A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver

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Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver. These transcripts are differentially expressed across areas of steatosis in spatial transcriptomics, and several are dynamic during stages of steatosis. Circulating multi-protein signatures of steatosis strongly associate with fatty liver disease and multi-system metabolic outcomes. Using a humanized “liver-on-a-chip” model, we induce hepatic steatosis, confirming cell-specific expression of prioritized targets. These results underscore the utility of this approach to identify a prognostic, functional, dynamic “liquid biopsy” of human liver, relevant to biomarker discovery and mechanistic research applications. • Proteomics of hepatic steatosis identifies targets enriched in the liver • Prioritized targets are differentially expressed in steatosis and disease stages • A multi-protein score of hepatic steatosis is related to cardiometabolic disease • Liver-on-a-chip reproduces targets identified by the circulating proteome Perry et al. use a translational approach across phenotypes, outcomes, circulating proteomics, and tissue transcriptomics to identify functional biomarkers of hepatic steatosis. These markers are associated with metabolically relevant clinical outcomes and appear spatially enriched in human tissue in areas of steatosis and dynamically expressed during in vitro steatosis induction.

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