Integrated liver-secreted and plasma proteomics identify a predictive model that stratifies MASH
Obesity is a major risk factor for metabolic-associated steatotic liver disease (MASLD), which can progress to metabolic-associated steatohepatitis (MASH). There are no validated non-invasive tests to stratify persons with obesity with a greater risk for MASH. Herein, we assess plasma and liver from 266 obese individuals spanning the MASLD spectrum. Ninety-six human livers were precision-cut, and mass spectrometry-based proteomics identifies 3,333 proteins in the liver-secretion medium, of which 107 are differentially secreted in MASH compared with no pathology. The plasma proteome is markedly remodeled in MASH but is not different between patients with steatosis and no pathology. The APASHA model, comprising plasma apolipoprotein F (APOF), proprotein convertase subtilisin/kexin type 9 (PCSK9), afamin (AFM), S100 calcium-binding protein A6 (S100A6), HbA1c, and zinc-alpha-2-glycoprotein (AZGP1), stratifies MASH (area under receiver operating characteristic [AUROC] = 0.88). Our investigations detail the evolution of liver-secreted and plasma proteins with MASLD progression, providing a rich resource defining human liver-secreted proteins and creating a predictive model to stratify patients with obesity at risk of MASH.
Authors
- Geraldine Ooi (ORCID: https://orcid.org/0000-0002-4540-408X)
- Stuart Keith Roberts (ORCID: https://orcid.org/0000-0002-9015-7997)
- Yazmin Johari (ORCID: https://orcid.org/0000-0002-1531-9749)
- Mark Larance (ORCID: https://orcid.org/0000-0002-8579-2267)
- Matthew J. Watt (ORCID: https://orcid.org/0000-0003-4064-4188)
- Antoni Ruciński (ORCID: https://orcid.org/0000-0002-5815-4606)
- Paula M. Miotto (ORCID: https://orcid.org/0000-0002-4841-2552)
- Benjamin L. Parker (ORCID: https://orcid.org/0000-0003-1818-2183)
- Wendy A. Brown (ORCID: https://orcid.org/0000-0002-0137-2688)
- William De Nardo (ORCID: https://orcid.org/0000-0002-1441-1295)
- Olivia W. Lee (ORCID: https://orcid.org/0000-0001-5389-6267)
- M. Pensa
- Stacey N. Keenan (ORCID: https://orcid.org/0000-0001-6852-321X)
- Andrew Ryan (ORCID: https://orcid.org/0000-0002-5337-4714)
- Magdalene K. Montgomery (ORCID: https://orcid.org/0000-0003-2551-4174)
- Jacqueline Bayliss (ORCID: https://orcid.org/0000-0002-7324-3551)
- Paul R. Burton (ORCID: https://orcid.org/0000-0001-7324-0695)
- William Kemp (ORCID: https://orcid.org/0000-0002-1891-4578)
- Tessa M Svinos
Institutions
- The University of Sydney (AU)
- Barwon Health (AU)
- The University of Melbourne (AU)
- The Alfred Hospital (AU)
- Monash Alfred Psychiatry Research centre (AU)
- Bendigo Health (AU)
- TissuPath (AU)
- Monash University (AU)
- RMIT University (AU)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102085
- Citations
- 10
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 13.54
Funders
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- National Health and Medical Research Council
- Melbourne Research, University of Melbourne