高果糖饮食致非酒精性脂肪肝病的机制探讨及其与内质网应激的关系

Overconsumption of fructose is an important dietary factors leading to the development of non-alcholic fatty liver disease, mainly due to the stimulation of hepatic de novo lipogenesis by fructose. The upstream and initiating mechanisms by which fructose stimulates lipogenesis remain unclear. Our previous study and preliminary research suggest that endoplasmic reticulum stress (ERS) is involved in the fructose-induced hepatic steatosis. The underlying mechanisms require further investigation. Unfolded protein response pathways of ERS are indicated to regulate hepatic de novo lipogenesis. Therefore, our hypothesis is that fructose induces ERS directly, then stimulates lipogenesis through the activation of unfolded protein response pathway of ERS and leads to lipids accumulation in liver. To verify this hypothesis, the animal model of high-fructose-diet-induced mice fatty liver and human hepatoma cell line HepG2 are used. The techniques including isotopic tracer techniques, liver morphology study, PCR, Western blot and gene recombination are applied. By these means we hope to clarify the profound mechanism of high-fructose-feeding-incuced non-alcholic fatty liver disease and its association with ERS from the respects of whole-body level and cells in vairous angles. With the new insight of ERS, the present study is expected to reveal the hazards of fructose on metabolism and the mechanisms of the development of non-alcholic fatty liver disease and to provide the new target for the prevention and treatment of non-alcholic fatty liver disease.

果糖过量摄入是引起非酒精性脂肪肝病的重要饮食因素，主要是因果糖刺激肝脏内源性脂质合成，迄今对果糖刺激脂质从头合成的上游和始动机制尚未阐明。我们的前期研究提示内质网应激（ERS）介导了果糖诱导的非酒精性脂肪肝病，具体机制尚待探讨。ERS的非折叠蛋白反应通路可调控肝脂质从头合成，为此，我们提出假说，果糖直接诱导肝ERS，继而通过 ERS的非折叠蛋白反应通路激活刺激脂质从头合成，引起肝脏脂质沉积。为了验证这一假说，我们将通过高果糖喂养诱导小鼠脂肪肝模型、人肝癌细胞系HepG2，采用核素示踪技术、肝脏形态学检测、PCR、Western blot、基因重组等手段，从整体、细胞水平多方面多角度地探讨高果糖摄入诱导非酒精性脂肪肝的深层机制及其与ERS的关系。本研究将从ERS这个新视点为揭示果糖的代谢危害和非酒精性脂肪肝病的发生发展机制提供新的思路，并为非酒精性脂肪肝病的防治提供新的可能的防治靶点。

一、项目完成情况 . 本课题通过高果糖喂养诱导小鼠脂肪肝模型、人肝癌细胞系HepG2，采用肝脏形态学检测、PCR、Western blot、基因重组等手段，从整体、细胞水平多方面多角度地探讨高果糖摄入诱导非酒精性脂肪肝的深层机制及其与ERS的关系。本研究从ERS这个新视点为揭示果糖的代谢危害和非酒精性脂肪肝病的发生发展机制提供新的思路，并为非酒精性脂肪肝病的防治提供新的可能的防治靶点。 . 课题组按时、圆满完成了计划书的研究内容。..二、项目取得成果 . 1. 本项目结果提示：内质网应激介导了高果糖摄入所致的脂肪肝和肝胰岛素抵抗的发生发展，内质网应激抑制剂4-PBA治疗可改善高果糖喂养大鼠的肝脏脂质沉积和胰岛素抵抗，并伴有糖代谢指标的显著改善，其机制与内质网应激对肝脏脂质合成通路的影响有关。ERS通过促进脂质从头合成导致肝细胞脂质沉积。内质网应激中的ATF-4通路和XBP-1通路可促进肝脏脂质合成。通过本研究，进一步深入了解果糖对代谢的危害及脂肪肝发生发展的机制及其与内质网应激的关系，为临床寻找防治非酒精性脂肪肝提供了新的治疗靶点。.2.在本项目支持下，共培养博士1名、硕士3名；在国内外期刊发表论著数篇，获得与本项目相关的河北省科技进步奖二等奖1项（第二完成人）。