Notch signaling increases PPARγ protein stability and enhances lipid uptake through AKT in IL-4-stimulated THP-1 and primary human macrophages.,FEBS Open Bio

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Notch signaling increases PPARγ protein stability and enhances lipid uptake through AKT in IL-4-stimulated THP-1 and primary human macrophages.
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-04-26 , DOI: 10.1002/2211-5463.12858
Naunpun Sangphech _{1,

2} , Pornlapat Keawvilai _{2,

3} , Tanapat Palaga _{3,

4}

Affiliation

Notch signaling and nuclear receptor PPARγ are involved in macrophage polarization, but cross talk between them has not been reported in macrophages. In this study, the effect of Notch signaling on PPARγ in IL‐4‐stimulated human macrophages (M(IL‐4)) was investigated using THP‐1‐derived macrophages and human monocyte‐derived macrophages as models. Human M(IL‐4) increased the expression of JAGGED1 and activated Notch signaling. Overexpression of Notch1 intracellular domain (NIC1) increased PPARγ expression, while inhibiting Notch signaling decreased PPARγ levels in M(IL‐4). NIC1 overexpression in THP‐1‐derived macrophages increased PPARγ protein stability by delaying its proteasome‐mediated degradation, but did not affect its mRNA. Phosphorylation of AKT was enhanced in NIC1‐overexpressing cells, and a specific AKT inhibitor reduced the level of PPARγ. NIC1‐overexpressing THP‐1 cells exhibited increased CD36 levels via activation of PPARγ, resulting in enhanced intracellular lipid accumulation. In summary, this study provides evidence linking Notch signaling and PPARγ via AKT in M(IL‐4).

中文翻译：

Notch信号可提高IL-4刺激的THP-1和原代人巨噬细胞中PPARγ蛋白的稳定性，并通过AKT增强脂质摄取。

Notch信号和核受体PPARγ参与巨噬细胞极化，但是巨噬细胞中尚未报道它们之间的串扰。在这项研究中，以THP-1衍生的巨噬细胞和人类单核细胞衍生的巨噬细胞为模型，研究了Notch信号对IL-4刺激的人类巨噬细胞（M（IL-4））中PPARγ的影响。人类M（IL-4）增加JAGGED1的表达并激活Notch信号传导。Notch1细胞内结构域（NIC1）的过表达增加了PPARγ的表达，而抑制Notch信号则降低了M（IL-4）中PPARγ的水平。THP-1来源的巨噬细胞中NIC1的过表达通过延迟其蛋白酶体介导的降解而提高了PPARγ蛋白的稳定性，但并未影响其mRNA。在NIC1过表达的细胞中，AKT的磷酸化增强了，特定的AKT抑制剂可降低PPARγ的水平。NIC1过表达的THP-1细胞通过激活PPARγ表现出增加的CD36水平，从而导致细胞内脂质蓄积增加。总而言之，这项研究提供了在M（IL-4）中通过AKT将Notch信号和PPARγ联系起来的证据。

更新日期：2020-04-26

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