Weight Loss-Induced Metabolic Remodeling in Metabolic dysfunction-associated steatotic liver disease: A Cohort Study Stratified by Genetic Risk.

BACKGROUND

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the hepatic expression of systemic metabolic derangement; however, we have limited understanding of its progression or improvement, and there's a lack of adequate tools to monitor these changes. Metabolomics can provide dynamic biomarkers that reflect pathophysiological change.

OBJECTIVE

To describe the effects of weight-loss oriented Mediterranean diet on clinical, laboratory and metabolomic profiles in a cohort of genetically characterized obese and overweight MASLD patients.

METHODS

In a prospective cohort, 148 adults with ultrasound-confirmed MASLD started a personalized, nutritionist-guided, hypocaloric Mediterranean diet, supported by regular counselling. Weight loss was classified as <5%, 5-10%, or >10% of baseline. Single-nucleotide polymorphisms in PNPLA3, TM6SF2, MBOAT7 and GCKR were genotyped and combined into a weighted polygenic risk score. Untargeted gas chromatography-mass spectrometry profiled fasting serum samples at baseline and study end. Data were processed by partial least squares discriminant analysis, variable importance in projection scoring, and pathway enrichment.

RESULTS

Mean weight decreased by about 8% and controlled attenuation parameter declined by nearly 17%, with greatest steatosis reduction in PNPLA3 G-allele carriers. Metabolomic modelling achieved 92% classification accuracy and revealed fourteen key metabolites. Caproic acid, glycerol and hydroxypropanedioic acid increased consistently, whereas palmitic acid and d-galactose decreased. Enriched pathways included galactose, butanoate and glycerolipid metabolism. Metabolic shifts scaled with weight loss intensity and differed by genotype.

CONCLUSIONS

Mediterranean diet-induced weight loss triggers rapid, weight-dependent and genotype-modulated metabolomic reprogramming that parallels hepatic fat clearance. Caproic acid, glycerol and hydroxypropanedioic acid constitute biomarkers and combined with genetic risk assessment, may support precision nutrition strategies for MASLD.