Abstract：
OBJECTIVE: The excessive accumulation of lipid droplets (LDs) is a defining characteristic of nonalcoholic fatty liver disease (NAFLD). The interaction between LDs and mitochondria is functionally important for lipid metabolism homeostasis. Exercise improves NAFLD, but it is not known if it has an effect on hepatic LD-mitochondria interactions. Here, we investigated the influence of exercise on LD-mitochondria interactions and its significance in the context of NAFLD.
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.
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.
摘要：
目的：脂滴（LD）的过度积累是非酒精性脂肪性肝病（NAFLD）的决定性特征。LD和线粒体之间的相互作用对于脂质代谢稳态在功能上很重要。运动改善NAFLD，但不知道它是否对肝脏LD-线粒体相互作用有影响。这里,我们研究了运动对LD-线粒体相互作用的影响及其在NAFLD中的意义。
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。
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。
