Arachidonoyl-taurine is elevated in human MASLD and protects against hepatic steatosis and inflammation in preclinical models

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive, inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are a global health challenge that are intricately linked to lipid dysregulation and systemic inflammation. Identifying markers and causative molecules is necessary. N-acyl taurines (NATs) are endogenous metabolites that are involved in whole-body metabolic regulation, but their roles in liver disease have not previously been elucidated. METHODS: To study the relationship between NATs and MASLD, we analyzed the NAT profiles in human blood samples from subjects with clinical MASLD or short-term overfeeding-induced hepatic steatosis. Mouse models of MASLD and MASH were used to determine effects of those alterations and mechanisms of action. RESULTS: We identified an endogenous, uncharacterized arachidonic acid (ARA) metabolite, arachidonoyl-taurine (ARA-T), capable of mitigating steatotic liver disease and reducing hepatic inflammation. ARA-T levels increased in human plasma from individuals with chronic and overfeeding-induced liver steatosis, and its abundance can be driven in humans and mice by dietary ARA supplementation. Despite ARA's association with pro-inflammatory mediators, administration of ARA-T reduced hepatic lipid deposition and inflammation. Chronic elevation through genetic and dietary models mitigated the development of steatosis and fibrosis through increased hepatic oxidation of fatty acids. CONCLUSIONS: ARA-T is an endogenous metabolite that increases with human hepatic steatosis and reduces murine hepatic lipid content independent of weight loss, demonstrating its direct action and potential to reverse the progression of liver disease. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is among the most prevalent forms of liver disease worldwide and is likely to affect more than half of the global population in the next decade, with limited treatment options available. Here, we identified an endogenous, uncharacterized omega-6 fatty acid metabolite, arachidonoyl-taurine (ARA-T), capable of mitigating steatotic liver disease and reducing hepatic inflammation by increasing hepatic fatty acid oxidation. This study positions ARA-T as an endogenous molecule with hepatoprotective effects and provides a potential target that lays the foundation for future treatment of MASLD.