Short- and Medium-Chain Fatty Acid Profiles in Biopsy-Proven Metabolic Dysfunction-Associated Steatotic Liver Disease: A Cross-Sectional Study

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common metabolic liver disease with increasing prevalence worldwide. Increasing evidence suggests that short-chain fatty acids (SCFAs) play an important role in MASLD. Medium-chain fatty acids (MCFAs), although less studied, may also contribute to MASLD pathogenesis. The aim of this study was to evaluate plasma SCFA and MCFA profiles across the MASLD histological spectrum and their associations with clinical, biochemical, and histopathological features of disease severity. Methods: We included 115 adults with obesity undergoing bariatric surgery. Intraoperative liver biopsies were assessed using the Steatosis, Activity, Fibrosis (SAF) score. Participants were classified as no MASLD (n = 26), metabolic dysfunction-associated steatotic liver (MASL; n = 42), or metabolic dysfunction-associated steatohepatitis (MASH; n = 47). Six SCFAs and two MCFAs were quantified in plasma by liquid chromatography–mass spectrometry. Results: Patients with MASH showed lower acetate and higher hexanoate plasma levels than those without MASLD. Acetate was inversely associated with ALT, AST, GGT, glucose, HbA1c, cytokeratin-18, SAF score, steatosis and lobular inflammation, whereas hexanoate was positively associated with SAF score and lobular inflammation. Higher acetate concentrations were independently associated with lower odds of MASH (OR 0.973; p = 0.040), while ALT levels were independently associated with increased odds of MASH (OR 1.083, p = 0.001). Conclusions: MASH in patients with obesity is characterized by a distinct circulating fatty acid profile, with reduced acetate and increased hexanoate. Lower acetate levels were independently associated with MASH and markers of metabolic and histological disease severity.