Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.
Department of Biochemistry, McGill University, Montréal, Quebec, Canada.
Endocrinology. 2018 May 1;159(5):2153-2164. doi: 10.1210/en.2018-00115.
Given the increasing prevalence of obesity and the metabolic syndrome, identification of intrinsic molecular programs responsible for ensuring fuel homeostasis and preventing metabolic disease is needed. We investigated whether the orphan nuclear receptor estrogen-related receptor α (ERRα), a major regulator of energy metabolism, plays a role in lipid homeostasis and the development of nonalcoholic fatty liver disease (NAFLD) in response to chronic high-fat diet (HFD) consumption and long-term fasting. Systemic ablation of ERRα in mice demonstrated clear beneficial effects for loss of ERRα function in protection from HFD-provoked body weight gain manifested not only from a reduction in white adipose tissue stores but also from an impediment in intrahepatic lipid accumulation. The prevention of HFD-induced NAFLD in ERRα-null mice was underscored by transcriptional repression of de novo lipogenesis, which was upregulated in wild-type mice, a known contributing factor to lipid-stimulated hepatic steatosis. Surprisingly, given these findings, ERRα deficiency had no significant impact on the degree of fasting-induced NAFLD, involving the mobilization of adipocyte triglyceride (TG) stores into the liver. However, the presence of ERRα was essential for acute refeeding-mediated reversal of fasting-induced hepatic TG accretion, underpinned by impaired downregulation of adipose TG lipolysis and reduced hepatic mitochondrial oxidative activity. Taken together, the regulation of lipid handling by ERRα depended on the nutritional state, suggesting that negative modulation of ERRα activity could be envisaged to prevent lipid-induced NAFLD, whereas inducing its activity would be useful to treat and reverse the instilled disease.
鉴于肥胖症和代谢综合征的发病率不断上升，需要确定负责确保燃料稳态和预防代谢疾病的内在分子程序。我们研究了孤儿核受体雌激素相关受体α（ERRα），即能量代谢的主要调节剂，是否在慢性高脂肪饮食（HFD）消耗和长期禁食时对脂质稳态和非酒精性脂肪肝疾病（NAFLD）的发展起作用。在小鼠中系统敲除 ERRα 表明，ERRα 功能丧失具有明显的有益作用，可以防止 HFD 引起的体重增加，这不仅表现在白色脂肪组织储存减少，还表现在肝内脂质积累受到阻碍。ERRα 缺失型小鼠中 HFD 诱导的 NAFLD 的预防作用突出表现在从头合成脂质的转录抑制，在野生型小鼠中，这是脂质刺激肝脂肪变性的已知促成因素，其被上调。令人惊讶的是，鉴于这些发现，ERRα 缺乏对禁食诱导的 NAFLD 的程度没有重大影响，涉及到脂肪细胞甘油三酯（TG）储存向肝脏的动员。然而，ERRα 的存在对于急性重新喂养介导的禁食诱导的肝 TG 积累的逆转是必不可少的，其基础是脂肪 TG 水解的下调受损和肝线粒体氧化活性降低。综上所述，ERRα 对脂质处理的调节取决于营养状态，这表明可以设想负调节 ERRα 活性以预防脂质诱导的 NAFLD，而诱导其活性将有助于治疗和逆转所诱导的疾病。
