Molecular characterization of liver steatosis through circulating proteins, metabolites and lipids

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) is among the most prevalent liver disorders in Western countries. While steatosis is prevalent, molecular mechanisms associated with steatosis grades and how nutrition modulates related metabolic disturbances remain poorly understood. MethodsWe analyzed data from 327 participants of the CHRIS NAFLD study with Type 2 diabetes (T2D) and matched controls, integrating 148 plasma proteins with 175 serum metabolites and lipids to identify circulating biomarkers associated with hepatic steatosis severity. Associations between dietary intake and steatosis were investigated, and a potential influence of diet on the identified biomarkers was evaluated through a sensitivity analysis. Participants were stratified by steatosis grade based on ultrasound-derived measurements. ResultsSteatosis grade was strongly positively correlated with BMI and T2D. Several proteins (e.g., GC, AFM, AZGP1, SERPINC1, VTN, LRG1) and metabolites (e.g., glutamate, tyrosine, valine, lysoPCs) were associated with the highest steatosis grade, mainly reflecting a broader metabolically unhealthy phenotype. Adherence to a plant-based diet was associated with lower steatosis grades independent of circulating proteins, metabolites, and lipids. ConclusionResults suggest that circulating metabolic signatures of steatosis reflect broader metabolic dysregulation and are independent of dietary intake. These data support the use of blood-based multi-omics profiling to distinguish between metabolically healthy and unhealthy individuals, and may thus improve MASLD risk stratification. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/25341334v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@3e7799org.highwire.dtl.DTLVardef@11e03e3org.highwire.dtl.DTLVardef@191529corg.highwire.dtl.DTLVardef@1c68ff4_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMulti-omics profiling reveals biomarkers associated with hepatic steatosis severity C_LIO_LISubstantial overlap between steatosis biomarkers and metabolic health indicators C_LIO_LISteatosis-associated profiles reflect broad metabolic dysfunction C_LIO_LIPlant-based diet is associated with lower steatosis grade C_LIO_LIDietary habits did not affect the identified steatosis blood biomarkers C_LI