A Comparative Study of Beinaglutide and Liraglutide in Ameliorating Metabolically Associated Fatty Liver Disease Using Transcriptomic Analysis
Background: Metabolically associated fatty liver disease (MAFLD), a common metabolic liver disease with a steadily increasing global incidence, poses a growing public health challenge. Its pathogenesis is closely associated with metabolic dysregulations such as obesity and insulin resistance, significantly impairing patients' quality of life and potentially progressing to severe liver conditions including cirrhosis and hepatocellular carcinoma. Recent studies indicate that glucagon-like peptide-1 receptor agonists (GLP-1RAs) , such as liraglutide, can ameliorate MAFLD. However, the efficacy and underlying mechanisms of beinaglutide in improving MAFLD remain incompletely understood, particularly in direct comparison with liraglutide. This study aims to compare the effects of beinaglutide and liraglutide on hepatic lipid metabolism in vitro and to elucidate the similarities and differences in their mechanisms of action, thereby providing a theoretical foundation for clinical treatment strategies.Methods: A steatotic cell model was established using the human hepatoma cell line HepG2, induced with a 2:1 mixture of oleic acid and palmitic acid (free fatty acids, FFA). The cells were divided into the following groups: a model group, beinaglutide intervention groups (0.01 uM, 0.1 uM, 1 uM), and liraglutide intervention groups (0.01 uM, 0.1 uM, 1 uM). Lipid accumulation was evaluated via Oil Red O staining and triglyceride (TG) content measurement. RNA sequencing was employed to identify differentially expressed genes (DEGs) between the model group and the drug-treated groups. Bioinformatics analysis was further applied to uncover the key pathways modulated by beinaglutide and liraglutide.Results: FFA induction successfully triggered steatosis in HepG2 cells, as evidenced by pronounced intracellular lipid accumulation and significantly elevated TG levels compared to the control. Both beinaglutide and liraglutide dose-dependently attenuated FFA-induced lipid deposition and reduced TG content. At equivalent concentrations, there was no statistically significant difference in the lipid-lowering effects between the two drugs, indicating that beinaglutide is non-inferior to liraglutide in alleviating hepatic steatosis. RNA sequencing analysis revealed that beinaglutide mainly influenced lipid metabolism by modulating the MAPK and Hippo signaling pathways, along with other metabolic and transcription-related processes. In contrast, liraglutide exhibited more pronounced enrichment in pathways related to steroid biosynthesis, cholesterol metabolism, and the PPAR signaling pathway, highlighting distinct mechanistic profiles between the two agents.Conclusions: This study systematically compared the mechanisms by which beinaglutide and liraglutide improve hepatic lipid metabolism. Although both agents effectively and equivalently reduce lipid accumulation, their mechanisms of action differ significantly: beinaglutide modulates lipid metabolism disorders in hepatocytes by regulating signaling pathways such as MAPK and Hippo, as well as the expression of genes related to cellular metabolism. Liraglutide, however, acts more directly on lipid synthesis and metabolic pathways (such as steroid biosynthesis and PPAR signaling pathways). The study findings indicate that beinaglutide represents an effective alternative to liraglutide in improving MAFLD, with its unique mechanism of action providing crucial theoretical support for the individualized selection of GLP-1 receptor agonists (GLP-1RAs) in clinical practice for MAFLD patients exhibiting distinct pathological characteristics.Keywords: Metabolically associated fatty liver disease (MAFLD), Beinaglutide, Liraglutide, GLP-1 receptor agonists (GLP-1RAs), Lipid metabolism, RNA sequencing