ANGPTL8 R59W 变异通过 TNFα 刺激下的 NF-κB 信号通路在调节炎症中的促炎作用。
The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation.
机构信息
Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait.
Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait.
出版信息
Cells. 2023 Nov 2;12(21):2563. doi: 10.3390/cells12212563.
BACKGROUND
Angiopoietin-like protein 8 (ANGPTL8) is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity and with IKK to modulate NF-κB activity. Further, a single nucleotide polymorphism (SNP) leading to the ANGPTL8 R59W variant associates with reduced low-density lipoprotein/high-density lipoprotein (LDL/HDL) and increased fasting blood glucose (FBG) in Hispanic and Arab individuals, respectively. In this study, we investigate the impact of the R59W variant on the inflammatory activity of ANGPTL8.
METHODS
The ANGPTL8 R59W variant was genotyped in a discovery cohort of 867 Arab individuals from Kuwait. Plasma levels of ANGPTL8 and inflammatory markers were measured and tested for associations with the genotype; the associations were tested for replication in an independent cohort of 278 Arab individuals. Impact of the ANGPTL8 R59W variant on NF-κB activity was examined using approaches including overexpression, luciferase assay, and structural modeling of binding dynamics.
RESULTS
The ANGPTL8 R59W variant was associated with increased circulatory levels of tumor necrosis factor alpha (TNFα) and interleukin 7 (IL7). Our in vitro studies using HepG2 cells revealed an increased phosphorylation of key inflammatory proteins of the NF-κB pathway in individuals with the R59W variant as compared to those with the wild type, and TNFα stimulation further elevated it. This finding was substantiated by increased luciferase activity of NF-κB p65 with the R59W variant. Modeled structural and binding variation due to R59W change in ANGPTL8 agreed with the observed increase in NF-κB activity.
CONCLUSION
ANGPTL8 R59W is associated with increased circulatory TNFα, IL7, and NF-κB p65 activity. Weak transient binding of the ANGPTL8 R59W variant explains its regulatory role on the NF-κB pathway and inflammation.
背景
血管生成素样蛋白 8（ANGPTL8）已知可调节脂质代谢和炎症。它与 ANGPTL3 和 ANGPTL4 相互作用以调节脂蛋白脂肪酶（LPL）活性，并与 IKK 相互作用以调节 NF-κB 活性。此外，导致 ANGPTL8 R59W 变体的单核苷酸多态性（SNP）分别与西班牙裔和阿拉伯个体的低密度脂蛋白/高密度脂蛋白（LDL/HDL）降低和空腹血糖（FBG）升高相关。在这项研究中，我们研究了 R59W 变体对 ANGPTL8 炎症活性的影响。
方法
在科威特的 867 名阿拉伯个体的发现队列中对 ANGPTL8 R59W 变体进行了基因分型。测量了 ANGPTL8 和炎症标志物的血浆水平，并对其与基因型的相关性进行了测试；在另一个独立的 278 名阿拉伯个体队列中对其相关性进行了复制测试。通过包括过表达、荧光素酶测定和结合动力学结构建模在内的方法，检查了 ANGPTL8 R59W 变体对 NF-κB 活性的影响。
结果
ANGPTL8 R59W 变体与肿瘤坏死因子-α（TNFα）和白细胞介素 7（IL7）的循环水平升高有关。我们使用 HepG2 细胞进行的体外研究表明，与野生型相比，R59W 变体个体中 NF-κB 途径的关键炎症蛋白磷酸化增加，TNFα 刺激进一步增加了磷酸化。这一发现得到了 NF-κB p65 与 R59W 变体的荧光素酶活性增加的证实。由于 ANGPTL8 中的 R59W 改变导致的模型结构和结合变化与观察到的 NF-κB 活性增加一致。
结论
ANGPTL8 R59W 与循环 TNFα、IL7 和 NF-κB p65 活性增加有关。ANGPTL8 R59W 变体的弱瞬时结合解释了其对 NF-κB 途径和炎症的调节作用。
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