PML-RARα interaction with TRIB3 impedes PPARγ/RXR function and triggers dyslipidemia in acute promyelocytic leukemia
PML-RARα interaction with TRIB3 impedes PPARγ/RXR function and triggers dyslipidemia in acute promyelocytic leukemia
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PML-RARα 与 TRIB3 相互作用阻碍 PPARγ/RXR 功能并引发急性早幼粒细胞白血病血脂异常
DOI：
10.7150/thno.45924
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhu, Hong-Hu
中科院分区：
文献类型：
--
作者：
Li, Ke;Wang, Feng;Zhu, Hong-Hu
尽管急性早幼粒细胞白血病（APL）患者在抗APL治疗后通常会出现血脂异常，但其潜在机制和新诊断APL患者的脂质状态仍有待研究。方法：我们对APL患者的脂质谱进行了回顾性研究。采用PML-RARα转基因小鼠和APL细胞移植小鼠，观察APL细胞对血脂水平的影响。随后，通过基因集富集分析、western blot和双荧光素酶报告基因检测，探讨PML-RARα和TRIB3在APL患者诱导治疗前和诱导治疗后脂质代谢调节中的作用和机制。结果：基于一项回顾性研究，APL患者在抗APL治疗前表现出较高的血脂异常患病率。此外，APL细胞引起肝细胞分泌甘油三酯、胆固醇和PCSK9，并降解肝细胞中的低密度脂蛋白受体，从而升高APL细胞移植小鼠和Pml-Rarα转基因小鼠的脂质水平。机制上，伪激酶TRIB3与PML-RARα相互作用，通过干扰PPARγ与RXR的相互作用，促进PPARγ降解，从而抑制PPARγ活性。因此，APL细胞中PPARγ活性的降低降低了瘦素，但增加了抵抗素的表达，导致肝细胞脂质代谢紊乱和随后的小鼠血脂异常。尽管砷/ATRA治疗降低了PML-RARα并恢复了PPARγ的表达，但它加重了APL患者的血脂异常。砷/ATRA治疗导致TRIB3表达升高，通过破坏PPARγ/RXR二聚体抑制PPARγ活性，导致接受治疗的APL患者血脂异常。事实上，PPAR激活剂不仅通过抑制TRIB3表达来增强砷/ATRA的抗APL作用，还可以降低APL患者治疗性血脂异常。结论：我们的工作揭示了PML-RARα/PPARγ/TRIB3轴在APL患者血脂异常发展中的关键作用，可能为ATRA/砷联合PPAR激活剂治疗APL提供了理论依据。
Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy, the underlying mechanism and the lipid statuses of patients with newly diagnosed APL remain to be addressed. Methods: We conducted a retrospective study to investigate the lipid profiles of APL patients. PML-RARα transgenic mice and APL cells-transplanted mice were used to assess the effects of APL cells on the blood/liver lipid levels. Subsequently, gene set enrichment analysis, western blot and dual luciferase reporter assay were performed to examine the role and mechanism of PML-RARα and TRIB3 in lipid metabolism regulation in APL patients at pretreatment and after induction therapy. Results: APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy based on a retrospective study. Furthermore, APL cells caused secretion of triglycerides, cholesterol, and PCSK9 from hepatocytes and degradation of low-density lipoprotein receptors in hepatocytes, which elevated the lipid levels in APL cell-transplanted mice and Pml-Rarα transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RARα to inhibit PPARγ activity by interfering with the interaction of PPARγ and RXR and promoting PPARγ degradation. Thus, reduced PPARγ activity in APL cells decreased leptin but increased resistin expression, causing lipid metabolism disorder in hepatocytes and subsequent dyslipidemia in mice. Although arsenic/ATRA therapy degraded PML-RARα and restored PPARγ expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPARγ activity by disrupting the PPARγ/RXR dimer, which resulted in dyslipidemia in APL patients undergoing therapy. Indeed, the PPAR activator not only enhanced the anti-APL effects of arsenic/ATRA by suppressing TRIB3 expression but also reduced therapy-induced dyslipidemia in APL patients. Conclusion: Our work reveals the critical role of the PML-RARα/PPARγ/TRIB3 axis in the development of dyslipidemia in APL patients, potentially conferring a rationale for combining ATRA/arsenic with the PPAR activator for APL treatment.