美国宾州大学Zoltan Arany研究小组揭示选择性抑制雷帕霉素复合物1（mTORC1）对小鼠非酒精性脂肪肝的抑制作用。2022年4月15日出版的《科学》杂志发表了这项成果。

据研究人员介绍，非酒精性脂肪肝（NAFLD）和非酒精性脂肪性肝炎（NASH）仍然没有有效的治疗手段。mTORC1途径是一个潜在的治疗靶标，但对于mTORC1如何控制脂质平衡，人们提出了相互矛盾的解释。

研究人员表明，通过删除RagC/D鸟苷三磷酸酶激活蛋白folliculin（FLCN），选择性地抑制小鼠的mTORC1信号传导，会促进肝脏中转录因子E3（TFE3）的激活，而不影响其他mTORC1靶点，并对非酒精性脂肪肝和NASH起到保护作用。疾病保护是由TFE3介导的，它既能诱导脂质消耗，又能抑制合成脂肪的产生。TFE3通过抑制甾醇调节元件结合蛋白-1c（SREBP-1c）的蛋白水解加工和激活，以及与染色质上的SREBP-1c相互作用来抑制脂肪的生成。

这些数据调和了以前相互矛盾的研究，并确定选择性地抑制mTORC1是治疗NASH和NAFLD的一种潜在方法。

附：英文原文

Title: Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1

Author: Bridget S. Gosis, Shogo Wada, Chelsea Thorsheim, Kristina Li, Sunhee Jung, Joshua H. Rhoades, Yifan Yang, Jeffrey Brandimarto, Li Li, Kahealani Uehara, Cholsoon Jang, Matthew Lanza, Nathan B. Sanford, Marc R. Bornstein, Sunhye Jeong, Paul M. Titchenell, Sudha B. Biddinger, Zoltan Arany

Issue&Volume: 2022-04-15

Abstract: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have been proposed for how mTORC1 controls lipid homeostasis. We show that selective inhibition of mTORC1 signaling in mice, through deletion of the RagC/D guanosine triphosphatase–activating protein folliculin (FLCN), promotes activation of transcription factor E3 (TFE3) in the liver without affecting other mTORC1 targets and protects against NAFLD and NASH. Disease protection is mediated by TFE3, which both induces lipid consumption and suppresses anabolic lipogenesis. TFE3 inhibits lipogenesis by suppressing proteolytic processing and activation of sterol regulatory element–binding protein-1c (SREBP-1c) and by interacting with SREBP-1c on chromatin. Our data reconcile previously conflicting studies and identify selective inhibition of mTORC1 as a potential approach to treat NASH and NAFLD.

DOI: abf8271

Source: https://www.science.org/doi/10.1126/science.abf8271