Kristensen Caroline M, Dethlefsen Maja M, Tøndering Anna S, Lassen Signe B, Meldgaard Jacob N, Ringholm Stine, Pilegaard Henriette
Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Physiol Rep. 2018 Aug;6(15):e13819. doi: 10.14814/phy2.13819.
Diet-induced obesity is associated with hepatic steatosis, which has been linked with activation of the unfolded protein response (UPR). PGC-1α is a transcriptional coactivator involved in exercise training-induced adaptations in muscle and liver. Therefore, the aim of this study was to test the hypothesis that PGC-1α is required for exercise training-mediated prevention of diet-induced steatosis and UPR activation in liver. Male liver-specific PGC-1α knockout (LKO) and littermate floxed (lox/lox) mice were divided into two groups receiving either control diet (CON) or high-fat high-fructose diet (HFF). After 9 weeks, half of the HFF mice were treadmill exercise trained for 4 weeks (HFF+ExT), while the rest were kept sedentary. HFF resulted in increased body and liver weight, adiposity, hepatic steatosis and whole body glucose intolerance as well as decreased hepatic IRE1α phosphorylation. Exercise training prevented the HFF-induced weight gain and partially prevented increased liver weight, adiposity and glucose intolerance, but with no effect on liver triglycerides. In addition, BiP protein and CHOP mRNA content increased with exercise training compared with CON and HFF, respectively. Lack of PGC-1α in the liver only resulted in minor changes in the PERK pathway. In conclusion, this study provides evidence for dissociation between diet-induced hepatic triglyceride accumulation and hepatic UPR activation. In addition, PGC-1α was not required for maintenance of basal UPR in the liver and due to only minor exercise training effects on UPR further studies are needed to conclude on the potential role of PGC-1α in exercise training-induced adaptations in hepatic UPR.
饮食诱导的肥胖与肝脂肪变性有关，而肝脂肪变性与未折叠蛋白反应（UPR）的激活有关。PGC-1α是一种转录共激活因子，参与运动训练诱导的肌肉和肝脏适应性变化。因此，本研究的目的是检验以下假设：PGC-1α是运动训练介导的预防饮食诱导的肝脂肪变性和肝脏UPR激活所必需的。雄性肝脏特异性PGC-1α基因敲除（LKO）小鼠和同窝对照（lox/lox）小鼠被分为两组，分别给予对照饮食（CON）或高脂高果糖饮食（HFF）。9周后，将一半的HFF小鼠进行4周的跑步机运动训练（HFF+ExT），其余小鼠保持 sedentary。HFF导致体重、肝脏重量、肥胖、肝脂肪变性和全身葡萄糖不耐受增加，同时肝脏IRE1α磷酸化降低。运动训练可防止HFF诱导的体重增加，并部分防止肝脏重量、肥胖和葡萄糖不耐受增加，但对肝脏甘油三酯无影响。此外，与CON组和HFF组相比，运动训练使BiP蛋白和CHOP mRNA含量增加。肝脏中缺乏PGC-1α仅导致PERK通路的微小变化。总之，本研究为饮食诱导的肝脏甘油三酯积累与肝脏UPR激活之间的分离提供了证据。此外，肝脏中维持基础UPR不需要PGC-1α，并且由于运动训练对UPR的影响较小，需要进一步研究来确定PGC-1α在运动训练诱导的肝脏UPR适应性变化中的潜在作用。
