小柯机器人

美国加州大学医学院Michael Karin团队提出果糖-1,6-二磷酸酶(FBP1)是一种非酶安全阀，可抑制AKT的激活以防止胰岛素高反应性。2023年4月20日出版的《细胞—代谢》发表了这项成果。

FBP1是糖异生的速率控制因子。然而，先天的人类FBP1缺乏不会引起低血糖，除非伴有禁食或饥饿，这也会引发矛盾的肝肿大、肝骨化症和高脂血症。肝细胞FBP1消融小鼠表现出相同的禁食条件病变，同时AKT过度激活，其抑制逆转肝肿大、肝骨化症和高脂血症，但不可逆转低血糖。令人惊讶的是，禁食介导的AKT过度激活是胰岛素依赖性的。

不依赖其催化活性，FBP1通过与AKT、PP2A-C和醛缩酶B (ALDOB)形成稳定的复合物，特异性地加速AKT的去磷酸化，从而阻止胰岛素高反应性。禁食增强FBP1:PP2A-C:ALDOB:AKT复合物的形成，而胰岛素升高减弱其形成，该复合物的形成被人类FBP1缺乏突变或C端FBP1截断所破坏，从而防止胰岛素引发的肝脏病变并维持脂质和葡萄糖的稳态。相反，fbp1衍生的复杂干扰肽逆转饮食诱导的胰岛素抵抗。

据悉，胰岛素抑制糖异生，刺激葡萄糖转化为糖原和脂质。这些活动如何协调以预防低血糖和肝骨赘病尚不清楚。

附：英文原文

Title: Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness

Author: Li Gu, Yahui Zhu, Kosuke Watari, Maiya Lee, Junlai Liu, Sofia Perez, Melinda Thai, Joshua E. Mayfield, Bichen Zhang, Karina Cunha e Rocha, Fuming Li, Laura C. Kim, Alexander C. Jones, Igor H. Wierzbicki, Xiao Liu, Alexandra C. Newton, Tatiana Kisseleva, Jun Hee Lee, Wei Ying, David J. Gonzalez, Alan R. Saltiel, M. Celeste Simon, Michael Karin

Issue&Volume: 2023-04-20

Abstract: Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen andlipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosisis unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis.However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompaniedby fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis,and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditionalpathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly,hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediatedAKT hyperactivation is insulin dependent. Independently of its catalytic activity,FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C,and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhancedby fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation,which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation,prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis.Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulinresistance.

DOI: 10.1016/j.cmet.2023.03.021

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00126-2

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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