SUMMARY
Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk. The MASLD proteome was encoded by genes that demonstrated transcriptional enrichment in liver, with spatial transcriptional activity in areas of steatosis in human liver biopsy and dynamicity for select targets in human liver across stages of steatosis. We replicated several top relations from proteomics and spatial tissue transcriptomics in a humanized “liver-on-a-chip” model of MASLD, highlighting the power of a full translational approach to discovery in MASLD. Collectively, these results underscore utility of blood-based proteomics as a dynamic “liquid biopsy” of human liver relevant to clinical biomarker and mechanistic applications.
Competing Interest Statement
R.S. is supported in part by grants from the National Institutes of Health (NIH) and the American Heart Association (AHA). R.S. has served for a consultant for Amgen and Cytokinetics. R.S. is a co-inventor on a patent for ex-RNAs signatures of cardiac remodeling (not relevant to the current work). A.S.P. is supported by the AHA Strategically Focused Research Network in Cardiometabolic Disease. R.S., J.B., A.S.P. have filed for a patent relevant to the findings in this manuscript. J.F.K.S. and G.M. are employees of Emulate Inc. (a maker of the liver-on-a-chip) and may hold equity interest in Emulate, Inc. S.D. holds a research grant from Bristol Myers Squibb, is a founder and holds equity in Switch Therapeutics, and is a founder and consultant and holds equity for Thryv Therapeutics. N.B. receives consulting fees from Deepcell. J.R.K. has served as a consultant to Gilead, Merck, ViiV Healthcare and Janssen and also received research support from Gilead Sciences and Merck. R.K. is supported in part by grants from the NIH, has received grants from AstraZeneca, PneumRx/BTG, and Spiration, has received consulting fees from CVS Caremark, AstraZeneca, GlaxoSmithKline, and CSA Medical, and has received speaking fees from GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim. K.A. is supported by an AHA Career Development Award (#929347). J.A.F. serves as a consultant or advisory board member for Kynos Therapeutics, Resolution Therapeutics, Ipsen, River 2 Renal Corp., Stimuliver, Galecto Biotech, Global Clinical Trial Partners, and Guidepoint and has received research grant funding from Intercept Pharmaceuticals and Genentech. T.J.K. undertakes consultancy work for Perspectum, Clinnovate Health, Kynos Therapeutics, Fibrofind, HistoIndex, Concept Life Sciences, and Resolution Therapeutics, and has received speaker's fees from Incyte Corporation and Servier Laboratories. K.V.K.J. is a member of the scientific advisory board at Dyrnamix. J.J.C. receives project funding from GE Healthcare, Siemens Healthineers, TheraTech, and the NIH. M.N. has received speaking honoraria from Cytokinetics. The other authors report no relevant financial disclosures.
Funding Statement
CARDIA is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201800005I & HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). Proteomics quantification was funded by the NHLBI (HL122477; PI Kalhan).
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IRB of Vanderbilt University Medical Center gave ethical approval for this work.
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Footnotes
↵* A.S.P, N.H, and E.C. are co-first authors.
J.A.F., N.E.B., S.D., and R.S. are co-senior authors.
Corrected authorship