Integrated Proteomics and Metabolomics Reveal the Direct Hepatic Protection of Propionate Against Alcoholic Liver Disease via the RGN-PPARα Pathway

<b>Background:</b> Propionate, a gut microbiota-derived metabolite, has previously been shown to alleviate chronic alcoholic liver disease (ALD) by preserving intestinal barrier integrity. However, its direct hepatoprotective mechanisms remain unclear. <b>Methods:</b> In this study, employing an acute ALD model to minimize the interference from gut-liver axis effects, we investigated the direct hepatic protection of propionate. <b>Results:</b> Our results demonstrated that propionate administration significantly attenuated hepatic steatosis and oxidative stress. Consistently, in EtOH/OA (oleic acid)-exposed AML-12 hepatocytes, propionate enhanced cell viability and reduced lipid accumulation. Integrated proteomic and metabolomic analyses revealed that propionate altered hepatic proteins and metabolites profiles to stimulate lipolysis, promote fatty acid oxidation, and strengthen antioxidant defenses, consequently restoring lipid homeostasis in ALD mice. Mechanistically, we identified that these beneficial effects may be driven by the upregulation of regucalcin (RGN) following propionate treatments, which, in turn, may activate downstream PPARα signaling via increased levels of p-AMPK, PPARα, ACOX1 and CPT1A. <b>Conclusions:</b> These findings provide novel insight into the liver-centric mechanism through which propionate ameliorates ALD and further support its therapeutic potential in ALD treatment.