首都医科大学李兵辉研究小组发现，AMPK调控的甘油排泄维持还原应激与能量应激之间的代谢互作。该研究于2025年1月2日在线发表于国际一流学术期刊《自然—细胞生物学》。

研究人员发现缺氧通过诱导NADH积累来促进甘油排泄，这一途径持续消耗NADH，从而减轻其积累和还原应激。醛缩酶B通过与甘油3-磷酸脱氢酶GPD1和GPD1L形成复合物来催化甘油的生物合成。阻断GPD1、GPD1L或甘油3-磷酸磷酸酶会加剧还原应激，并在缺氧条件下抑制细胞增殖和体内肿瘤生长。

这些酶的过表达增加了甘油排泄，但由于能量应激，仍然降低了缺氧条件下细胞的生存率和肿瘤的增殖。AMPK使醛缩酶B失活，从而减轻了消耗ATP的甘油合成，缓解了NADH积累引发的能量危机。

因此，甘油的生物合成/排泄调节了还原应激和能量应激之间的平衡。此外，这种调控模式似乎在还原应激驱动的转化中普遍存在，增强了人们对代谢复杂性的理解，并为肿瘤治疗提供了指导。

研究人员表示，葡萄糖代谢已经被广泛研究，但葡萄糖衍生的排泄性甘油的作用仍不清楚。

附：英文原文

Title: AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress

Author: Zhai, Xuewei, Yang, Ronghui, Chu, Qiaoyun, Guo, Zihao, Hou, Pengjiao, Li, Xuexue, Bai, Changsen, Lu, Ziwen, Qiao, Luxin, Fu, Yanxia, Niu, Jing, Li, Binghui

Issue&Volume: 2025-01-02

Abstract: Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.

DOI: 10.1038/s41556-024-01549-x

Source: https://www.nature.com/articles/s41556-024-01549-x