，暗示需要新颖的模型，以及更深入的临床和实验研究的比较。考虑到瘦肉NAFLD患者的纤维化患病率，通过解决特定的途径，临床研究可以揭示新的靶向治疗以及新的生物标志物,用于早期发现和加强瘦肉NAFLD患者的临床管理.
