Fasting plasma fructose is associated with postprandial ethanol levels and mitochondrial dysfunction: linking fasting fructose to MASLD

High dietary fructose consumption is a recognized risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), but the clinical relevance of fasting fructose levels remains unexplored. This study investigated gut microbiota and hepatic transcriptional alterations associated with fasting fructose levels and their potential link to MASLD. We analyzed data from a subset of 49 morbidly obese individuals enrolled in the prospective BARIA cohort. Fasting plasma fructose levels were significantly higher in individuals with MASLD and were associated with polyol pathway downregulation and lipogenic gene upregulation. Fasting fructose also positively correlated with postprandial plasma ethanol increase, suggesting enhanced microbial endogenous production and/or altered ethanol catabolism, the latter supported by suppressed hepatic alcohol dehydrogenase gene expression. In addition, fasting fructose was associated with fecal gut microbiota alterations, including significant shifts in beta diversity and correlations with specific bacterial species. At the transcriptomic level, elevated fasting fructose was linked to impaired mitochondrial energy metabolism and antioxidant defense, signatures associated with MASLD-related metabolic disruption. In conclusion, our data indicate that fasting plasma fructose reflects dietary intake rather than endogenous production and increased levels are associated with metabolic and microbiota changes linked to MASLD. Although not intended to replace established glycemic markers, our findings suggest that fasting fructose may provide complementary insights into the metabolic state of the liver and MASLD-related dysregulation, supporting its potential as a MASLD risk biomarker.