在体力活动治疗脂肪变性期间,性二态和线粒体自噬对肝线粒体适应的影响在很大程度上是未知的。这里,我们测试了肝脏特异性过氧化物酶体增殖激活受体-γ共激活因子-1α(PGC-1α)是否缺乏,生物发生的转录共激活因子,和BCL-2/腺病毒EIB19-kDa相互作用蛋白(BNIP3),有丝分裂调节因子,会影响肝脏线粒体适应(呼吸能力,H2O2生产,线粒体自噬)对高脂肪饮食(HFD)和HFD以及通过自愿车轮跑步(VWR)进行体育锻炼。雄性和雌性野生型(WT),肝脏特异性PGC-1α杂合子(LPGC-1α),和BNIP3无效小鼠进行热中性饲养(29-31°C),并分为三组:久坐低脂饮食(LFD),16周(HFD),或16周的HFD和VWR,最后8周(HFD+VWR)(n=5-7/性别/组)。HFD在任何组中都没有损害线粒体呼吸能力或偶联;然而,仅在WT和PGC-1α雌性中,HFDVWR显着增加了最大呼吸能力。雄性需要VWR来引起静坐雌性固有存在的线粒体适应,包括更大的线粒体偶联控制和减少的H2O2产生。女性的线粒体自噬标志物总体减少,脂肪变性,和肝损伤。在HFD上久坐的雄性小鼠中存在脂肪变性和肝损伤标志物,并且尽管没有脂肪变性的消退,但VWR有效地减少了脂肪变性。总的来说,PGC-1α的减少和BNIP3的丢失仅适度影响线粒体对HFD和HFDVWR的适应,在BNIP3雌性中效果最大。总之,与PGC-1α或BNIP3相比,肝线粒体对HFD的适应和用VWR治疗HFD诱导的脂肪变性更依赖于性别。
The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific peroxisome proliferative activated-receptor-γ coactivator-1α (PGC-1α), a transcriptional coactivator of biogenesis, and BCL-2/ADENOVIRUS EIB 19-kDa interacting protein (BNIP3), a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2 production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild-type (WT), liver-specific PGC-1α heterozygote (LPGC-1α), and BNIP3 null mice were thermoneutral housed (29-31°C) and divided into three groups: sedentary-low-fat diet (LFD), 16 wk of (HFD), or 16 wk of HFD with VWR for the final 8 wk (HFD + VWR) (n = 5-7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group; however, HFD + VWR significantly increased maximal respiratory capacity only in WT and PGC-1α females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling control and reduced H2O2 production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1α and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD + VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1α or BNIP3.