Influence of dietary sucrose and copper content in a rat model of non-alcoholic fatty-liver disease

Nutrigenomics analysis was used to investigate the molecular responses to dietary Cu deficiency independently and in combination with 30% (w/w) sucrose in a mature rat model of NAFLD. Low Cu significantly decreased hepatic and serum Cu, and induced NAFLD-like histopathology, mild steatosis, up-regulated transcripts in inflammation and hepatic stellate cell activation, and significantly increased oxidative stress. Rats fed low Cu together with 30% sucrose also developed insulin resistance, increased ATP citrate lyase and FASN expression, and greater oxidative stress. High sucrose with adequate Cu also promoted inflammation and fibrosis, but not steatosis. This study indicates that low dietary Cu and sucrose consumption are singular and synergistic dietary factors in promotion of NAFLD and NASH that act independently of obesity or severe steatosis, likely by promoting oxidative stress and activation of inflammation and fibrosis.本研究采用营养基因组学（Nutrigenomics）分析方法，在非酒精性脂肪性肝病（NAFLD，Non-Alcoholic Fatty Liver Disease）成熟大鼠模型中，分别探究膳食铜缺乏、以及膳食铜缺乏联合30%（质量分数）蔗糖对机体的分子应答效应。低铜膳食可显著降低大鼠肝脏与血清中的铜水平，诱发类非酒精性脂肪性肝病的组织病理学改变，出现轻度脂肪变性，上调炎症与肝星状细胞活化相关的转录本表达，并显著升高氧化应激水平。同时饲喂低铜膳食与30%蔗糖的大鼠还出现了胰岛素抵抗，上调ATP柠檬酸裂解酶（ATP citrate lyase）与脂肪酸合成酶FASN的表达，且氧化应激水平进一步升高。仅饲喂高蔗糖与足量铜的大鼠同样可出现炎症与纤维化，但未发生脂肪变性。本研究表明，膳食铜摄入不足与蔗糖过量摄入分别是推动非酒精性脂肪性肝病（NAFLD）与非酒精性脂肪性肝炎（NASH，Non-Alcoholic Steatohepatitis）发生发展的独立与协同膳食危险因素，其作用不依赖肥胖或重度脂肪变性，可能通过升高氧化应激水平、活化炎症与纤维化通路实现。