Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway
<p dir="ltr">Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to t...
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2022
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| _version_ | 1864513528355880960 |
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| author | Olfa Khalifa (10914452) |
| author2 | Neyla S. AL-Akl (17886050) Khaoula Errafii (10914446) Abdelilah Arredouani (10914455) |
| author2_role | author author author |
| author_facet | Olfa Khalifa (10914452) Neyla S. AL-Akl (17886050) Khaoula Errafii (10914446) Abdelilah Arredouani (10914455) |
| author_role | author |
| dc.creator.none.fl_str_mv | Olfa Khalifa (10914452) Neyla S. AL-Akl (17886050) Khaoula Errafii (10914446) Abdelilah Arredouani (10914455) |
| dc.date.none.fl_str_mv | 2022-02-09T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-022-06143-5 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Exendin-4_alleviates_steatosis_in_an_in_vitro_cell_model_by_lowering_FABP1_and_FOXA1_expression_via_the_Wnt_-catenin_signaling_pathway/25125068 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Non-alcoholic fatty liver disease (NAFLD) liver disease diabetes |
| dc.title.none.fl_str_mv | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating the cells with 400 µM oleic acid (OA) overnight. Further treatment with 200 nM Ex-4 for 3 h significantly reduced the OA-induced lipid accumulation (p < 0.05). Concomitantly, Ex-4 substantially reduced the expression levels of Fatty Acid-Binding Protein 1 (FABP1) and its primary activator, Forkhead box protein A1 (FOXA1). Interestingly, the silencing of β-catenin with siRNA abolished the effect of Ex-4 on these genes, suggesting dependency on the Wnt/β-catenin pathway. Additionally, after β-catenin silencing, OA treatment significantly increased the expression of nuclear transcription factors SREBP-1 and TCF4, whereas Ex-4 significantly decreased this upregulation. Our findings suggest that direct activation of GLP-1R by Ex-4 reduces OA-induced steatosis in HepG2 cells by reducing fatty acid uptake and transport via FABP1 downregulation.</p><h2>Other Information</h2><p dir="ltr">Published in: Scientific Reports<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41598-022-06143-5" target="_blank">https://dx.doi.org/10.1038/s41598-022-06143-5</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_496aae119b47b89d6a809812d3a9114d |
| identifier_str_mv | 10.1038/s41598-022-06143-5 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25125068 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathwayOlfa Khalifa (10914452)Neyla S. AL-Akl (17886050)Khaoula Errafii (10914446)Abdelilah Arredouani (10914455)Biomedical and clinical sciencesClinical sciencesNon-alcoholic fatty liver disease (NAFLD)liver diseasediabetes<p dir="ltr">Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating the cells with 400 µM oleic acid (OA) overnight. Further treatment with 200 nM Ex-4 for 3 h significantly reduced the OA-induced lipid accumulation (p < 0.05). Concomitantly, Ex-4 substantially reduced the expression levels of Fatty Acid-Binding Protein 1 (FABP1) and its primary activator, Forkhead box protein A1 (FOXA1). Interestingly, the silencing of β-catenin with siRNA abolished the effect of Ex-4 on these genes, suggesting dependency on the Wnt/β-catenin pathway. Additionally, after β-catenin silencing, OA treatment significantly increased the expression of nuclear transcription factors SREBP-1 and TCF4, whereas Ex-4 significantly decreased this upregulation. Our findings suggest that direct activation of GLP-1R by Ex-4 reduces OA-induced steatosis in HepG2 cells by reducing fatty acid uptake and transport via FABP1 downregulation.</p><h2>Other Information</h2><p dir="ltr">Published in: Scientific Reports<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41598-022-06143-5" target="_blank">https://dx.doi.org/10.1038/s41598-022-06143-5</a></p>2022-02-09T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-022-06143-5https://figshare.com/articles/journal_contribution/Exendin-4_alleviates_steatosis_in_an_in_vitro_cell_model_by_lowering_FABP1_and_FOXA1_expression_via_the_Wnt_-catenin_signaling_pathway/25125068CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/251250682022-02-09T03:00:00Z |
| spellingShingle | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway Olfa Khalifa (10914452) Biomedical and clinical sciences Clinical sciences Non-alcoholic fatty liver disease (NAFLD) liver disease diabetes |
| status_str | publishedVersion |
| title | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway |
| title_full | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway |
| title_fullStr | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway |
| title_full_unstemmed | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway |
| title_short | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway |
| title_sort | Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway |
| topic | Biomedical and clinical sciences Clinical sciences Non-alcoholic fatty liver disease (NAFLD) liver disease diabetes |