Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury.
Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury.
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成纤维细胞生长因子 21 缺乏会加剧慢性酒精引起的肝脂肪变性和损伤
DOI：
10.1038/srep31026
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发表时间：
2016-08-08
影响因子：
4.6
通讯作者：
Feng W
中科院分区：
文献类型：
--
作者：
Liu Y;Zhao C;Xiao J;Liu L;Zhang M;Wang C;Wu G;Zheng MH;Xu LM;Chen YP;Mohammadi M;Chen SY;Cave M;McClain C;Li X;Feng W
成纤维细胞生长因子21（FGF 21）是一种肝因子，可调节肝脏中的葡萄糖和脂质代谢。我们试图确定FGF 21在慢性酒精治疗小鼠肝脂肪变性中的作用，并辨别潜在的机制。将雄性FGF 21敲除（FGF 21 KO）和对照（WT）小鼠分成喂食含有5%酒精的Lieber DeCarli饮食或等热量（对照）饮食4周的组。一组暴露于酒精的WT小鼠在过去5天内接受了重组人FGF 21（rhFGF 21）。评估肝脏脂肪变性和炎症。将原代小鼠肝细胞和AML-12细胞与二甲双胍或rhFGF 21孵育。分析了肝脏原位脂肪生成和脂肪酸β-氧化相关基因及其产物。酒精暴露增加循环水平和肝脏表达的FGF 21。FGF 21耗竭加剧了酒精诱导的肝脂肪变性和肝损伤，这与SREBP 1c介导的参与脂肪生成的基因活化增加和PGC 1 α介导的参与脂肪酸β氧化的基因表达减少有关。rhFGF 21给药减少WT小鼠中酒精诱导的肝脂肪变性和炎症。这些结果表明，酒精诱导的FGF 21表达是肝脏对脂质失调的适应性反应。靶向FGF 21信号传导可能是酒精性脂肪性肝炎的一种新的治疗方法。
Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates glucose and lipid metabolism in the liver. We sought to determine the role of FGF21 in hepatic steatosis in mice exposed to chronic alcohol treatment and to discern underlying mechanisms. Male FGF21 knockout (FGF21 KO) and control (WT) mice were divided into groups that were fed either the Lieber DeCarli diet containing 5% alcohol or an isocaloric (control) diet for 4 weeks. One group of WT mice exposed to alcohol received recombinant human FGF21 (rhFGF21) in the last 5 days. Liver steatosis and inflammation were assessed. Primary mouse hepatocytes and AML-12 cells were incubated with metformin or rhFGF21. Hepatic genes and the products involved in in situ lipogenesis and fatty acid β-oxidation were analyzed. Alcohol exposure increased circulating levels and hepatic expression of FGF21. FGF21 depletion exacerbated alcohol-induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by SREBP1c and decreased expression of genes involved in fatty acid β-oxidation mediated by PGC1α. rhFGF21 administration reduced alcohol-induced hepatic steatosis and inflammation in WT mice. These results reveal that alcohol-induced FGF21 expression is a hepatic adaptive response to lipid dysregulation. Targeting FGF21 signaling could be a novel treatment approach for alcoholic steatohepatitis.