Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease
Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/100708 |
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| author | Edwin A Homan Ankit Gilani Alfonso Rubio-Navarro Maya A Johnson Odin M Schaepkens Eric Cortada Renan Pereira de Lima Lisa Stoll James C Lo |
| author_facet | Edwin A Homan Ankit Gilani Alfonso Rubio-Navarro Maya A Johnson Odin M Schaepkens Eric Cortada Renan Pereira de Lima Lisa Stoll James C Lo |
| author_sort | Edwin A Homan |
| collection | DOAJ |
| description | Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MφKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MφKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3ar1, has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model. |
| format | Article |
| id | doaj-art-f5a4d24d751b40c1b4db48ffd20800b6 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-f5a4d24d751b40c1b4db48ffd20800b62025-01-08T15:36:46ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.100708Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver diseaseEdwin A Homan0https://orcid.org/0000-0002-2923-9635Ankit Gilani1Alfonso Rubio-Navarro2Maya A Johnson3Odin M Schaepkens4Eric Cortada5Renan Pereira de Lima6Lisa Stoll7James C Lo8https://orcid.org/0000-0003-0244-1670Division of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesDivision of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesDivision of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesDivision of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesDivision of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesDivision of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesDivision of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesDivision of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesDivision of Cardiology, Department of Medicine, Cardiovascular Research Institute, Weill Center for Metabolic Health, Weill Cornell Medicine, New York, United StatesTogether with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MφKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MφKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3ar1, has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.https://elifesciences.org/articles/100708C3ar1macrophageskupffer cellsmetabolic dysfunction-associated steatotic liver diseasefatty liver diseasenon-alcoholic fatty liver disease |
| spellingShingle | Edwin A Homan Ankit Gilani Alfonso Rubio-Navarro Maya A Johnson Odin M Schaepkens Eric Cortada Renan Pereira de Lima Lisa Stoll James C Lo Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease eLife C3ar1 macrophages kupffer cells metabolic dysfunction-associated steatotic liver disease fatty liver disease non-alcoholic fatty liver disease |
| title | Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease |
| title_full | Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease |
| title_fullStr | Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease |
| title_full_unstemmed | Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease |
| title_short | Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease |
| title_sort | complement 3a receptor 1 on macrophages and kupffer cells is not required for the pathogenesis of metabolic dysfunction associated steatotic liver disease |
| topic | C3ar1 macrophages kupffer cells metabolic dysfunction-associated steatotic liver disease fatty liver disease non-alcoholic fatty liver disease |
| url | https://elifesciences.org/articles/100708 |
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