RESULTS: Mice were fed high-fat diet (HFD) or HFD-0.1 % methionine and choline-deficient diet (MCD) to emulate simple hepatic steatosis or non-alcoholic steatohepatitis, respectively. In both models, aerobic exercise decreased the size of LDs bound to mitochondria and the number of LD-mitochondria contacts. Analysis showed that the effects of exercise on HOMA-IR and liver triglyceride levels were independent of changes in body weight, and a positive correlation was observed between the number of LD-mitochondria contacts and NAFLD severity and with the lipid droplet size bound to mitochondria. Cellular fractionation studies revealed that ATP-coupled respiration and fatty acid oxidation (FAO) were greater in hepatic peridroplet mitochondria (PDM) from HFD-fed exercised mice than from equivalent sedentary mice. Finally, exercise increased FAO and mitofusin-2 abundance exclusively in PDM through a mechanism involving the curvature of mitochondrial membranes and the abundance of saturated lipids. Accordingly, hepatic mitofusin-2 ablation prevented exercise-induced FAO in PDM.
CONCLUSIONS: This study demonstrates that aerobic exercise has beneficial effects in murine NAFLD models by lessening the interactions between hepatic LDs and mitochondria, and by decreasing LD size, correlating with a reduced severity of NAFLD. Additionally, aerobic exercise increases FAO in PDM and this process is reliant on Mfn-2 enrichment, which modifies LD-mitochondria communication.
结果:给小鼠喂食高脂饮食(HFD)或HFD-0.1%蛋氨酸和胆碱缺乏饮食(MCD)以模拟单纯性肝性脂肪变性或非酒精性脂肪性肝炎,分别。在这两种模型中,有氧运动减少了与线粒体结合的LD的大小和LD-线粒体接触的数量。分析表明,运动对HOMA-IR和肝脏甘油三酯水平的影响独立于体重的变化,LD-线粒体接触的数量与NAFLD严重程度以及与线粒体结合的脂滴大小呈正相关。细胞分馏研究表明,HFD喂养的运动小鼠的肝周线粒体线粒体(PDM)中的ATP耦合呼吸和脂肪酸氧化(FAO)比同等久坐的小鼠更大。最后,通过涉及线粒体膜曲率和饱和脂质丰度的机制,运动仅在PDM中增加了FAO和mitofusin-2的丰度。因此,肝mitofusin-2消融可预防PDM中运动诱导的FAO。
结论:这项研究表明,有氧运动通过减少肝脏LD和线粒体之间的相互作用,在小鼠NAFLD模型中具有有益的作用,通过减小LD尺寸,与NAFLD严重程度降低相关。此外,有氧运动增加了PDM中的FAO,这一过程依赖于Mfn-2的富集,它改变了LD-线粒体的通讯。