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 相互作用来调节脂蛋白脂肪酶 (LPL) 活性，并与 IKK 相互作用来调节 NF-κB 活性。此外，导致 ANGPTL8 R59W 变异的单核苷酸多态性 (SNP) 分别与西班牙人和阿拉伯人的低密度脂蛋白/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。ANGPTL8 R59W 变体在来自科威特的 867 名阿拉伯人的发现队列中进行了基因分型。测量 ANGPTL8 和炎症标记物的血浆水平并测试其与基因型的关联；这些关联在 278 名阿拉伯人的独立队列中进行了复制测试。使用过表达、荧光素酶测定和结合动力学结构建模等方法检查了 ANGPTL8 R59W 变体对 NF-κB 活性的影响。ANGPTL8 R59W 变体与肿瘤坏死因子 α (TNFα) 和白细胞介素 7 的循环水平增加相关。 IL7）。我们使用 HepG2 细胞进行的体外研究表明，与野生型个体相比，R59W 变体个体中 NF-κB 通路关键炎症蛋白的磷酸化程度增加，并且 TNFα 刺激进一步提高了磷酸化程度。 R59W 变体的 NF-κB p65 荧光素酶活性增加证实了这一发现。 ANGPTL8 中 R59W 变化引起的建模结构和结合变异与观察到的 NF-κB 活性增加一致。ANGPTL8 R59W 与循环 TNFα、IL7 和 NF-κB p65 活性增加相关。 ANGPTL8 R59W 变体的微弱瞬时结合解释了其对 NF-κB 通路和炎症的调节作用。

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.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.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.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.