FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation
FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation
复制标题
DOI：
10.1530/ec-20-0152
复制
发表时间：
2020-08-01
影响因子：
2.9
通讯作者：
Kjaergaard, Marina
中科院分区：
文献类型：
--
作者：
Keinicke, Helle;Sunz, Gao;Kjaergaard, Marina
非酒精性脂肪性肝病(NAFLD)的患病率在全球范围内急剧增加，随后也增加了发展为非酒精性脂肪性肝炎(NASH)、肝纤维化、肝硬变和癌症的风险。今天，减肥是唯一可用的治疗方法，但服用成纤维细胞生长因子21(FGF21)类似物，除了减肥外，还显示出改善肝脏代谢健康的作用，但背后的机制尚不完全清楚。本研究的目的是研究FGF21治疗对肝脏代谢的影响。给饮食诱导的肥胖(DIO)小鼠灌胃S.C.给予FGF21或通过改变高脂饮食(HFD)来限制热量摄入，以诱导体重减轻20%，并将其变化与赋形剂剂量的DIO小鼠进行比较。食物减少了累积热量摄入量，而FGF21和赋形剂剂量的小鼠之间没有观察到差异。两个治疗组的体重减轻与体脂质量和肝脏甘油三酯(TG)的减少有关，而肝脏胆固醇略有下降。FGF21可降低小鼠肝糖原含量，而饲料可使肝糖原含量增加。肝脏基因表达谱表明，FGF21增加了对脂肪酸和脂蛋白的摄取，引导TGS产生胆固醇和胆汁酸，减少脂肪生成，增加肝脏葡萄糖输出。此外，FGF21似乎可以减轻炎症并调节肝脏瘦素受体-a的表达。总之，FGF21影响了几个减少肝脏脂肪变性和改善肝脏健康的代谢途径，而且明显多于饮食限制(在89个被研究的基因中，61个比16个)。
The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased dramatically worldwide and, subsequently, also the risk of developing non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis and cancer. Today, weight loss is the only available treatment, but administration of fibroblast growth factor 21 (FGF21) analogues have, in addition to weight loss, shown improvements on liver metabolic health but the mechanisms behind are not entirely clear. The aim of this study was to investigate the hepatic metabolic profile in response to FGF21 treatment. Diet-induced obese (DIO) mice were treated with s.c. administration of FGF21 or subjected to caloric restriction by switching from high fat diet (HFD) to chow to induce 20% weight loss and changes were compared to vehicle dosed DIO mice. Cumulative caloric intake was reduced by chow, while no differences were observed between FGF21 and vehicle dosed mice. The body weight loss in both treatment groups was associated with reduced body fat mass and hepatic triglycerides (TG), while hepatic cholesterol was slightly decreased by chow. Liver glycogen was decreased by FGF21 and increased by chow. The hepatic gene expression profiles suggest that FGF21 increased uptake of fatty acids and lipoproteins, channeled TGs toward the production of cholesterol and bile acid, reduced lipogenesis and increased hepatic glucose output. Furthermore, FGF21 appeared to reduce inflammation and regulate hepatic leptin receptor-a expression. In conclusion, FGF21 affected several metabolic pathways to reduce hepatic steatosis and improve hepatic health and markedly more genes than diet restriction (61 vs 16 out of 89 investigated genes).