The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation.

Autor: Abu-Farha M; Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait., Madhu D; Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait., Hebbar P; Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait., Mohammad A; Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait., Channanath A; Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait., Kavalakatt S; Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait., Alam-Eldin N; Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait., Alterki F; Department of internal Medicine, Amiri Hospital, Ministry of Health, Kuwait City 15462, Kuwait., Taher I; Microbiology Unit, Department of Pathology, College of Medicine, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia., Alsmadi O; Department of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman 1269, Jordan., Shehab M; Division of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Kuwait City 47061, Kuwait., Arefanian H; Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman 15462, Kuwait., Ahmad R; Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman 15462, Kuwait., Thanaraj TA; Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait., Al-Mulla F; Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait., Abubaker J; Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait.
Jazyk: angličtina
Zdroj: Cells [Cells] 2023 Nov 02; Vol. 12 (21). Date of Electronic Publication: 2023 Nov 02.
DOI: 10.3390/cells12212563
Abstrakt: 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.
Databáze: MEDLINE
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