The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation
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 ANGPTL...
| Main Authors: | , , , , , , , , , , , , , , , |
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MDPI AG
2023-11-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/21/2563 |
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| author | Mohamed Abu-Farha Dhanya Madhu Prashantha Hebbar Anwar Mohammad Arshad Channanath Sina Kavalakatt Nada Alam-Eldin Fatima Alterki Ibrahim Taher Osama Alsmadi Mohammad Shehab Hossein Arefanian Rasheed Ahmad Thangavel Alphonse Thanaraj Fahd Al-Mulla Jehad Abubaker |
| author_facet | Mohamed Abu-Farha Dhanya Madhu Prashantha Hebbar Anwar Mohammad Arshad Channanath Sina Kavalakatt Nada Alam-Eldin Fatima Alterki Ibrahim Taher Osama Alsmadi Mohammad Shehab Hossein Arefanian Rasheed Ahmad Thangavel Alphonse Thanaraj Fahd Al-Mulla Jehad Abubaker |
| author_sort | Mohamed Abu-Farha |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T11:32:34Z |
| format | Article |
| id | doaj.art-58af7644c19a46d09ac517ee0f9f76a1 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T11:32:34Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-58af7644c19a46d09ac517ee0f9f76a12023-11-10T15:00:47ZengMDPI AGCells2073-44092023-11-011221256310.3390/cells12212563The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα StimulationMohamed Abu-Farha0Dhanya Madhu1Prashantha Hebbar2Anwar Mohammad3Arshad Channanath4Sina Kavalakatt5Nada Alam-Eldin6Fatima Alterki7Ibrahim Taher8Osama Alsmadi9Mohammad Shehab10Hossein Arefanian11Rasheed Ahmad12Thangavel Alphonse Thanaraj13Fahd Al-Mulla14Jehad Abubaker15Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of internal Medicine, Amiri Hospital, Ministry of Health, Kuwait City 15462, KuwaitMicrobiology Unit, Department of Pathology, College of Medicine, Jouf University, Sakaka P.O. Box 2014, Saudi ArabiaDepartment of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman 1269, JordanDivision of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Kuwait City 47061, KuwaitDepartment of Immunology & Microbiology, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Immunology & Microbiology, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, KuwaitDepartment of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, KuwaitBackground: 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.https://www.mdpi.com/2073-4409/12/21/2563ANGPTL8TNFαNF-κBglucose metabolismsingle nucleotide polymorphism |
| spellingShingle | Mohamed Abu-Farha Dhanya Madhu Prashantha Hebbar Anwar Mohammad Arshad Channanath Sina Kavalakatt Nada Alam-Eldin Fatima Alterki Ibrahim Taher Osama Alsmadi Mohammad Shehab Hossein Arefanian Rasheed Ahmad Thangavel Alphonse Thanaraj Fahd Al-Mulla Jehad Abubaker The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation Cells ANGPTL8 TNFα NF-κB glucose metabolism single nucleotide polymorphism |
| title | The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation |
| title_full | The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation |
| title_fullStr | The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation |
| title_full_unstemmed | The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation |
| title_short | The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation |
| title_sort | proinflammatory role of angptl8 r59w variant in modulating inflammation through nf κb signaling pathway under tnfα stimulation |
| topic | ANGPTL8 TNFα NF-κB glucose metabolism single nucleotide polymorphism |
| url | https://www.mdpi.com/2073-4409/12/21/2563 |
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