ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance
Abstract Chronic hepatitis C (CHC) is associated with the development of metabolic disorders, including both hepatic and extra-hepatic insulin resistance (IR). Here, we aimed at identifying liver-derived factor(s) potentially inducing peripheral IR and uncovering the mechanisms whereby HCV can regul...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-33728-5 |
| _version_ | 1797836496079683584 |
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| author | Diana Gomes Cyril Sobolewski Stéphanie Conzelmann Tifany Schaer Etienne Lefai Dulce Alfaiate Eirini D. Tseligka Nicolas Goossens Caroline Tapparel Francesco Negro Michelangelo Foti Sophie Clément |
| author_facet | Diana Gomes Cyril Sobolewski Stéphanie Conzelmann Tifany Schaer Etienne Lefai Dulce Alfaiate Eirini D. Tseligka Nicolas Goossens Caroline Tapparel Francesco Negro Michelangelo Foti Sophie Clément |
| author_sort | Diana Gomes |
| collection | DOAJ |
| description | Abstract Chronic hepatitis C (CHC) is associated with the development of metabolic disorders, including both hepatic and extra-hepatic insulin resistance (IR). Here, we aimed at identifying liver-derived factor(s) potentially inducing peripheral IR and uncovering the mechanisms whereby HCV can regulate the action of these factors. We found ANGPTL4 (Angiopoietin Like 4) mRNA expression levels to positively correlate with HCV RNA (r = 0.46, p < 0.03) and HOMA-IR score (r = 0.51, p = 0.01) in liver biopsies of lean CHC patients. Moreover, we observed an upregulation of ANGPTL4 expression in two models recapitulating HCV-induced peripheral IR, i.e. mice expressing core protein of HCV genotype 3a (HCV-3a core) in hepatocytes and hepatoma cells transduced with HCV-3a core. Treatment of differentiated myocytes with recombinant ANGPTL4 reduced insulin-induced Akt-Ser473 phosphorylation. In contrast, conditioned medium from ANGPTL4-KO hepatoma cells prevented muscle cells from HCV-3a core induced IR. Treatment of HCV-3a core expressing HepG2 cells with PPARγ antagonist resulted in a decrease of HCV-core induced ANGPTL4 upregulation. Together, our data identified ANGPTL4 as a potential driver of HCV-induced IR and may provide working hypotheses aimed at understanding the pathogenesis of IR in the setting of other chronic liver disorders. |
| first_indexed | 2024-04-09T15:10:54Z |
| format | Article |
| id | doaj.art-a040a358d8ae4ba69685c5dd95b1ac81 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T15:10:54Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a040a358d8ae4ba69685c5dd95b1ac812023-04-30T11:14:17ZengNature PortfolioScientific Reports2045-23222023-04-0113111210.1038/s41598-023-33728-5ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistanceDiana Gomes0Cyril Sobolewski1Stéphanie Conzelmann2Tifany Schaer3Etienne Lefai4Dulce Alfaiate5Eirini D. Tseligka6Nicolas Goossens7Caroline Tapparel8Francesco Negro9Michelangelo Foti10Sophie Clément11Department of Pathology and Immunology, University of GenevaCell Physiology and Metabolism, University of GenevaDepartment of Pathology and Immunology, University of GenevaDepartment of Pathology and Immunology, University of GenevaUnité de Nutrition Humaine, INRAE, Université Clermont AuvergneDepartment of Pathology and Immunology, University of GenevaDepartment of Pathology and Immunology, University of GenevaGastroenterology and Hepatology Division, University HospitalsDepartment of Microbiology and Molecular Medicine, University of GenevaGastroenterology and Hepatology Division, University HospitalsCell Physiology and Metabolism, University of GenevaDepartment of Microbiology and Molecular Medicine, University of GenevaAbstract Chronic hepatitis C (CHC) is associated with the development of metabolic disorders, including both hepatic and extra-hepatic insulin resistance (IR). Here, we aimed at identifying liver-derived factor(s) potentially inducing peripheral IR and uncovering the mechanisms whereby HCV can regulate the action of these factors. We found ANGPTL4 (Angiopoietin Like 4) mRNA expression levels to positively correlate with HCV RNA (r = 0.46, p < 0.03) and HOMA-IR score (r = 0.51, p = 0.01) in liver biopsies of lean CHC patients. Moreover, we observed an upregulation of ANGPTL4 expression in two models recapitulating HCV-induced peripheral IR, i.e. mice expressing core protein of HCV genotype 3a (HCV-3a core) in hepatocytes and hepatoma cells transduced with HCV-3a core. Treatment of differentiated myocytes with recombinant ANGPTL4 reduced insulin-induced Akt-Ser473 phosphorylation. In contrast, conditioned medium from ANGPTL4-KO hepatoma cells prevented muscle cells from HCV-3a core induced IR. Treatment of HCV-3a core expressing HepG2 cells with PPARγ antagonist resulted in a decrease of HCV-core induced ANGPTL4 upregulation. Together, our data identified ANGPTL4 as a potential driver of HCV-induced IR and may provide working hypotheses aimed at understanding the pathogenesis of IR in the setting of other chronic liver disorders.https://doi.org/10.1038/s41598-023-33728-5 |
| spellingShingle | Diana Gomes Cyril Sobolewski Stéphanie Conzelmann Tifany Schaer Etienne Lefai Dulce Alfaiate Eirini D. Tseligka Nicolas Goossens Caroline Tapparel Francesco Negro Michelangelo Foti Sophie Clément ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance Scientific Reports |
| title | ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance |
| title_full | ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance |
| title_fullStr | ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance |
| title_full_unstemmed | ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance |
| title_short | ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance |
| title_sort | angptl4 is a potential driver of hcv induced peripheral insulin resistance |
| url | https://doi.org/10.1038/s41598-023-33728-5 |
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