Liu Longhua, Tao Zhipeng, Zheng Louise D, Brooke Joseph P, Smith Cayleen M, Liu Dongmin, Long Yun Chau, Cheng Zhiyong
Department of Human Nutrition, Foods and Exercise, Virginia Tech, Fralin Life Science Institute, College of Agriculture and Life Science , Blacksburg, VA, USA.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Singapore.
Cell Death Discov. 2016 Oct 3;2:16066. doi: 10.1038/cddiscovery.2016.66. eCollection 2016.
Mitochondrial uncoupling proteins (UCPs) are inducible and play an important role in metabolic and redox homeostasis. Recent studies have suggested that FoxO1 controls mitochondrial biogenesis and morphology, but it remains largely unknown how FoxO1 may regulate mitochondrial UCPs. Here we show that FoxO1 interacted with transcription factor EB (Tfeb), a key regulator of autophagosome and lysosome, and mediated the expression of UCP1, UCP2 and UCP3 differentially via autophagy in adipocytes. UCP1 was down-regulated but UCP2 and UCP3 were upregulated during adipocyte differentiation, which was associated with increased Tfeb and autophagy activity. However, inhibition of FoxO1 suppressed Tfeb and autophagy, attenuating UCP2 and UCP3 but increasing UCP1 expression. Pharmacological blockade of autophagy recapitulated the effects of FoxO1 inhibition on UCPs. Chromatin immunoprecipitation assay demonstrated that FoxO1 interacted with Tfeb by directly binding to its promoter, and silencing FoxO1 led to drastic decrease in Tfeb transcript and protein levels. These data provide the first line of evidence that FoxO1 interacts with Tfeb to regulate autophagy and UCP expression in adipocytes. Dysregulation of FoxO1→autophagy→UCP pathway may account for metabolic changes in obesity.
线粒体解偶联蛋白（UCPs）是可诱导的，在代谢和氧化还原稳态中发挥重要作用。最近的研究表明，FoxO1控制线粒体的生物发生和形态，但FoxO1如何调节线粒体UCPs在很大程度上仍不清楚。在这里，我们表明FoxO1与自噬体和溶酶体的关键调节因子转录因子EB（Tfeb）相互作用，并通过脂肪细胞中的自噬差异介导UCP1、UCP2和UCP3的表达。在脂肪细胞分化过程中，UCP1被下调，但UCP2和UCP3被上调，这与Tfeb和自噬活性增加有关。然而，抑制FoxO1会抑制Tfeb和自噬，减弱UCP2和UCP3的表达，但增加UCP1的表达。自噬的药理学阻断重现了FoxO1抑制对UCPs的影响。染色质免疫沉淀分析表明，FoxO1通过直接结合其启动子与Tfeb相互作用，沉默FoxO1会导致Tfeb转录本和蛋白水平急剧下降。这些数据提供了首个证据，表明FoxO1与Tfeb相互作用以调节脂肪细胞中的自噬和UCP表达。FoxO1→自噬→UCP途径的失调可能是肥胖症代谢变化的原因。
