Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease Homan, Edwin A. Ankit, Gilani Rubio-Navarro, Alfonso Johnson, Maya A. Schaepkens, Odin M. Cortada, Eric Pereira de Lima, Renan Stoll, Lisa Lo, James C. C3ar1 Fatty liver disease Human We would like to thank Dr. Baran Ersoy, Dr. Robert Schwartz, and Dr. Saloni Sinha for their technical advice and assistance. EAH was supported by NIH T32 5T32HL160520-02. AG was supported by ADA 9–22-PDFPM- 01. RPL was supported by AHA 23DIVSUP1074485. LS was supported by AHA 908952 and an Ehrenkranz Young Scientist Award. JCL was supported by NIH R01 DK121140, R01 DK121844, and R01 DK132879. 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. 2026-02-19T10:25:22Z 2026-02-19T10:25:22Z 2025-01-08 journal article Homan EA, Gilani A, Rubio-Navarro A, Johnson MA, Schaepkens OM, Cortada E, Pereira de Lima R, Stoll L, Lo JC. Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease. Elife. 2025 Jan 8;13:RP100708. https://doi.org/10.7554/eLife.100708.3 https://hdl.handle.net/10481/111249 10.7554/eLife.100708.3 eng open access eLife Sciences Publications