Exercise of high intensity ameliorates hepatic inflammation and the progression of NASH.
Exercise of high intensity ameliorates hepatic inflammation and the progression of NASH.
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DOI：
10.1016/j.molmet.2021.101270
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发表时间：
2021-11
影响因子：
8.1
通讯作者：
Revelo XS
中科院分区：
文献类型：
--
作者：
Fredrickson G;Barrow F;Dietsche K;Parthiban P;Khan S;Robert S;Demirchian M;Rhoades H;Wang H;Adeyi O;Revelo XS
非酒精性脂肪性肝病（NAFLD）涵盖了广泛的肝脏病理，从单纯性脂肪肝到非酒精性脂肪性肝炎（NASH）。值得注意的是，免疫细胞驱动的炎症是脂肪肝向更严重的NASH转变的关键机制。尽管运动训练在改善肥胖相关疾病方面是有效的，但运动有益效果的潜在机制尚不清楚。目前尚不清楚是否存在治疗NAFLD的最佳运动方式和强度。本研究的目的是确定高强度间歇训练（HIIT）或中等强度连续训练（MIT）在改善NASH进展方面是否更有效。野生型小鼠被喂食高脂肪、高碳水化合物（HFHC）饮食6周，然后静止不动（SED），或者被分配到MIT或HIIT方案中，使用跑步机跑步另外16周。MIT组和HIIT组成对进食，以确保运动组之间的能量摄入相似。为了确定全身代谢的变化，我们进行了胰岛素和葡萄糖耐量试验、间接量热法和磁共振成像。NASH的进展由甘油三酯积累、炎症基因表达和纤维化的组织学评估来确定。肝脏中的免疫细胞群用飞行时间质谱测定，骨髓中的祖细胞群用流式细胞术测定。最后，我们通过大量RNA测序分析了肝脏的转录谱。与SED小鼠相比，HIIT和MIT均抑制了体重增加，改善了全身代谢参数，并通过降低肝脏甘油三酯水平、炎症和纤维化来改善NASH的进展。然而，HIIT在减少肥胖、改善全身葡萄糖耐量、改善肝脏脂肪变性、炎症和纤维化方面优于MIT，而体重没有任何变化。HIIT小鼠NASH进展的改善伴随着促炎浸润频率的显著降低，肝脏中单核细胞来源的巨噬细胞和骨髓中骨髓祖细胞数量的减少。值得注意的是，急性发作的MIT或HIIT运动对肝内和脾免疫细胞群没有影响。此外，整个肝组织的大量mRNA测序显示了一种基因表达模式，证实HIIT在改善肝脏炎症和脂质生物合成方面比MIT更有效。我们的数据表明，运动可以通过减少肝单核细胞来源的炎性巨噬细胞和骨髓前体细胞的积累来减轻NASH期间的肝脏炎症。我们的研究结果还表明，在NASH饮食小鼠模型中，HIIT在改善疾病方面优于MIT。高强度运动在减少NASH方面比中等强度运动更有效。高强度运动可降低肝脏中炎性巨噬细胞的浸润。巨噬细胞积累减少与祖细胞减少有关。
Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH). Notably, immune cell-driven inflammation is a key mechanism in the transition from fatty liver to the more serious NASH. Although exercise training is effective in ameliorating obesity-related diseases, the underlying mechanisms of the beneficial effects of exercise remain unclear. It is unknown whether there is an optimal modality and intensity of exercise to treat NAFLD. The objective of this study was to determine whether high-intensity interval training (HIIT) or moderate-intensity continuous training (MIT) is more effective at ameliorating the progression of NASH. Wild-type mice were fed a high-fat, high-carbohydrate (HFHC) diet for 6 weeks and left sedentary (SED) or assigned to either an MIT or HIIT regimen using treadmill running for an additional 16 weeks. MIT and HIIT groups were pair-fed to ensure that energy intake was similar between the exercise cohorts. To determine changes in whole-body metabolism, we performed insulin and glucose tolerance tests, indirect calorimetry, and magnetic resonance imaging. NASH progression was determined by triglyceride accumulation, expression of inflammatory genes, and histological assessment of fibrosis. Immune cell populations in the liver were characterized by cytometry by time-of-flight mass spectrometry, and progenitor populations within the bone marrow were assessed by flow cytometry. Finally, we analyzed the transcriptional profile of the liver by bulk RNA sequencing. Compared with SED mice, both HIIT and MIT suppressed weight gain, improved whole-body metabolic parameters, and ameliorated the progression of NASH by reducing hepatic triglyceride levels, inflammation, and fibrosis. However, HIIT was superior to MIT at reducing adiposity, improving whole-body glucose tolerance, and ameliorating liver steatosis, inflammation, and fibrosis, without any changes in body weight. Improved NASH progression in HIIT mice was accompanied by a substantial decrease in the frequency of pro-inflammatory infiltrating, monocyte-derived macrophages in the liver and reduced myeloid progenitor populations in the bone marrow. Notably, an acute bout of MIT or HIIT exercise had no effect on the intrahepatic and splenic immune cell populations. In addition, bulk mRNA sequencing of the entire liver tissue showed a pattern of gene expression confirming that HIIT was more effective than MIT in improving liver inflammation and lipid biosynthesis. Our data suggest that exercise lessens hepatic inflammation during NASH by reducing the accumulation of hepatic monocyte-derived inflammatory macrophages and bone marrow precursor cells. Our findings also indicate that HIIT is superior to MIT in ameliorating the disease in a dietary mouse model of NASH. High-intensity is more effective than moderate-intensity exercise at reducing NASH. High-intensity exercise lowers the infiltration of inflammatory macrophages in the liver. Reduced macrophage accumulation was associated with lower progenitor cells.
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作者：
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通讯作者：
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