Gut-Derived Hippuric Acid Alleviates Hepatic Lipid Metabolism via UGDH/FOXK1/CD36 Axis in Obese Mice

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally, creating an urgent need to elucidate its pathogenesis and develop effective therapeutic strategies. Methods: In this study, we established obese mouse models using distinct dietary patterns. We then employed 16S rRNA sequencing and metabolomics to profile gut microbiota composition and identify differential metabolites in serum and intestinal contents. Using Limited proteolysis mass spectrometry, co-immunoprecipitation mass spectrometry and luciferase reporter assays were used to identify the downstream molecular mechanisms. Results: Our findings revealed that the abundance of hippuric acid (HA) was significantly decreased in the serum and gut of obese C57BL/6 mice, and it positively correlated with the abundance of Akkermansia and Alistipes . Notably, HA supplementation effectively reduced body weight and alleviated hepatic lipid accumulation in obese mice. Mechanistically, we found that HA directly binds to UDP-glucose dehydrogenase (UGDH), enhancing its interaction with forkhead box protein K1 (FOXK1) in the cytoplasm, thereby preventing FOXK1 nuclear translocation. This event suppresses Cd36 transcription and mitigates hepatic lipid accumulation. Furthermore, silencing Ugdh attenuated the inhibitory effect of HA on FOXK1-mediated regulation of Cd36 transcription. Conclusion: We demonstrate a novel mechanism for regulating hepatic lipid metabolism through HA/UGDH/FOXK1/CD36 pathway. This study provides evidence supporting the potential of HA as a therapeutic metabolite for MASLD. Moreover, these results are derived from preclinical murine models, and further clinical studies are warranted to validate the efficacy of HA. Keywords: hippuric acid, MASLD, gut-liver axis, UGDH, FOXK1