Zhou B, Jia L, Zhang Z, et al, The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36. Advanced science, 2020. (IF: 14.3)

Abstract: This study identifies NR2F6 as a crucial regulator of hepatic triglyceride (TG) homeostasis and a causal factor in the development of non-alcoholic fatty liver disease (NAFLD). Overexpression of NR2F6 in the liver through adeno-associated virus (AAV) promotes TG accumulation in lean mice, while hepatic-specific suppression of NR2F6 ameliorates obesity-associated hepatosteatosis, insulin resistance, and non-alcoholic steatohepatitis (NASH) induced by a methionine and choline-deficient (MCD) diet.  Pathophysiologically, NR2F6 is significantly upregulated in the livers of obese mice and NAFLD patients. Moreover, treatment with metformin reduces NR2F6 expression in obese mice, leading to the suppression of CD36 and decreased hepatic TG content.

摘要：这项研究揭示了NR2F6作为调控肝脏甘油三酯（TG）稳态的重要调节因子，以及在非酒精性脂肪肝病（NAFLD）发展中的致病因素。通过腺相关病毒（AAV）介导的NR2F6在肝脏中的过表达可以在瘦小鼠中促进TG积累，而肝脏特异性抑制NR2F6则可以改善肥胖相关的肝脂肪变性、胰岛素抵抗以及蛋氨酸和胆碱缺乏（MCD）饮食诱导的非酒精性脂肪性肝炎（NASH）。在病理生理学上，NR2F6在肥胖小鼠和NAFLD患者的肝脏中显著上调。此外，用二甲双胍治疗可以降低肥胖小鼠的NR2F6表达，从而抑制CD36并减少肝脏TG含量。令人惊讶的是，RP11-295G20.2诱导的PTEN降解是通过溶酶体途径而不是蛋白酶体途径。RP11-295G20.2与PTEN的N端结合，并促进p62与PTEN的相互作用。因此，PTEN被转运到溶酶体中并被降解。RP11-295G20.2还影响AKT的磷酸化和FOXO3a转移到细胞核，进而调节自噬相关基因的转录。总的来说，RP11-295G20.2直接与PTEN结合并使其在溶酶体中降解。这个新发现的RP11-295G20.2/PTEN轴揭示了肝癌中PTEN丢失的一个未被探索的分子机制。