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Goldberg, D.T.* ; Yaskolka Meir, A.* ; Tsaban, G.* ; Rinott, E.* ; Kaplan, A.* ; Zelicha, H.* ; Klöting, N. ; Ceglarek, U.* ; Iserman, B.* ; Shelef, I.* ; Rosen, P.* ; Blüher, M. ; Stumvoll, M. ; Etzion, O.* ; Stampfer, M.J.* ; Hu, F.B.* ; Shai, I.

Novel proteomic signatures may indicate MRI-assessed intrahepatic fat state and changes; the DIRECT PLUS clinical trial.

Hepatology, DOI: 10.1097/HEP.0000000000000867 (2024)
DOI PMC
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Hepatology
Verlag Wiley
Verlagsort Hoboken, NJ
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen 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)