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Novel proteomic signatures may indicate MRI-assessed intrahepatic fat state and changes; the DIRECT PLUS clinical trial.
Hepatology, DOI: 10.1097/HEP.0000000000000867 (2024)
OBJECTIVE: We demonstrated in the randomized 18-month DIRECT PLUS trial (n=294) that a Mediterranean (MED) diet, supplemented with polyphenol-rich Mankai duckweed, green tea, and walnuts and restricted in red/processed meat, caused substantial intrahepatic fat (IHF%) loss compared with two other healthy diets, reducing NAFLD by half, regardless similar weight loss. Here, we investigated the baseline proteomic profile associated with IHF% and the changes in proteomics associated with IHF% changes induced by lifestyle intervention. METHODS: We calculated IHF% by proton-magnetic-resonance-spectroscopy (H-MRS; normal-IHF%<5%; abnormal-IHF%>=5%). We assayed baseline and 18-month samples for 95 proteomic biomarkers. RESULTS: Participants (age=51.3±10.8years; 89%men; body-mass-index=31.3±3.9 kg/m2) had an 89.8% 18-month-retention-rate; 83% had eligible follow-up proteomics-measurements, and 78% had follow-up H-MRS. At baseline, 39-candidate-proteins were significantly associated with IHF% (FDR<0.05), mostly related to immune-function-pathways (e.g., HAOX1). An IHF%-prediction based on the DIRECT PLUS by combined-model (R2=0.47, RMSE=1.05) successfully predicted IHF% (R2=0.53) during testing and was stronger than separately-inputting-proteins/traditional markers (R2=0.43/0.44). The 18-month lifestyle intervention induced changes in 18 of the 39-candidate-proteins, which were significantly associated with IHF% change, with proteins related to metabolism, extracellular-matrix-remodeling, and immune-function pathways. THBS2 protein-change was higher in the green-MED compared to the MED group, beyond weight-and-IHF%-loss (p-value=0.01). Protein principal-component-analysis revealed differences in the 3rd-principal-component time-distinct interactions across abnormal/normal-IHF% trajectory combinations; p<0.05 for all). CONCLUSIONS: Our findings suggest novel proteomic signatures that may indicate MRI-assessed intrahepatic fat state and changes during lifestyle intervention. Specifically, CA5A, HAOX1, and THBS2 protein changes are independently associated with IHF% change, and THBS2 protein change is greater in the green-MED/high-polyphenols diet.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Non-alcoholic Fatty Liver Disease; Randomized controlled trial; Dietary interventions; Prediction; Omics; Liver-disease; Progression; Biopsies
ISSN (print) / ISBN
0270-9139
e-ISSN
1527-3350
Journal
Hepatology
Publisher
Wiley
Publishing Place
Hoboken, NJ
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants
Council for Higher Education- Zuckerman support program for outstanding postdoctoral female researchers
California Walnuts Commission
Israel Ministry of Science and Technology
Israel Ministry of Health
German Research Foundation
German Research Foundation (DFG)
California Walnuts Commission
Israel Ministry of Science and Technology
Israel Ministry of Health
German Research Foundation
German Research Foundation (DFG)