Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
Research Service, Kansas City Veterans Affairs Medical Center, Kansas City, Kansas.
Am J Physiol Endocrinol Metab. 2021 Jun 1;320(6):E1020-E1031. doi: 10.1152/ajpendo.00013.2021. Epub 2021 Apr 19.
We recently reported that compared with males, female mice have increased hepatic mitochondrial respiratory capacity and are protected against high-fat diet-induced steatosis. Here, we sought to determine the role of estrogen in hepatic mitochondrial function, steatosis, and bile acid metabolism in female mice and investigate potential benefits of exercise in the absence or presence of estrogen via ovariectomy (OVX). Female C57BL mice ( = 6 per group) were randomly assigned to sham surgery (sham), ovariectomy (OVX), or OVX plus estradiol replacement therapy (OVX + Est). Half of the mice in each treatment group were sedentary (SED) or had access to voluntary wheel running (VWR). All mice were fed a high-fat diet (HFD) and were housed at thermoneutral temperatures. We assessed isolated hepatic mitochondrial respiratory capacity using the Oroboros O2k with both pyruvate and palmitoylcarnitine as substrates. As expected, OVX mice presented with greater hepatic steatosis, weight gain, and fat mass gain compared with sham and OVX + Est animals. Hepatic mitochondrial coupling (basal/state 3 respiration) with pyruvate was impaired following OVX, but both VWR and estradiol treatment rescued coupling to levels greater than or equal to sham animals. Estradiol and exercise also had different effects on liver electron transport chain protein expression depending on OVX status. Markers of bile acid metabolism and excretion were also impaired by ovariectomy but rescued with estradiol add-back. Together our data suggest that estrogen depletion impairs hepatic mitochondrial function and liver health, and that estradiol replacement and modest exercise can aid in rescuing this phenotype. OVX induces hepatic steatosis in sedentary mice which can be prevented by modest physical activity (VWR) and/or estradiol treatment. Estrogen impacts hepatic mitochondrial coupling in a substrate-specific manner. OVX mice have impaired fecal bile acid excretion, which was rescued with estradiol treatment.
我们最近报道称，与雄性相比，雌性小鼠的肝线粒体呼吸能力增加，并且对高脂肪饮食诱导的脂肪变性具有保护作用。在这里，我们试图确定雌激素在雌性小鼠肝线粒体功能、脂肪变性和胆汁酸代谢中的作用，并研究在没有或存在去卵巢（OVX）的情况下运动的潜在益处。将雌性 C57BL 小鼠（每组 6 只）随机分为假手术（sham）、去卵巢（OVX）或去卵巢加雌二醇替代治疗（OVX+Est）。每组一半的小鼠为久坐（SED）或可以自由使用轮式跑步（VWR）。所有小鼠均喂食高脂肪饮食（HFD），并在恒温下饲养。我们使用 Oroboros O2k 评估了分离的肝线粒体呼吸能力，使用丙酮酸和棕榈酰肉碱作为底物。正如预期的那样，与 sham 和 OVX+Est 动物相比，OVX 小鼠表现出更大的肝脂肪变性、体重增加和脂肪量增加。OVX 后，肝线粒体偶联（基础/状态 3 呼吸）用丙酮酸受损，但 VWR 和雌二醇治疗均使偶联恢复到等于或大于 sham 动物的水平。雌二醇和运动也根据 OVX 状态对肝脏电子传递链蛋白表达产生不同的影响。胆汁酸代谢和排泄标志物也因去卵巢而受损，但用雌二醇补充可恢复。总的来说，我们的数据表明，雌激素耗竭会损害肝线粒体功能和肝脏健康，而雌二醇替代和适度运动可以帮助挽救这种表型。久坐的 OVX 小鼠会引起肝脂肪变性，适度的体力活动（VWR）和/或雌二醇治疗可以预防这种情况。雌激素以底物特异性的方式影响肝线粒体偶联。OVX 小鼠的粪便胆汁酸排泄减少，用雌二醇治疗可恢复。
