Leung Christopher, Herath Chandana B, Jia Zhiyuan, Andrikopoulos Sof, Brown Bronwyn E, Davies Michael J, Rivera Leni R, Furness John B, Forbes Josephine M, Angus Peter W
Christopher Leung, Chandana B Herath, Zhiyuan Jia, Sof Andrikopoulos, Peter W Angus, Department of Medicine, the University of Melbourne, Austin Health, Heidelberg, Melbourne, Victoria 3084, Australia.
World J Gastroenterol. 2016 Sep 21;22(35):8026-40. doi: 10.3748/wjg.v22.i35.8026.
To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE.
Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined.
Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE(-/-) animals developed NASH of similar severity to RAGE(+/+) animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury.
In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.
确定饮食中晚期糖基化终产物（AGE）摄入量的改变是否会影响非酒精性脂肪性肝病（NAFLD）的进展，以及这些影响是否通过晚期糖基化终产物受体（RAGE）介导。
将雄性C57Bl6小鼠喂食高脂肪、高果糖、高胆固醇（HFHC）饮食持续33周，并与喂食正常食物的动物进行比较。第三组喂食富含AGE的HFHC饮食。另一组喂食用醋腌制以防止AGE形成的HFHC饮食。在第二个实验中，给RAGE基因敲除（KO）动物喂食HFHC饮食或高AGE的HFHC饮食，并与野生型对照进行比较。测定肝脏生化指标、组织学、苦味酸天狼星红形态计量学和肝脏mRNA。
长期食用HFHC饮食33周后产生了显著的脂肪性肝炎和肝纤维化。在该模型中，肝脏4-羟基壬烯醛含量（慢性氧化应激的标志物）、肝细胞气球样变、苦味酸天狼星红染色、α-平滑肌肌动蛋白和1A型胶原基因表达均显著增加。通过烘烤增加HFHC饮食中的AGE含量进一步增加了这些肝损伤标志物，但通过在醋酸中预先腌制可消除这种影响。对于HFHC饮食，RAGE（-/-）动物发展出与RAGE（+/+）动物严重程度相似的非酒精性脂肪性肝炎（NASH），但免受含高AGE饮食的额外有害影响。对分离的库普弗细胞的研究表明，AGEs增加细胞增殖和氧化应激，这为这些化合物导致肝损伤提供了一种可能的机制。
在NAFLD的HFHC模型中，饮食中AGEs的改变通过RAGE依赖性途径调节肝损伤、炎症和肝纤维化。这表明针对AGE/RAGE途径的药理学和饮食策略可能会减缓NAFLD的进展。
